Medical Physiology

Medical Physiology
Copyright Page
Contributors
Video Table of Contents
Preface to the Third Edition
The eBook
Acknowledgments
Preface to the First Edition
Target Audience
Content of the Textbook
Emphasis of the Textbook
Creating the Textbook
Special Features
Acknowledgments
Section I: Introduction
Chapter 1: Foundations of Physiology
What is physiology?
Physiological genomics is the link between the organ and the gene
Cells live in a highly protected milieu intérieur
Homeostatic mechanisms—operating through sophisticated feedback control mechanisms— are responsible for maintaining the constancy of the milieu intérieur
Medicine is the study of “physiology gone awry”
References
Section II: Physiology of Cells and Molecules
Chapter 2: Functional Organization of the Cell
Structure of Biological Membranes
The surface of the cell is defined by a membrane
The cell membrane is composed primarily of phospholipids
Phospholipids form complex structures in aqueous solution
The diffusion of individual lipids within a leaflet of a bilayer is determined by the chemical makeup of its constituents
Phospholipid bilayer membranes are impermeable to charged molecules
The plasma membrane is a bilayer
Membrane proteins can be integrally or peripherally associated with the plasma membrane
The membrane-spanning portions of transmembrane proteins are usually hydrophobic α helices
Some membrane proteins are mobile in the plane of the bilayer
Function of Membrane Proteins
Integral membrane proteins can serve as receptors
Integral membrane proteins can serve as adhesion molecules
Integral membrane proteins can carry out the transmembrane movement of water-soluble substances
Integral membrane proteins can also be enzymes
Integral membrane proteins can participate in intracellular signaling
Peripheral membrane proteins participate in intracellular signaling and can form a submembranous cytoskeleton
Cellular Organelles and the Cytoskeleton
The cell is composed of discrete organelles that subserve distinct functions
The nucleus stores, replicates, and reads the cell’s genetic information
Lysosomes digest material derived from the interior and exterior of the cell
The mitochondrion is the site of oxidative energy production
The cytoplasm is not amorphous but is organized by the cytoskeleton
Intermediate filaments provide cells with structural support
Microtubules provide structural support and provide the basis for several types of subcellular motility
Thin filaments (actin) and thick filaments (myosin) are present in almost every cell type
Synthesis and Recycling of Membrane Proteins
Secretory and membrane proteins are synthesized in association with the rough ER
Simultaneous protein synthesis and translocation through the rough ER membrane requires machinery for signal recognition and protein translocation
Proper insertion of membrane proteins requires start- and stop-transfer sequences
Newly synthesized secretory and membrane proteins undergo post-translational modification and folding in the lumen of the rough ER
Secretory and membrane proteins follow the secretory pathway through the cell
Carrier vesicles control the traffic between the organelles of the secretory pathway
Specialized protein complexes, such as clathrin and coatamers, mediate the formation and fusion of vesicles in the secretory pathway
Vesicle Formation in the Secretory Pathway
Vesicle Fusion in the Secretory Pathway
Newly synthesized secretory and membrane proteins are processed during their passage through the secretory pathway
Newly synthesized proteins are sorted in the trans-Golgi network
A mannose-6-phosphate recognition marker is required to target newly synthesized hydrolytic enzymes to lysosomes
Cells internalize extracellular material and plasma membrane through the process of endocytosis
Receptor-mediated endocytosis is responsible for internalizing specific proteins
Endocytosed proteins can be targeted to lysosomes or recycled to the cell surface
Certain molecules are internalized through an alternative process that involves caveolae
Specialized Cell Types
Epithelial cells form a barrier between the internal and external milieu
Tight Junctions
Adhering Junctions
Gap Junctions
Desmosomes
Epithelial cells are polarized
References
Books and Reviews
Journal Articles
Chapter 3: Signal Transduction
Mechanisms of Cellular Communication
Cells can communicate with one another via chemical signals
Soluble chemical signals interact with target cells via binding to surface or intracellular receptors
Cells can also communicate by direct interactions—juxtacrine signaling
Gap Junctions
Adhering and Tight Junctions
Membrane-Associated Ligands
Ligands in the Extracellular Matrix
Second-messenger systems amplify signals and integrate responses among cell types
Receptors That are Ion Channels
Ligand-gated ion channels transduce a chemical signal into an electrical signal
Receptors Coupled to G Proteins
General Properties of G Proteins
G proteins are heterotrimers that exist in many combinations of different α, β, and γ subunits
G-protein activation follows a cycle
Activated α subunits couple to a variety of downstream effectors, including enzymes and ion channels
βγ subunits can activate downstream effectors
Small GTP-binding proteins are involved in a vast number of cellular processes
G-Protein Second Messengers: Cyclic Nucleotides
cAMP usually exerts its effect by increasing the activity of protein kinase A
Protein phosphatases reverse the action of kinases
cGMP exerts its effect by stimulating a nonselective cation channel in the retina
G-Protein Second Messengers: Products of Phosphoinositide Breakdown
Many messengers bind to receptors that activate phosphoinositide breakdown
IP3 liberates Ca2+ from intracellular stores
Calcium activates calmodulin-dependent protein kinases
DAGs and Ca2+ activate protein kinase C
G-Protein Second Messengers: Arachidonic Acid Metabolites
Phospholipase A2 is the primary enzyme responsible for releasing AA
Cyclooxygenases, lipoxygenases, and epoxygenases mediate the formation of biologically active eicosanoids
Prostaglandins, prostacyclins, and thromboxanes (cyclooxygenase products) are vasoactive, regulate platelet action, and modulate ion transport N3-16
The leukotrienes (5-lipoxygenase products) play a major role in inflammatory responses
The HETEs and EETs (epoxygenase products) tend to enhance Ca2+ release from intracellular stores and to enhance cell proliferation
Degradation of the eicosanoids terminates their activity
Receptors That are Catalytic
The receptor guanylyl cyclase transduces the activity of atrial natriuretic peptide, whereas a soluble guanylyl cyclase transduces the activity of nitric oxide
Receptor (Membrane-Bound) Guanylyl Cyclase
Soluble Guanylyl Cyclase
Some catalytic receptors are serine/threonine kinases
RTKs produce phosphotyrosine motifs recognized by SH2 and phosphotyrosine-binding domains of downstream effectors
Creation of Phosphotyrosine Motifs
Recognition of pY Motifs by SH2 and Phosphotyrosine-Binding Domains
The MAPK Pathway
The Phosphatidylinositol-3-Kinase Pathway
Tyrosine kinase–associated receptors activate cytosolic tyrosine kinases such as Src and JAK
Receptor tyrosine phosphatases are required for lymphocyte activation
Nuclear Receptors
Steroid and thyroid hormones enter the cell and bind to members of the nuclear receptor superfamily in the cytoplasm or nucleus
Activated nuclear receptors bind to sequence elements in the regulatory region of responsive genes and either activate or repress DNA transcription
References
Books and Reviews
Journal Articles
Chapter 4: Regulation of Gene Expression
From Genes to Proteins
Gene expression differs among tissues and—in any tissue—may vary in response to external stimuli
Genetic information flows from DNA to proteins
The gene consists of a transcription unit
DNA is packaged into chromatin
Gene expression may be regulated at multiple steps
Transcription factors are proteins that regulate gene transcription
The Promoter and Regulatory Elements
The basal transcriptional machinery mediates gene transcription
The promoter determines the initiation site and direction of transcription
Positive and negative regulatory elements modulate gene transcription
Locus control regions and insulator elements influence transcription within multigene chromosomal domains
Transcription Factors
DNA-binding transcription factors recognize specific DNA sequences
Transcription factors that bind to DNA can be grouped into families based on tertiary structure
Zinc Finger
Basic Zipper
Basic Helix-Loop-Helix
Helix-Turn-Helix
Coactivators and corepressors are transcription factors that do not bind to DNA
Transcriptional activators stimulate transcription by three mechanisms
Recruitment of the Basal Transcriptional Machinery
Chromatin Remodeling
Stimulation of Pol II
Transcriptional activators act in combination
Transcriptional repressors act by competition, quenching, or active repression
The activity of transcription factors may be regulated by post-translational modifications
Phosphorylation
Site-Specific Proteolysis
Other Post-Translational Modifications
The expression of some transcription factors is tissue specific
Regulation of Inducible Gene Expression by Signal-Transduction Pathways
cAMP regulates transcription via the transcription factors CREB and CBP
Receptor tyrosine kinases regulate transcription via a Ras-dependent cascade of protein kinases
Tyrosine kinase–associated receptors can regulate transcription via JAK-STAT
Nuclear receptors are transcription factors
Modular Construction
Dimerization
Activation of Transcription
Repression of Transcription
Physiological stimuli can modulate transcription factors, which can coordinate complex cellular responses
Epigenetic Regulation of Gene Expression
Epigenetic regulation can result in long-term gene silencing
Alterations in chromatin structure may mediate epigenetic regulation, stimulating or inhibiting gene transcription
Histone methylation may stimulate or inhibit gene expression
DNA methylation is associated with gene inactivation
Post-Translational Regulation of Gene Expression
Alternative splicing generates diversity from single genes
Retained Intron
Alternative 3′ Splice Sites
Alternative 5′ Splice Sites
Cassette Exons
Mutually Exclusive Exons
Alternative 5′ Ends
Alternative 3′ Ends
Regulatory elements in the 3′ untranslated region control mRNA stability
MicroRNAs regulate mRNA abundance and translation
References
Books and Reviews
Journal Articles
Glossary
Chapter 5: Transport of Solutes and Water
The Intracellular and Extracellular Fluids
Total-body water is the sum of the ICF and ECF volumes
Plasma Volume
Interstitial Fluid
Transcellular Fluid
ICF is rich in K+, whereas ECF is rich in Na+ and Cl−
Volume Occupied by Plasma Proteins
Effect of Protein Charge
All body fluids have approximately the same osmolality, and each fluid has equal numbers of positive and negative charges
Osmolality
Electroneutrality
Solute Transport Across Cell Membranes
In passive, noncoupled transport across a permeable membrane, a solute moves down its electrochemical gradient
At equilibrium, the chemical and electrical potential energy differences across the membrane are equal but opposite
(Vm − EX) is the net electrochemical driving force acting on an ion
In simple diffusion, the flux of an uncharged substance through membrane lipid is directly proportional to its concentration difference
Some substances cross the membrane passively through intrinsic membrane proteins that can form pores, channels, or carriers
Water-filled pores can allow molecules, some as large as 45 kDa, to cross membranes passively
Gated channels, which alternately open and close, allow ions to cross the membrane passively
Na+ Channels
K+ Channels
Ca2+ Channels
Proton Channels
Anion Channels
Some carriers facilitate the passive diffusion of small solutes such as glucose
The physical structures of pores, channels, and carriers are quite similar
The Na-K pump, the most important primary active transporter in animal cells, uses the energy of ATP to extrude Na+ and take up K+
Besides the Na-K pump, other P-type ATPases include the H-K and Ca pumps
H-K Pump
Ca Pumps
Other Pumps
The F-type and the V-type ATPases transport H+
F-type or FoF1 ATPases
V-type H Pump
ATP-binding cassette transporters can act as pumps, channels, or regulators
ABCA Subfamily
MDR Subfamily
MRP/CFTR Subfamily
Cotransporters, one class of secondary active transporters, are generally driven by the energy of the inwardly directed Na+ gradient
Na/Glucose Cotransporter
Na+-Driven Cotransporters for Organic Solutes
Na/HCO3 Cotransporters
Na+-Driven Cotransporters for Other Inorganic Anions
Na/K/Cl Cotransporter
Na/Cl Cotransporter
K/Cl Cotransporter
H+-Driven Cotransporters
Exchangers, another class of secondary active transporters, exchange ions for one another
Na-Ca Exchanger
Na-H Exchanger
Na+-Driven Cl-HCO3 Exchanger
Cl-HCO3 Exchanger
Other Anion Exchangers
Regulation of Intracellular Ion Concentrations
The Na-K pump keeps [Na+] inside the cell low and [K+] high
The Ca pump and the Na-Ca exchanger keep intracellular [Ca2+] four orders of magnitude lower than extracellular [Ca2+]
Ca Pump (SERCA) in Organelle Membranes
Ca Pump (PMCA) on the Plasma Membrane
Na-Ca Exchanger (NCX) on the Plasma Membrane
In most cells, [Cl−] is modestly above equilibrium because Cl− uptake by the Cl-HCO3 exchanger and Na/K/Cl cotransporter balances passive Cl− efflux through channels
The Na-H exchanger and Na+-driven transporters keep the intracellular pH and [] above their equilibrium values
Water Transport and the Regulation of Cell Volume
Water transport is driven by osmotic and hydrostatic pressure differences across membranes
Because of the presence of impermeant, negatively charged proteins within the cell, Donnan forces will lead to cell swelling
The Na-K pump maintains cell volume by doing osmotic work that counteracts the passive Donnan forces
Cell volume changes trigger rapid changes in ion channels or transporters, returning volume toward normal
Response to Cell Shrinkage
Response to Cell Swelling
Cells respond to long-term hyperosmolality by accumulating new intracellular organic solutes
The gradient in tonicity—or effective osmolality—determines the osmotic flow of water across a cell membrane
Water Exchange Across Cell Membranes
Water Exchange Across the Capillary Wall
Adding isotonic saline, pure water, or pure NaCl to the ECF will increase ECF volume but will have divergent effects on ICF volume and ECF osmolality
Infusion of Isotonic Saline
Infusion of “Solute-Free” Water
Ingestion of Pure NaCl Salt
Whole-body Na+ content determines ECF volume, whereas whole-body water content determines osmolality
Transport of Solutes and Water Across Epithelia
The epithelial cell generally has different electrochemical gradients across its apical and basolateral membranes
Tight and leaky epithelia differ in the permeabilities of their tight junctions
Epithelial cells can absorb or secrete different solutes by inserting specific channels or transporters at either the apical or basolateral membrane
Na+ Absorption
K+ Secretion
Glucose Absorption
Cl− Secretion
Water transport across epithelia passively follows solute transport
Absorption of a Hyperosmotic Fluid
Absorption of an Isosmotic Fluid
Absorption of a Hypo-osmotic Fluid
Epithelia can regulate transport by controlling transport proteins, tight junctions, and the supply of the transported substances
Increased Synthesis (or Degradation) of Transport Proteins
Recruitment of Transport Proteins to the Cell Membrane
Post-translational Modification of Pre-existing Transport Proteins
Changes in the Paracellular Pathway
Luminal Supply of Transported Species and Flow Rate
References
Books and Reviews
Journal Articles
Chapter 6: Electrophysiology of the Cell Membrane
Ionic Basis of Membrane Potentials
Principles of electrostatics explain why aqueous pores formed by channel proteins are needed for ion diffusion across cell membranes
Membrane potentials can be measured with microelectrodes as well as dyes or fluorescent proteins that are voltage sensitive
Membrane potential is generated by ion gradients
For mammalian cells, Nernst potentials for ions typically range from −100 mV for K+ to +100 mV for Ca2+
Currents carried by ions across membranes depend on the concentration of ions on both sides of the membrane, the membrane potential, and the permeability of the membrane to each ion
Membrane potential depends on ionic concentration gradients and permeabilities
Electrical Model of a Cell Membrane
The cell membrane model includes various ionic conductances and electromotive forces in parallel with a capacitor
The separation of relatively few charges across the bilayer capacitance maintains the membrane potential
Ionic current is directly proportional to the electrochemical driving force (Ohm’s law)
Capacitative current is proportional to the rate of voltage change
A voltage clamp measures currents across cell membranes
The patch-clamp technique resolves unitary currents through single channel molecules
Single channel currents sum to produce macroscopic membrane currents
Single channels can fluctuate between open and closed states
Molecular Physiology of Ion Channels
Classes of ion channels can be distinguished on the basis of electrophysiology, pharmacological and physiological ligands, intracellular messengers, and sequence homology
Electrophysiology
Pharmacological Ligands
Physiological Ligands
Intracellular Messengers
Sequence Homology
Many channels are formed by a radially symmetric arrangement of subunits or domains around a central pore
Gap junction channels are made up of two connexons, each of which has six identical subunits called connexins
An evolutionary tree called a dendrogram illustrates the relatedness of ion channels
Hydrophobic domains of channel proteins can predict how these proteins weave through the membrane
Protein superfamilies, subfamilies, and subtypes are the structural bases of channel diversity
Connexins
K+ Channels
HCN, CNG, and TRP Channels
NAADP Receptor
Voltage-Gated Na+ Channels
Voltage-Gated Ca2+ Channels
CatSper Channels
Hv Channels
Ligand-Gated Channels
Other Ion Channels
References
Books and Reviews
Journal Articles
Chapter 7: Electrical Excitability and Action Potentials
Mechanisms of Nerve and Muscle Action Potentials
An action potential is a transient depolarization triggered by a depolarization beyond a threshold
In contrast to an action potential, a graded response is proportional to stimulus intensity and decays with distance along the axon
Excitation of a nerve or muscle depends on the product (strength × duration) of the stimulus and on the refractory period
The action potential arises from changes in membrane conductance to Na+ and K+
The Na+ and K+ currents that flow during the action potential are time and voltage dependent
Time Dependence of Na+ and K+ Currents
Voltage Dependence of Na+ and K+ Currents
Macroscopic Na+ and K+ currents result from the opening and closing of many channels
The Hodgkin-Huxley model predicts macroscopic currents and the shape of the action potential
Physiology of Voltage-Gated Channels and Their Relatives
A large superfamily of structurally related membrane proteins includes voltage-gated and related channels
Na+ channels generate the rapid initial depolarization of the action potential
Na+ channels are blocked by neurotoxins and local anesthetics
Ca2+ channels contribute to action potentials in some cells and also function in electrical and chemical coupling mechanisms
Ca2+ channels are characterized as L-, T-, P/Q-, N-, and R-type channels on the basis of kinetic properties and inhibitor sensitivity
K+ channels determine resting potential and regulate the frequency and termination of action potentials
The Kv (or Shaker-related) family of K+ channels mediates both the delayed outward-rectifier current and the transient A-type current
Two families of KCa K+ channels mediate Ca2+-activated K+ currents
The Kir K+ channels mediate inward-rectifier K+ currents, and K2P channels may sense stress
Propagation of Action Potentials
The propagation of electrical signals in the nervous system involves local current loops
Myelin improves the efficiency with which axons conduct action potentials
The cable properties of the membrane and cytoplasm determine the velocity of signal propagation
References
Books and Reviews
Journal Articles
Chapter 8: Synaptic Transmission and the Neuromuscular Junction
Mechanisms of Synaptic Transmission
Electrical continuity between cells is established by electrical or chemical synapses
Electrical synapses directly link the cytoplasm of adjacent cells
Chemical synapses use neurotransmitters to provide electrical continuity between adjacent cells
Neurotransmitters can activate ionotropic or metabotropic receptors
Synaptic Transmission at the Neuromuscular Junction
Neuromuscular junctions are specialized synapses between motor neurons and skeletal muscle
ACh activates nicotinic AChRs to produce an excitatory end-plate current
The nicotinic AChR is a member of the pentameric Cys-loop receptor family of ligand-gated ion channels
Activation of AChR channels requires binding of two ACh molecules
Miniature EPPs reveal the quantal nature of transmitter release from the presynaptic terminals
Direct sensing of extracellular transmitter also shows quantal release of transmitter
Synaptic vesicles package, store, and deliver neurotransmitters
Neurotransmitter release occurs by exocytosis of synaptic vesicles
Re-uptake or cleavage of the neurotransmitter terminates its action
Toxins and Drugs Affecting Synaptic Transmission
Guanidinium neurotoxins such as tetrodotoxin prevent depolarization of the nerve terminal, whereas dendrotoxins inhibit repolarization
ω-Conotoxin blocks Ca2+ channels that mediate Ca2+ influx into nerve terminals, inhibiting synaptic transmission
Bacterial toxins such as tetanus and botulinum toxins cleave proteins involved in exocytosis, preventing fusion of synaptic vesicles
Both agonists and antagonists of the nicotinic AChR can prevent synaptic transmission
Inhibitors of AChE prolong and magnify the EPP
References
Books and Reviews
Journal Articles
Chapter 9: Cellular Physiology of Skeletal, Cardiac, and Smooth Muscle
Skeletal Muscle
Contraction of skeletal muscle is initiated by motor neurons that innervate motor units
Action potentials propagate from the sarcolemma to the interior of muscle fibers along the transverse tubule network
Depolarization of the T-tubule membrane results in Ca2+ release from the SR at the triad
Striations of skeletal muscle fibers correspond to ordered arrays of thick and thin filaments within myofibrils
Thin and thick filaments are supramolecular assemblies of protein subunits
Thin Filaments
Thick Filaments
During the cross-bridge cycle, contractile proteins convert the energy of ATP hydrolysis into mechanical energy
An increase in [Ca2+]i triggers contraction by removing the inhibition of cross-bridge cycling
Termination of contraction requires re-uptake of Ca2+ into the SR
Muscle contractions produce force under isometric conditions and force with shortening under isotonic conditions
Muscle length influences tension development by determining the degree of overlap between actin and myosin filaments
At higher loads, the velocity of shortening is lower because more cross-bridges are simultaneously active
In a single skeletal muscle fiber, the force developed may be increased by summing multiple twitches in time
In a whole skeletal muscle, the force developed may be increased by summing the contractions of multiple fibers
Cardiac Muscle
Action potentials propagate between adjacent cardiac myocytes through gap junctions
Cardiac contraction requires Ca2+ entry through L-type Ca2+ channels
Cross-bridge cycling and termination of cardiac muscle contraction are similar to the events in skeletal muscle
In cardiac muscle, increasing the entry of Ca2+ enhances the contractile force
Smooth Muscle
Smooth muscles may contract in response to synaptic transmission or electrical coupling
Action potentials of smooth muscles may be brief or prolonged
Some smooth-muscle cells spontaneously generate either pacemaker currents or slow waves
Some smooth muscles contract without action potentials
In smooth muscle, both entry of extracellular Ca2+ and intracellular Ca2+ spark activate contraction
Ca2+ Entry via Voltage-Gated Channels
Ca2+ Release from the SR
Ca2+ Entry through Store-Operated Ca2+ Channels (SOCs)
Ca2+-dependent phosphorylation of the myosin regulatory light chain activates cross-bridge cycling in smooth muscle
Termination of smooth-muscle contraction requires dephosphorylation of myosin light chain
Smooth-muscle contraction may also occur independently of increases in [Ca2+]i
In smooth muscle, increases in both [Ca2+]i and the Ca2+ sensitivity of the contractile apparatus enhance contractile force
Smooth muscle maintains high force at low energy consumption
Diversity among Muscles
Skeletal muscle is composed of slow-twitch and fast-twitch fibers
The properties of cardiac cells vary with location in the heart
The properties of smooth-muscle cells differ markedly among tissues and may adapt with time
Smooth-muscle cells express a wide variety of neurotransmitter and hormone receptors
References
Books and Reviews
Journal Articles
Section III: The Nervous System
Chapter 10: Organization of the Nervous System
The nervous system can be divided into central, peripheral, and autonomic nervous systems
Each area of the nervous system has unique nerve cells and a different function
Cells of the Nervous System
The neuron doctrine first asserted that the nervous system is composed of many individual signaling units—the neurons
Nerve cells have four specialized regions: cell body, dendrites, axon, and presynaptic terminals
Cell Body
Dendrites
Axon
Presynaptic Terminals
The cytoskeleton helps compartmentalize the neuron and also provides the tracks along which material travels between different parts of the neuron
Fast Axoplasmic Transport
Fast Retrograde Transport
Slow Axoplasmic Transport
Neurons can be classified on the basis of their axonal projection, their dendritic geometry, and the number of processes emanating from the cell body
Axonal Projection
Dendritic Geometry
Number of Processes
Glial cells provide a physiological environment for neurons
Development of Neurons and Glial Cells
Neurons differentiate from the neuroectoderm
Neurons and glial cells originate from cells in the proliferating germinal matrix near the ventricles
Neurons migrate to their correct anatomical position in the brain with the help of adhesion molecules
Neurons do not regenerate
Neurons
Axons
Glia
Subdivisions of the Nervous System
The CNS consists of the telencephalon, cerebellum, diencephalon, midbrain, pons, medulla, and spinal cord
Telencephalon
Cerebellum
Diencephalon
Brainstem (Midbrain, Pons, and Medulla)
Spinal Cord
The PNS comprises the cranial and spinal nerves, their associated sensory ganglia, and various sensory receptors
The ANS innervates effectors that are not under voluntary control
References
Books and Reviews
Journal Articles
Chapter 11: The Neuronal Microenvironment
Extracellular fluid in the brain provides a highly regulated environment for central nervous system neurons
The brain is physically and metabolically fragile
Cerebrospinal Fluid
CSF fills the ventricles and subarachnoid space
The brain floats in CSF, which acts as a shock absorber
The choroid plexuses secrete CSF into the ventricles, and the arachnoid granulations absorb it
The epithelial cells of the choroid plexus secrete the CSF
Brain Extracellular Space
Neurons, glia, and capillaries are packed tightly together in the CNS
The CSF communicates freely with the BECF, which stabilizes the composition of the neuronal microenvironment
The ion fluxes that accompany neural activity cause large changes in extracellular ion concentration
The Blood-Brain Barrier
The blood-brain barrier prevents some blood constituents from entering the brain extracellular space
Continuous tight junctions link brain capillary endothelial cells
Uncharged and lipid-soluble molecules more readily pass through the blood-brain barrier
Transport by capillary endothelial cells contributes to the blood-brain barrier
Glial Cells
Glial cells constitute half the volume of the brain and outnumber neurons
Astrocytes supply fuel to neurons in the form of lactic acid
Astrocytes are predominantly permeable to K+ and also help regulate [K+]o
Gap junctions couple astrocytes to one another, allowing diffusion of small solutes
Astrocytes synthesize neurotransmitters, take them up from the extracellular space, and have neurotransmitter receptors
Astrocytes secrete trophic factors that promote neuronal survival and synaptogenesis
Astrocytic endfeet modulate cerebral blood flow
Oligodendrocytes and Schwann cells make and sustain myelin
Oligodendrocytes are involved in pH regulation and iron metabolism in the brain
Microglial cells are the macrophages of the CNS
References
Books and Reviews
Journal Articles
Chapter 12: Physiology of Neurons
Neurons receive, combine, transform, store, and send information
Neural information flows from dendrite to soma to axon to synapse
Signal Conduction in Dendrites
Dendrites attenuate synaptic potentials
Dendritic membranes have voltage-gated ion channels
Control of Spiking Patterns in the Soma
Neurons can transform a simple input into a variety of output patterns
Intrinsic firing patterns are determined by a variety of ion currents with relatively slow kinetics
Axonal Conduction
Axons are specialized for rapid, reliable, and efficient transmission of electrical signals
Action potentials are usually initiated at the initial segment
Conduction velocity of a myelinated axon increases linearly with diameter
Demyelinated axons conduct action potentials slowly, unreliably, or not at all
References
Books and Reviews
Journal Articles
Chapter 13: Synaptic Transmission in the Nervous System
Neuronal Synapses
The molecular mechanisms of neuronal synapses are similar but not identical to those of the neuromuscular junction
Presynaptic terminals may contact neurons at the dendrite, soma, or axon and may contain both clear vesicles and dense-core granules
The postsynaptic membrane contains transmitter receptors and numerous proteins clustered in the postsynaptic density
Some transmitters are used by diffusely distributed systems of neurons to modulate the general excitability of the brain
Electrical synapses serve specialized functions in the mammalian nervous system
Neurotransmitter Systems of the Brain
Most of the brain’s transmitters are common biochemicals
Synaptic transmitters can stimulate, inhibit, or modulate the postsynaptic neuron
Excitatory Synapses
Inhibitory Synapses
Modulatory Synapses
G proteins may affect ion channels directly, or indirectly through second messengers
Signaling cascades allow amplification, regulation, and a long duration of transmitter responses
Neurotransmitters may have both convergent and divergent effects
Fast Amino Acid–Mediated Synapses in the CNS
Most EPSPs in the brain are mediated by two types of glutamate-gated channels
Most IPSPs in the brain are mediated by the GABAA receptor, which is activated by several classes of drugs
The ionotropic receptors for ACh, serotonin, GABA, and glycine belong to the superfamily of ligand-gated/pentameric channels
Most neuronal synapses release a very small number of transmitter quanta with each action potential
When multiple transmitters colocalize to the same synapse, the exocytosis of large vesicles requires high-frequency stimulation
Plasticity of Central Synapses
Use-dependent changes in synaptic strength underlie many forms of learning
Short-term synaptic plasticity usually reflects presynaptic changes
Long-term potentiation in the hippocampus may last for days or weeks
Long-term depression exists in multiple forms
Long-term depression in the cerebellum may be important for motor learning
References
Books and Reviews
Journal Articles
Chapter 14: The Autonomic Nervous System
Organization of the Visceral Control System
The ANS has sympathetic, parasympathetic, and enteric divisions
Sympathetic preganglionic neurons originate from spinal segments T1 to L3 and synapse with postganglionic neurons in paravertebral or prevertebral ganglia
Preganglionic Neurons
Paravertebral Ganglia
Prevertebral Ganglia
Postganglionic Neurons
Cranial Nerves III, VII, and IX
Cranial Nerve X
Sacral Nerves
The visceral control system also has an important afferent limb
The enteric division is a self-contained nervous system of the GI tract and receives sympathetic and parasympathetic input
Synaptic Physiology of the Autonomic Nervous System
The sympathetic and parasympathetic divisions have opposite effects on most visceral targets
All preganglionic neurons—both sympathetic and parasympathetic—release acetylcholine and stimulate N2 nicotinic receptors on postganglionic neurons
All postganglionic parasympathetic neurons release ACh and stimulate muscarinic receptors on visceral targets
Most postganglionic sympathetic neurons release norepinephrine onto visceral targets
Postganglionic sympathetic and parasympathetic neurons often have muscarinic as well as nicotinic receptors
Nonclassic transmitters can be released at each level of the ANS
Two of the most unusual nonclassic neurotransmitters, ATP and nitric oxide, were first identified in the ANS
ATP
Nitric Oxide
Central Nervous System Control of the Viscera
Sympathetic output can be massive and nonspecific, as in the fight-or-flight response, or selective for specific target organs
Parasympathetic neurons participate in many simple involuntary reflexes
A variety of brainstem nuclei provide basic control of the ANS
The forebrain can modulate autonomic output, and reciprocally, visceral sensory input integrated in the brainstem can influence or even overwhelm the forebrain
CNS control centers oversee visceral feedback loops and orchestrate a feed-forward response to meet anticipated needs
The ANS has multiple levels of reflex loops
References
Books and Reviews
Journal Articles
Chapter 15: Sensory Transduction
Sensory receptors convert environmental energy into neural signals
Sensory transduction uses adaptations of common molecular signaling mechanisms
Sensory transduction requires detection and amplification, usually followed by a local receptor potential
Chemoreception
Chemoreceptors are ubiquitous, diverse, and evolutionarily ancient
Taste receptors are modified epithelial cells, whereas olfactory receptors are neurons
Taste Receptor Cells
Olfactory Receptor Cells
Complex flavors are derived from a few basic types of taste receptors, with contributions from sensory receptors of smell, temperature, texture, and pain
Taste transduction involves many types of molecular signaling systems
Salty
Sour
Sweet
Bitter
Amino Acids
Olfactory transduction involves specific receptors, G protein–coupled signaling, and a cyclic nucleotide–gated ion channel
Visual Transduction
The optical components of the eye collect light and focus it onto the retina
The retina is a small, displaced part of the CNS
There are three primary types of photoreceptors: rods, cones, and intrinsically photosensitive ganglion cells
Rods and cones hyperpolarize in response to light
Rhodopsin is a G protein–coupled “receptor” for light
The eye uses a variety of mechanisms to adapt to a wide range of light levels
Color vision depends on the different spectral sensitivities of the three types of cones
The ipRGCs have unique properties and functions
Vestibular and Auditory Transduction: Hair Cells
Bending the stereovilli of hair cells along one axis causes cation channels to open or to close
The otolithic organs (saccule and utricle) detect the orientation and linear acceleration of the head
The semicircular canals detect the angular acceleration of the head
The outer and middle ears collect and condition air pressure waves for transduction within the inner ear
Outer Ear
Middle Ear
The cochlea is a spiral of three parallel, fluid-filled tubes
Inner hair cells transduce sound, whereas the active movements of outer hair cells amplify the signal
The frequency sensitivity of auditory hair cells depends on their position along the basilar membrane of the cochlea
Somatic Sensory Receptors, Proprioception, and Pain
A variety of sensory endings in the skin transduce mechanical, thermal, and chemical stimuli
Mechanoreceptors in the skin provide sensitivity to specific stimuli such as vibration and steady pressure
Separate thermoreceptors detect warmth and cold
Nociceptors are specialized sensory endings that transduce painful stimuli
Muscle spindles sense changes in the length of skeletal muscle fibers, whereas Golgi tendon organs gauge the muscle’s force
References
Books and Reviews
Journal Articles
Chapter 16: Circuits of the Central Nervous System
Elements of Neural Circuits
Neural circuits process sensory information, generate motor output, and create spontaneous activity
Nervous systems have several levels of organization
Most local circuits have three elements: input axons, interneurons, and projection (output) neurons
Simple, Stereotyped Responses: Spinal Reflex Circuits
Passive stretching of a skeletal muscle causes a reflexive contraction of that same muscle and relaxation of the antagonist muscles
Force applied to the Golgi tendon organ regulates muscle contractile strength
Noxious stimuli can evoke complex reflexive movements
Spinal reflexes are strongly influenced by control centers within the brain
Rhythmic Activity: Central Pattern Generators
Central pattern generators in the spinal cord can create a complex motor program even without sensory feedback
Pacemaker cells and synaptic interconnections both contribute to central pattern generation
Central pattern generators in the spinal cord take advantage of sensory feedback, interconnections among spinal segments, and interactions with brainstem control centers
Spatial Representations: Sensory and Motor Maps in the Brain
The nervous system contains maps of sensory and motor information
The cerebral cortex has multiple visuotopic maps
Maps of somatic sensory information magnify some parts of the body more than others
The cerebral cortex has a motor map that is adjacent to and well aligned with the somatosensory map
Sensory and motor maps are fuzzy and plastic
Temporal Representations: Time-Measuring Circuits
To localize sound, the brain compares the timing and intensity of input to the ears
The brain measures interaural timing by a combination of neural delay lines and coincidence detectors
References
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Journal Articles
Section IV: The Cardiovascular System
Chapter 17: Organization of the Cardiovascular System
Elements of the Cardiovascular System
The circulation is an evolutionary consequence of body size
The heart is a dual pump that drives the blood in two serial circuits: the systemic and the pulmonary circulations
Hemodynamics
Blood flow is driven by a constant pressure head across variable resistances
Blood pressure is always measured as a pressure difference between two points
Total blood flow, or cardiac output, is the product (heart rate) × (stroke volume)
Flow in an idealized vessel increases with the fourth power of radius (Poiseuille equation)
Viscous resistance to flow is proportional to the viscosity of blood but does not depend on properties of the blood vessel walls
The viscosity of blood is a measure of the internal slipperiness between layers of fluid
How Blood Flows
Blood flow is laminar
Pressure and flow oscillate with each heartbeat between maximum systolic and minimum diastolic values
Origins of Pressure in the Circulation
Gravity causes a hydrostatic pressure difference when there is a difference in height
Low compliance of a vessel causes the transmural pressure to increase when the vessel blood volume is increased
The viscous resistance of blood causes an axial pressure difference when there is flow
The inertia of the blood and vessels causes pressure to decrease when the velocity of blood flow increases
How to Measure Blood Pressure, Blood Flow, and Cardiac Volumes
Blood pressure can be measured directly by puncturing the vessel
Blood pressure can be measured indirectly by use of a sphygmomanometer
Blood flow can be measured directly by electromagnetic and ultrasound flowmeters
Invasive Methods
Noninvasive Methods
Cardiac output can be measured indirectly by the Fick method, which is based on the conservation of mass
Cardiac output can be measured indirectly by dilution methods
Regional blood flow can be measured indirectly by “clearance” methods
Ventricular dimensions, ventricular volumes, and volume changes can be measured by angiography and echocardiography
References
Books and Reviews
Journal Articles
Chapter 18: Blood
Blood Composition
Whole blood is a suspension of cellular elements in plasma
Bone marrow is the source of most blood cells
RBCs are mainly composed of hemoglobin
Leukocytes defend against infections
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Platelets are nucleus-free fragments
Blood Viscosity
Whole blood has an anomalous viscosity
Blood viscosity increases with the hematocrit and the fibrinogen plasma concentration
Fibrinogen
Hematocrit
Vessel Radius
Velocity of Flow
Temperature
Hemostasis and Fibrinolysis
Platelets can plug holes in small vessels
Adhesion
Activation
Aggregation
A controlled cascade of proteolysis creates a blood clot
Intrinsic Pathway (Surface Contact Activation)
Extrinsic Pathway (Tissue Factor Activation)
Common Pathway
Coagulation as a Connected Diagram
Anticoagulants keep the clotting network in check
Paracrine Factors
Anticoagulant Factors
Fibrinolysis breaks up clots
References
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Journal Articles
Chapter 19: Arteries and Veins
Arterial Distribution and Venous Collection Systems
Physical properties of vessels closely follow the level of branching in the circuit
Most of the blood volume resides in the systemic veins
The intravascular pressures along the systemic circuit are higher than those along the pulmonary circuit
Under normal conditions, the steepest pressure drop in the systemic circulation occurs in arterioles, the site of greatest vascular resistance
Local intravascular pressure depends on the distribution of vascular resistance
Elastic Properties of Blood Vessels
Blood vessels are elastic tubes
Because of the elastic properties of vessels, the pressure-flow relationship of passive vascular beds is nonlinear
Contraction of smooth muscle halts blood flow when driving pressure falls below the critical closing pressure
Elastic and collagen fibers determine the distensibility and compliance of vessels
Differences in compliance cause arteries to act as resistors and veins to act as capacitors
Laplace’s law describes how tension in the vessel wall increases with transmural pressure
The vascular wall is adapted to withstand wall tension, not transmural pressure
Elastin and collagen separately contribute to the wall tension of vessels
Aging reduces the distensibility of arteries
Active tension from smooth-muscle activity adds to the elastic tension of vessels
Elastic tension helps stabilize vessels under vasomotor control
References
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Journal Articles
Chapter 20: The Microcirculation
The microcirculation serves both nutritional and non-nutritional roles
The microcirculation extends from the arterioles to the venules
Capillary Exchange of Solutes
The exchange of O2 and CO2 across capillaries depends on the diffusional properties of the surrounding tissue
The O2 extraction ratio of a whole organ depends primarily on blood flow and metabolic demand
According to Fick’s law, the diffusion of small water-soluble solutes across a capillary wall depends on both the permeability and the concentration gradient
The whole-organ extraction ratio for small hydrophilic solutes provides an estimate of the solute permeability of capillaries
Small polar molecules have a relatively low permeability because they can traverse the capillary wall only by diffusing through water-filled pores (small-pore effect)
The exchange of macromolecules across capillaries can occur by transcytosis (large-pore effect)
Capillary Exchange of Water
Fluid transfer across capillaries is convective and depends on net hydrostatic and osmotic forces (i.e., Starling forces)
Capillary blood pressure (Pc) falls from ~35 mm Hg at the arteriolar end to ~15 mm Hg at the venular end
Arteriolar (Pa) and Venular (Pv) Pressure
Location
Time
Gravity
Interstitial fluid pressure (Pif) is slightly negative, except in encapsulated organs
Capillary colloid osmotic pressure (πc), which reflects the presence of plasma proteins, is ~25 mm Hg
Interstitial fluid colloid osmotic pressure (πif) varies between 0 and 10 mm Hg among different organs
The Starling principle predicts ultrafiltration at the arteriolar end and absorption at the venular end of most capillary beds
For continuous capillaries, the endothelial barrier for fluid exchange is more complex than considered by Starling
Lymphatics
Lymphatics return excess interstitial fluid to the blood
Flow in Initial Lymphatics
Flow in Collecting Lymphatics
Transport of Proteins and Cells
The circulation of extracellular fluids involves three convective loops: blood, interstitial fluid, and lymph
Regulation of the Microcirculation
The active contraction of vascular smooth muscle regulates precapillary resistance, which controls capillary blood flow
Contraction of Vascular Smooth Muscle
Relaxation of Vascular Smooth Muscle
Tissue metabolites regulate local blood flow in specific vascular beds, independently of the systemic regulation
The endothelium of capillary beds is the source of several vasoactive compounds, including nitric oxide, endothelium-derived hyperpolarizing factor, and endothelin
Nitric Oxide
Endothelium-Derived Hyperpolarizing Factor
Prostacyclin (Prostaglandin I2)
Endothelins
Thromboxane A2
Other Endothelial Factors
Autoregulation stabilizes blood flow despite large fluctuations in systemic arterial pressure
Blood vessels proliferate in response to growth factors by a process known as angiogenesis
Promoters of Vessel Growth
Inhibitors of Vessel Growth
References
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Journal Articles
Chapter 21: Cardiac Electrophysiology and the Electrocardiogram
Electrophysiology of Cardiac Cells
The cardiac action potential starts in specialized muscle cells of the sinoatrial node and then propagates in an orderly fashion throughout the heart
The cardiac action potential conducts from cell to cell via gap junctions
Cardiac action potentials have as many as five distinctive phases
The Na+ current is the largest current in the heart
The Ca2+ current in the heart passes primarily through L-type Ca2+ channels
The repolarizing K+ current turns on slowly
Early Outward K+ Current (A-type Current)
G Protein–Activated K+ Current
KATP Current
The If current is mediated by a nonselective cation channel
Different cardiac tissues uniquely combine ionic currents to produce distinctive action potentials
The SA node is the primary pacemaker of the heart
The Concept of Pacemaker Activity
SA Node
AV Node
Purkinje Fibers
Atrial and ventricular myocytes fire action potentials but do not have pacemaker activity
Atrial Muscle
Ventricular Muscle
Acetylcholine and catecholamines modulate pacemaker activity, conduction velocity, and contractility
Acetylcholine
Catecholamines
The Electrocardiogram
An ECG generally includes five waves
A pair of ECG electrodes defines a lead
The Limb Leads
The Precordial Leads
A simple two-cell model can explain how a simple ECG can arise
Cardiac Arrhythmias
Conduction abnormalities are a major cause of arrhythmias
Partial (or Incomplete) Conduction Block
Complete Conduction Block
Re-Entry
Accessory Conduction Pathways
Fibrillation
Altered automaticity can originate from the sinus node or from an ectopic locus
Depolarization-Dependent Triggered Activity
Long QT Syndrome
Ca2+ overload and metabolic changes can also cause arrhythmias
Ca2+ Overload
Metabolism-Dependent Conduction Changes
Electromechanical Dissociation
References
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Chapter 22: The Heart as a Pump
The Cardiac Cycle
The closing and opening of the cardiac valves define four phases of the cardiac cycle
Changes in ventricular volume, pressure, and flow accompany the four phases of the cardiac cycle N22-1
Diastasis Period (Middle of Phase 1)
Atrial Contraction (End of Phase 1)
Isovolumetric Contraction (Phase 2)
Ejection or Outflow (Phase 3)
Isovolumetric Relaxation (Phase 4)
Rapid Ventricular Filling Period (Beginning of Phase 1)
The ECG, phonocardiogram, and echocardiogram all follow the cyclic pattern of the cardiac cycle
Aortic Blood Flow
Jugular Venous Pulse
Electrocardiogram
Phonocardiogram and Heart Sounds
Echocardiogram
The cardiac cycle causes flow waves in the aorta and peripheral vessels
Aortic Arch
Thoracic-Abdominal Aorta and Large Arteries
The cardiac cycle also causes pressure waves in the aorta and peripheral vessels
Terminal Arteries and Arterioles
Capillaries
Distortion of pressure waves is the result of their propagation along the arterial tree
Effect of Frequency on Wave Velocity and Damping
Effect of Wall Stiffness on Wave Velocity
Pressure waves in veins do not originate from arterial waves
Effect of the Cardiac Cycle
Effect of the Respiratory Cycle
Effect of Skeletal Muscle Contraction (“Muscle Pump”)
Cardiac Dynamics
The right ventricle contracts like a bellows, whereas the left ventricle contracts like a hand squeezing a tube of toothpaste
The right atrium contracts before the left, but the left ventricle contracts before the right
Atrial Contraction
Initiation of Ventricular Contraction
Ventricular Ejection
Ventricular Relaxation
Measurements of ventricular volumes, pressures, and flows allow clinicians to judge cardiac performance
Definitions of Cardiac Volumes
Measurements of Cardiac Volumes
Measurement of Ventricular Pressures
Measurement of Flows
The pressure-volume loop of a ventricle illustrates the ejection work of the ventricle
Segment AB
Segment BC
Segment CD
Segment DE
Segment EF
Segment FA
The “pumping work” done by the heart accounts for a small fraction of the total energy the heart consumes
From Contractile Filaments to a Regulated Pump
The entry of Ca2+ from the outside triggers Ca2+-induced Ca2+ release from the sarcoplasmic reticulum
A global rise in [Ca2+]i initiates contraction of cardiac myocytes
Phosphorylation of phospholamban and of troponin I speeds cardiac muscle relaxation
Extrusion of Ca2+ into the ECF
Reuptake of Ca2+ by the SR
Uptake of Ca2+ by Mitochondria
Dissociation of Ca2+ from Troponin C
The overlap of thick and thin filaments cannot explain the unusual shape of the cardiac length-tension diagram
Starling’s law states that a greater fiber length (i.e., greater ventricular volume) causes the heart to deliver more mechanical energy
The velocity of cardiac muscle shortening falls when the contraction occurs against a greater opposing force (or pressure) or at a shorter muscle length (or lower volume)
Increases in heart rate enhance myocardial tension
Contractility is an intrinsic measure of cardiac performance
Effect of Changes in Contractility
Effect of Changes in Preload (i.e., Initial Sarcomere Length)
Effect of Changes in Afterload
Positive inotropic agents increase myocardial contractility by raising [Ca2+]i
Positive Inotropic Agents
Negative Inotropic Agents
References
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Journal Articles
Chapter 23: Regulation of Arterial Pressure and Cardiac Output
Short-Term Regulation of Arterial Pressure
Systemic mean arterial blood pressure is the principal variable that the cardiovascular system controls
Neural reflexes mediate the short-term regulation of mean arterial blood pressure
High-pressure baroreceptors at the carotid sinus and aortic arch are stretch receptors that sense changes in arterial pressure
Increased arterial pressure raises the firing rate of afferent baroreceptor nerves
The medulla coordinates afferent baroreceptor signals
The efferent pathways of the baroreceptor response include both sympathetic and parasympathetic divisions of the autonomic nervous system
Sympathetic Efferents
Parasympathetic Efferents
The principal effectors in the neural control of arterial pressure are the heart, the arteries, the veins, and the adrenal medulla
Sympathetic Input to the Heart (Cardiac Nerves)
Parasympathetic Input to the Heart (Vagus Nerve)
Sympathetic Input to Blood Vessels (Vasoconstrictor Response)
Parasympathetic Input to Blood Vessels (Vasodilator Response)
Sympathetic Input to Blood Vessels in Skeletal Muscle (Vasodilator Response)
Adrenal Medulla
The unique combination of agonists and receptors determines the end response in cardiac and vascular effector cells
Adrenergic Receptors in the Heart
Cholinergic Receptors in the Heart
Adrenergic Receptors in Blood Vessels
Cholinergic Receptors in or near Blood Vessels
Nonadrenergic, Noncholinergic Receptors in Blood Vessels
The medullary cardiovascular center tonically maintains blood pressure and is under the control of higher brain centers
Secondary neural regulation of arterial blood pressure depends on chemoreceptors
Carotid Bodies
Aortic Bodies
Afferent Fiber Input to the Medulla
Physiological Role of the Peripheral Chemoreceptors in Cardiovascular Control
Central Chemoreceptors
Regulation of Cardiac Output
Mechanisms intrinsic to the heart modulate both heart rate and stroke volume
Intrinsic Control of Heart Rate
Intrinsic Control of Stroke Volume
Mechanisms extrinsic to the heart also modulate heart rate and stroke volume
Baroreceptor Regulation
Chemoreceptor Regulation
Low-pressure baroreceptors in the atria respond to increased “fullness” of the vascular system, triggering tachycardia, renal vasodilation, and diuresis
Atrial Receptors
Ventricular Receptors
Cardiac output is roughly proportional to effective circulating blood volume
Matching of Venous Return and Cardiac Output
Increases in cardiac output cause right atrial pressure to fall
Changes in blood volume shift the vascular function curve to different RAPs, whereas changes in arteriolar tone alter the slope of the curve
Because vascular function and cardiac function depend on each other, cardiac output and venous return match at exactly one value of RAP
Intermediate- and Long-Term Control of the Circulation
Endocrine and paracrine vasoactive compounds control the circulatory system on an intermediate- to long-term basis
Biogenic Amines
Peptides
Prostaglandins
Nitric Oxide
Pathways for the renal control of ECF volume are the primary long-term regulators of mean arterial pressure
References
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Journal Articles
Chapter 24: Special Circulations
The blood flow to individual organs must vary to meet the needs of the particular organ, as well as of the whole body
Neural, myogenic, metabolic, and endothelial mechanisms control regional blood flow
Neural Mechanisms
Myogenic Mechanisms
Metabolic Mechanisms
Endothelial Mechanisms
The Brain
Anastomoses at the circle of Willis and among the branches of distributing arteries protect the blood supply to the brain, which is ~15% of resting cardiac output
Arteries
Veins
Capillaries
Lymphatics
Vascular Volume
Neural, metabolic, and myogenic mechanisms control blood flow to the brain
Neural Control
Metabolic Control
Myogenic Control
The neurovascular unit matches blood flow to local brain activity
Autoregulation maintains a fairly constant cerebral blood flow across a broad range of perfusion pressures
The Heart
The coronary circulation receives 5% of the resting cardiac output from the left heart and mostly returns it to the right heart
Extravascular compression impairs coronary blood flow during systole
Myocardial blood flow parallels myocardial metabolism
Although sympathetic stimulation directly constricts coronary vessels, accompanying metabolic effects predominate, producing an overall vasodilation
Collateral vessel growth can provide blood flow to ischemic regions
Vasodilator drugs may compromise myocardial flow through “coronary steal”
The Skeletal Muscle
A microvascular unit is the capillary bed supplied by a single terminal arteriole
Metabolites released by active muscle trigger vasodilation and an increase in blood flow
Sympathetic innervation increases the intrinsic tone of resistance vessels
Rhythmic contraction promotes blood flow through the “muscle pump”
The Splanchnic Organs
The vascular supply to the gut is highly interconnected
Blood flow to the gastrointestinal tract increases up to eight-fold after a meal (postprandial hyperemia)
Sympathetic activity directly constricts splanchnic blood vessels, whereas parasympathetic activity indirectly dilates them
Changes in the splanchnic circulation regulate total peripheral resistance and the distribution of blood volume
Exercise and hemorrhage can substantially reduce splanchnic blood flow
The liver receives its blood flow from both the systemic and the portal circulation
The Skin
The skin is the largest organ of the body
Specialized arteriovenous anastomoses in apical skin help control heat loss
Apical Skin
Nonapical Skin
Mechanical stimuli elicit local vascular responses in the skin
White Reaction
“Triple Response”
References
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Chapter 25: Integrated Control of the Cardiovascular System
Interaction among the Different Cardiovascular Control Systems
The control of the cardiovascular system involves “linear,” “branched,” and “connected” interactions
Regulation of the entire cardiovascular system depends on the integrated action of multiple subsystem controls as well as noncardiovascular controls
Response to Erect Posture
Because of gravity, standing up (orthostasis) tends to shift blood from the head and heart to veins in the legs
The ANS mediates an “orthostatic response” that raises heart rate and peripheral vascular resistance and thus tends to restore mean arterial pressure
Nonuniform Initial Distribution of Blood
Nonuniform Distensibility of the Vessels
Muscle Pumps
Autonomic Reflexes
Postural Hypotension
Temperature Effects
Responses to Acute Emotional Stress
The fight-or-flight reaction is a sympathetic response that is centrally controlled in the cortex and hypothalamus
The common faint reflects mainly a parasympathetic response caused by sudden emotional stress
Response to Exercise
Early physiologists suggested that muscle contraction leads to mechanical and chemical changes that trigger an increase in cardiac output
Mechanical Response: Increased Venous Return
Chemical Response: Local Vasodilation in Active Muscle
Central command organizes an integrated cardiovascular response to exercise
Muscle and baroreceptor reflexes, metabolites, venous return, histamine, epinephrine, and increased temperature reinforce the response to exercise
Response to Hemorrhage
After hemorrhage, cardiovascular reflexes restore mean arterial pressure
Tachycardia and Increased Contractility
Arteriolar Constriction
Venous Constriction
Circulating Vasoactive Agonists
After hemorrhage, transcapillary refill, fluid conservation, and thirst restore the blood volume
Transcapillary Refill
Renal Conservation of Salt and Water
Thirst
Positive-feedback mechanisms cause irreversible hemorrhagic shock
Failure of the Vasoconstrictor Response
Failure of the Capillary Refill
Failure of the Heart
CNS Depression
References
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Section V: The Respiratory System
Chapter 26: Organization of the Respiratory System
Comparative Physiology of Respiration
External respiration is the exchange of O2 and CO2 between the atmosphere and the mitochondria
Diffusion is the major mechanism of external respiration for small aquatic organisms
Convection enhances diffusion by producing steeper gradients across the diffusion barrier
Surface area amplification enhances diffusion
Respiratory pigments such as hemoglobin increase the carrying capacity of the blood for both O2 and CO2
Pathophysiology recapitulates phylogeny … in reverse
Organization of the Respiratory System in Humans
Humans optimize each aspect of external respiration—ventilation, circulation, area amplification, gas carriage, local control, and central control
Conducting airways deliver fresh air to the alveolar spaces
Alveolar air spaces are the site of gas exchange
The lungs play important nonrespiratory roles, including filtering the blood, serving as a reservoir for the left ventricle, and performing several biochemical conversions
Olfaction
Processing of Inhaled Air Before It Reaches the Alveoli
Left Ventricular Reservoir
Filtering Small Emboli from the Blood
Biochemical Reactions
Lung Volumes and Capacities
The spirometer measures changes in lung volume
The volume of distribution of helium or nitrogen in the lung is an estimate of the RV
Helium-Dilution Technique
N2-Washout Method
The plethysmograph, together with Boyle’s law, is a tool for estimation of RV
References
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Chapter 27: Mechanics of Ventilation
Static Properties of the Lung
The balance between the outward elastic recoil of the chest wall and the inward elastic recoil of the lungs generates a subatmospheric intrapleural pressure
Contraction of the diaphragm and selected intercostal muscles increases the volume of the thorax, producing an inspiration
Relaxation of the muscles of inspiration produces a quiet expiration
An increase of the static compliance makes it easier to inflate the lungs
Surface tension at the air-water interface of the airways accounts for most of the elastic recoil of the lungs
Pulmonary surfactant is a mixture of lipids—mainly dipalmitoylphosphatidylcholine—and apoproteins
Pulmonary surfactant reduces surface tension and increases compliance
Dynamic Properties of the Lung
Airflow is proportional to the difference between alveolar and atmospheric pressure, but inversely proportional to airway resistance
In the lung, airflow is transitional in most of the tracheobronchial tree
The smallest airways contribute only slightly to total airway resistance in healthy lungs
Vagal tone, histamine, and reduced lung volume all increase airway resistance
Intrapleural pressure has a static component (−PTP) that determines lung volume and a dynamic component (Pa) that determines airflow
Transpulmonary Pressure
Alveolar Pressure
During inspiration, a sustained negative shift in PIP causes Pa to become transiently more negative
Dynamic compliance falls as respiratory frequency rises
Transmural pressure differences cause airways to dilate during inspiration and to compress during expiration
Static Conditions
Inspiration
Expiration
Because of airway collapse, expiratory flow rates become independent of effort at low lung volumes
References
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Chapter 28: Acid-Base Physiology
pH and Buffers
pH values vary enormously among different intracellular and extracellular compartments
Buffers minimize the size of the pH changes produced by adding acid or alkali to a solution
According to the Henderson-Hasselbalch equation, pH depends on the ratio [CO2]/[]
has a far higher buffering power in an open than in a closed system
Acid-Base Chemistry When Is the Only Buffer
In the absence of other buffers, doubling causes pH to fall by 0.3 but causes almost no change in []
In the absence of other buffers, doubling [] causes pH to rise by 0.3
Acid-Base Chemistry in the Presence of and Buffers—The Davenport Diagram
The Davenport diagram is a graphical tool for interpreting acid-base disturbances in blood
The Buffer
Buffers
Solving the Problem
The amount of formed or consumed during “respiratory” acid-base disturbances increases with
Adding or removing an acid or base—at a constant —produces a “metabolic” acid-base disturbance
During metabolic disturbances, makes a greater contribution to total buffering when pH and are high and when is low
A metabolic change can compensate for a respiratory disturbance
A respiratory change can compensate for a metabolic disturbance
Position on a Davenport diagram defines the nature of an acid-base disturbance
pH Regulation of Intracellular Fluid
Ion transporters at the plasma membrane closely regulate the pH inside of cells
Indirect interactions between K+ and H+ make it appear as if cells have a K-H exchanger
Changes in intracellular pH are often a sign of changes in extracellular pH, and vice versa
References
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Chapter 29: Transport of Oxygen and Carbon Dioxide in the Blood
Carriage of O2
The amount of O2 dissolved in blood is far too small to meet the metabolic demands of the body
Hemoglobin consists of two α and two β subunits, each of which has an iron-containing “heme” and a polypeptide “globin”
The Hb-O2 dissociation curve has a sigmoidal shape because of cooperativity among the four subunits of the Hb molecule
Increases in temperature, [CO2], and [H+], all of which are characteristic of metabolically active tissues, cause Hb to dump O2
Temperature
Acid
Carbon Dioxide
2,3-Diphosphoglycerate reduces the affinity of adult, but not of fetal, Hb
Carriage of CO2
Blood carries “total CO2” mainly as
CO2 transport depends critically on carbonic anhydrase, the Cl-HCO3 exchanger, and Hb
The high in the lungs causes the blood to dump CO2
The O2-CO2 diagram describes the interaction of and in the blood
References
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Chapter 30: Gas Exchange in the Lungs
Diffusion of Gases
Gas flow across a barrier is proportional to diffusing capacity and concentration gradient (Fick’s law)
The total flux of a gas between alveolar air and blood is the summation of multiple diffusion events along each pulmonary capillary during the respiratory cycle
The flow of O2, CO, and CO2 between alveolar air and blood depends on the interaction of these gases with red blood cells
Diffusion and Perfusion Limitations on Gas Transport
The diffusing capacity normally limits the uptake of CO from alveolar air to blood
Perfusion normally limits the uptake of N2O from alveolar air to blood
In principle, CO transport could become perfusion limited and N2O transport could become diffusion limited under special conditions
The uptake of CO provides an estimate of DL
For both O2 and CO2, transport is normally perfusion limited
Uptake of O2
Escape of CO2
Pathological changes that reduce DL do not necessarily produce hypoxia
References
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Chapter 31: Ventilation and Perfusion of the Lungs
Ventilation
About 30% of total ventilation in a respiratory cycle is wasted ventilating anatomical dead space (i.e., conducting airways)
The Fowler single-breath N2-washout technique estimates anatomical dead space
The Bohr expired-[CO2] approach estimates physiological dead space
Alveolar ventilation is the ratio of CO2 production rate to CO2 mole fraction in alveolar air
Alveolar and arterial are inversely proportional to alveolar ventilation
Alveolar and arterial rise with increased alveolar ventilation
Because of the action of gravity on the lung, regional ventilation in an upright subject is normally greater at the base than the apex
Restrictive and obstructive pulmonary diseases can exacerbate the nonuniformity of ventilation
Restrictive Pulmonary Disease
Obstructive Pulmonary Disease
Perfusion of the Lung
The pulmonary circulation has low pressure and resistance but high compliance
Overall pulmonary vascular resistance is minimal at FRC
Alveolar Vessels
Extra-Alveolar Vessels
Increases in pulmonary arterial pressure reduce pulmonary vascular resistance by recruiting and distending pulmonary capillaries
Recruitment
Distention
Hypoxia is a strong vasoconstrictor, opposite to its effect in the systemic circulation
Oxygen
Carbon Dioxide and Low pH
Autonomic Nervous System
Hormones and Other Humoral Agents
Because of gravity, regional perfusion in an upright subject is far greater near the base than the apex of the lung
Zone 1: Pa > PPA > PPV
Zone 2: PPA > Pa > PPV
Zone 3: PPA > PPV > Pa
Zone 4: PPA > PPV > Pa
Matching Ventilation and Perfusion
The greater the ventilation-perfusion ratio, the higher the and the lower the in the alveolar air
Because of the action of gravity, the regional ratio in an upright subject is greater at the apex of the lung than at the base
The ventilation of unperfused alveoli (local = ∞) triggers compensatory bronchoconstriction and a fall in surfactant production
Alveolar Dead-Space Ventilation
Redirection of Blood Flow
Regulation of Local Ventilation
The perfusion of unventilated alveoli (local = 0) triggers a compensatory hypoxic vasoconstriction
Shunt
Redirection of Airflow
Asthma
Normal Anatomical Shunts
Pathological Shunts
Regulation of Local Perfusion
Even if whole-lung and are normal, exaggerated local mismatches produce hypoxia and respiratory acidosis
Normal Lungs
Alveolar Dead-Space Ventilation Affecting One Lung
Shunt Affecting One Lung
Mixed Mismatches
References
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Chapter 32: Control of Ventilation
Overview of the Respiratory Control System
Automatic centers in the brainstem activate the respiratory muscles rhythmically and subconsciously
Peripheral and central chemoreceptors—which sense , , and pH—drive the CPG
Other receptors as well as higher brain centers also modulate ventilation
Neurons That Control Ventilation
The neurons that generate the respiratory rhythm are located in the medulla
The pons modulates—but is not essential for—respiratory output
The dorsal and ventral respiratory groups contain many neurons that fire in phase with respiratory motor output
The dorsal respiratory group processes sensory input and contains primarily inspiratory neurons
The ventral respiratory group is primarily motor and contains both inspiratory and expiratory neurons
Generation of the Respiratory Rhythm
Different RRNs fire at different times during inspiration and expiration
The firing patterns of RRNs depend on the ion channels in their membranes and the synaptic inputs they receive
Intrinsic Membrane Properties
Synaptic Input
Pacemaker properties and synaptic interactions may both contribute to the generation of the respiratory rhythm
Pacemaker Activity
Synaptic Interactions
The respiratory CPG for eupnea could reside in a single site or in multiple sites, or could emerge from a complex network
Restricted-Site Model
Distributed Oscillator Models
Emergent Property Model
Chemical Control of Ventilation
Peripheral Chemoreceptors
Peripheral chemoreceptors (carotid and aortic bodies) respond to hypoxia, hypercapnia, and acidosis
Sensitivity to Decreased Arterial
Sensitivity to Increased Arterial
Sensitivity to Decreased Arterial pH
The glomus cell is the chemosensor in the carotid and aortic bodies
Hypoxia, hypercapnia, and acidosis inhibit K+ channels, raise glomus cell [Ca2+]i, and release neurotransmitters
Hypoxia N32-17
Hypercapnia
Extracellular Acidosis
Central Chemoreceptors
The blood-brain barrier separates the central chemoreceptors in the medulla from arterial blood
Central chemoreceptors are located in the ventrolateral medulla and other brainstem regions
Some neurons of the medullary raphé and VLM are unusually pH sensitive
Integrated Responses to Hypoxia, Hypercapnia, and Acidosis
Hypoxia accentuates the acute response to respiratory acidosis
Respiratory Acidosis
Metabolic Acidosis
Respiratory acidosis accentuates the acute response to hypoxia
Modulation of Ventilatory Control
Stretch and chemical/irritant receptors in the airways and lung parenchyma provide feedback about lung volume and the presence of irritants
Slowly Adapting Pulmonary Stretch Receptors
Rapidly Adapting Pulmonary Stretch (Irritant) Receptors
C-Fiber Receptors
Higher brain centers coordinate ventilation with other behaviors and can override the brainstem’s control of breathing
Coordination with Voluntary Behaviors That Use Respiratory Muscles
Coordination with Complex Nonventilatory Behaviors
Modification by Affective States
Balancing Conflicting Demands of Gas Exchange and Other Behaviors
References
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Section VI: The Urinary System
Chapter 33: Organization of the Urinary System
Functional Anatomy of the Kidney
The kidneys are paired, retroperitoneal organs with vascular and epithelial elements
The kidneys have a very high blood flow and glomerular capillaries flanked by afferent and efferent arterioles
The functional unit of the kidney is the nephron
The renal corpuscle has three components: vascular elements, the mesangium, and Bowman’s capsule and space
The tubule components of the nephron include the proximal tubule, loop of Henle, distal tubule, and collecting duct
The tightness of tubule epithelia increases from the proximal to the medullary collecting tubule
Main Elements of Renal Function
The nephron forms an ultrafiltrate of the blood plasma and then selectively reabsorbs the tubule fluid or secretes solutes into it
The JGA is a region where each thick ascending limb contacts its glomerulus
Sympathetic nerve fibers to the kidney regulate renal blood flow, glomerular filtration, and tubule reabsorption
The kidneys, as endocrine organs, produce renin, 1,25-dihydroxyvitamin D, erythropoietin, prostaglandins, and bradykinin
Measuring Renal Clearance and Transport
The clearance of a solute is the virtual volume of plasma that would be totally cleared of a solute in a given time
A solute’s urinary excretion is the algebraic sum of its filtered load, reabsorption by tubules, and secretion by tubules
Microscopic techniques make it possible to measure single-nephron rates of filtration, absorption, and secretion
Single-Nephron GFR
Handling of Water by Tubule Segments in a Single Nephron
Handling of Solutes by Tubule Segments in a Single Nephron
The Ureters and Bladder
The ureters propel urine from the renal pelvis to the bladder by peristaltic waves conducted along a syncytium of smooth-muscle cells
Sympathetic, parasympathetic, and somatic fibers innervate the urinary bladder and its sphincters
Bladder filling activates stretch receptors, initiating the micturition reflex, a spinal reflex under control of higher central nervous system centers
References
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Chapter 34: Glomerular Filtration and Renal Blood Flow
Glomerular Filtration
A high glomerular filtration rate is essential for maintaining stable and optimal extracellular levels of solutes and water
The clearance of inulin is a measure of GFR
The clearance of creatinine is a useful clinical index of GFR
Molecular size and electrical charge determine the filterability of solutes across the glomerular filtration barrier
Hydrostatic pressure in glomerular capillaries favors glomerular ultrafiltration, whereas oncotic pressure in capillaries and hydrostatic pressure in Bowman’s space oppose it
Renal Blood Flow
Increased glomerular plasma flow leads to an increase in GFR
Afferent and efferent arteriolar resistances control both glomerular plasma flow and GFR
Peritubular capillaries provide tubules with nutrients and retrieve reabsorbed fluid
Blood flow in the renal cortex exceeds that in the renal medulla
The clearance of para-aminohippurate is a measure of RPF
Control of Renal Blood Flow and Glomerular Filtration
Autoregulation keeps RBF and GFR relatively constant
Myogenic Response
Tubuloglomerular Feedback
Volume expansion and a high-protein diet increase GFR by reducing TGF
Four factors that modulate RBF and GFR play key roles in regulating effective circulating volume
Renin-Angiotensin-Aldosterone Axis
Sympathetic Nerves
Arginine Vasopressin
Atrial Natriuretic Peptide
Other vasoactive agents modulate RBF and GFR
Epinephrine
Dopamine
Endothelins
Prostaglandins
Leukotrienes
Nitric Oxide
References
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Journal Articles
Chapter 35: Transport of Sodium and Chloride
Na+ and Cl− Transport by Different Segments of The Nephron
Na+ and Cl− reabsorption decreases from proximal tubules to Henle’s loops to classic distal tubules to collecting tubules and ducts
The tubule reabsorbs Na+ via both the transcellular and the paracellular pathways
Transcellular Na+ Reabsorption
Paracellular Na+ Reabsorption
Na+ and Cl−, and Water Transport at the Cellular and Molecular Level
Na+ reabsorption involves apical transporters or ENaCs and a basolateral Na-K pump
Proximal Tubule
Thin Limbs of Henle’s Loop
Thick Ascending Limb
Distal Convoluted Tubule
Initial and Cortical Collecting Tubules
Medullary Collecting Duct
Cl− reabsorption involves both paracellular and transcellular pathways
Proximal Tubule
Thick Ascending Limb
Distal Convoluted Tubule
Collecting Ducts
Water reabsorption is passive and secondary to solute transport
Proximal Tubule
Loop of Henle and Distal Nephron
The kidney’s high O2 consumption reflects a high level of active Na+ transport
Regulation of Na+ and Cl− Transport
Glomerulotubular balance stabilizes fractional Na+ reabsorption by the proximal tubule in the face of changes in the filtered Na+ load
The proximal tubule achieves GT balance by both peritubular and luminal mechanisms
Peritubular Factors in the Proximal Tubule
Luminal Factors in the Proximal Tubule
ECF volume contraction or expansion upsets GT balance
The distal nephron also increases Na+ reabsorption in response to an increased Na+ load
Four parallel pathways that regulate effective circulating volume all modulate Na+ reabsorption
Renin-Angiotensin-Aldosterone Axis
Sympathetic Division of the Autonomic Nervous System
Arginine Vasopressin (Antidiuretic Hormone)
Atrial Natriuretic Peptide
Dopamine, elevated plasma [Ca2+], an endogenous steroid, prostaglandins, and bradykinin all decrease Na+ reabsorption
Dopamine
Elevated Plasma [Ca2+]
Endogenous Na-K Pump Inhibitor
Prostaglandins
Bradykinin
References
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Journal Articles
Chapter 36: Transport of Urea, Glucose, Phosphate, Calcium, Magnesium, and Organic Solutes
Urea
The kidney filters, reabsorbs, and secretes urea
Urea excretion rises with increasing urinary flow
Glucose
The proximal tubule reabsorbs glucose via apical, electrogenic Na/glucose cotransport and basolateral facilitated diffusion
Glucose excretion in the urine occurs only when the plasma concentration exceeds a threshold
Other Organic Solutes
The proximal tubule reabsorbs amino acids using a wide variety of apical and basolateral transporters
An H+-driven cotransporter takes up oligopeptides across the apical membrane, whereas endocytosis takes up proteins and other large organic molecules
Oligopeptides
Proteins
Two separate apical Na+-driven cotransporters reabsorb monocarboxylates and dicarboxylates/tricarboxylates
The proximal tubule secretes PAH and a variety of other organic anions
PAH secretion is an example of a Tm-limited mechanism
The proximal tubule both reabsorbs and secretes urate
Reabsorption
Secretion
The late proximal tubule secretes several organic cations
Nonionic diffusion of neutral weak acids and bases across tubules explains why their excretion is pH dependent
Phosphate
The proximal tubule reabsorbs phosphate via apical Na/phosphate cotransporters
Phosphate excretion in the urine already occurs at physiological plasma concentrations
PTH inhibits apical Na/phosphate uptake, promoting phosphate excretion
Fibroblast growth factor 23 and other phosphatonins also inhibit apical Na/phosphate uptake, promoting phosphate excretion
Calcium
Binding to plasma proteins and formation of Ca2+-anion complexes influence the filtration and reabsorption of Ca2+
The proximal tubule reabsorbs two thirds of filtered Ca2+, with more distal segments reabsorbing nearly all of the remainder
Proximal Tubule
Thick Ascending Limb
Distal Convoluted Tubule
Transcellular Ca2+ movement is a two-step process, involving passive Ca2+ entry through apical channels and basolateral extrusion by electrogenic Na/Ca exchange and a Ca pump
PTH and vitamin D stimulate—whereas high plasma Ca2+ inhibits—Ca2+ reabsorption
Parathyroid Hormone
Vitamin D
Plasma Ca2+ Levels
Diuretics
Magnesium
Most Mg2+ reabsorption takes place along the TAL
Mg2+ reabsorption increases with depletion of Mg2+ or Ca2+, or with elevated PTH levels
Mg2+ Depletion
Hypermagnesemia and Hypercalcemia
Hormones
Diuretics
References
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Journal Articles
Chapter 37: Transport of Potassium
Potassium Balance and the Overall Renal Handling of Potassium
Changes in K+ concentrations can have major effects on cell and organ function
K+ homeostasis involves external K+ balance between environment and body, and internal K+ balance between intracellular and extracellular compartments
External K+ Balance
Internal K+ Balance
Ingested K+ moves transiently into cells for storage before excretion by the kidney
The kidney excretes K+ by a combination of filtration, reabsorption, and secretion
Potassium Transport by Different Segments of the Nephron
The proximal tubule reabsorbs most of the filtered K+, whereas the distal nephron reabsorbs or secretes K+, depending on K+ intake
Low Dietary K+
Normal or High Dietary K+
Medullary trapping of K+ helps to maximize K+ excretion when K+ intake is high
Potassium Transport at the Cellular and Molecular Levels
Passive K+ reabsorption along the proximal tubule follows Na+ and fluid movements
K+ reabsorption along the TAL occurs predominantly via a transcellular route that exploits secondary active Na/K/Cl cotransport
K+ secretion by principal and intercalated cells of the ICT and CCT involves active K+ uptake across the basolateral membrane
K+ reabsorption by intercalated cells involves apical uptake via an H-K pump
K+ reabsorption along the MCD is both passive and active
Regulation of Renal Potassium Excretion
Increased luminal flow increases K+ secretion
An increased lumen-negative transepithelial potential increases K+ secretion
Low luminal [Cl−] enhances K+ secretion
Aldosterone increases K+ secretion
Mineralocorticoids
Glucocorticoids
High K+ intake promotes renal K+ secretion
Dietary K+ Loading
Dietary K+ Deprivation
Acidosis decreases K+ secretion
Epinephrine reduces and AVP enhances K+ excretion
Opposing factors stabilize K+ secretion
Attenuating Effects
Additive Effects
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Chapter 38: Urine Concentration and Dilution
Water Balance and the Overall Renal Handling of Water
The kidney can generate a urine as dilute as 40 mOsm (one seventh of plasma osmolality) or as concentrated as 1200 mOsm (four times plasma osmolality)
Free-water clearance () is positive if the kidney produces urine that is less concentrated than plasma and negative if the kidney produces urine that is more concentrated than plasma
Isosmotic Urine
Dilute Urine
Concentrated Urine
Water Transport by Different Segments of the Nephron
The kidney concentrates urine by driving water via osmosis from the tubule lumen into a hyperosmotic interstitium
Tubule fluid is isosmotic in the proximal tubule, becomes dilute in the loop of Henle, and then either remains dilute or becomes concentrated by the end of the collecting duct
Generation of a Hyperosmotic Medulla and Urine
The renal medulla is hyperosmotic to blood plasma during both antidiuresis (low urine flow) and water diuresis
NaCl transport generates only a ~200-mOsm gradient across any portion of the ascending limb, but countercurrent exchange can multiply this single effect to produce a 900-mOsm gradient between cortex and papilla
The single effect is the result of passive NaCl reabsorption in the thin ascending limb and active NaCl reabsorption in the TAL
The IMCD reabsorbs urea, producing high levels of urea in the interstitium of the inner medulla
Urea Handling
Urea Recycling
The vasa recta’s countercurrent exchange and relatively low blood flow minimize washout of medullary hyperosmolality
The MCD produces a concentrated urine by osmosis, driven by the osmotic gradient between the medullary interstitium and the lumen
Regulation by Arginine Vasopressin
AVP increases water permeability in all nephron segments beyond the DCT
AVP, via cAMP, causes vesicles containing AQP2 to fuse with apical membranes of principal cells of collecting tubules and ducts
AVP increases NaCl reabsorption in the outer medulla and urea reabsorption in the IMCD, enhancing urinary concentrating ability
References
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Chapter 39: Transport of Acids and Bases
Acid-Base Balance and the Overall Renal Handling of Acid
Whereas the lungs excrete the large amount of CO2 formed by metabolism, the kidneys are crucial for excreting nonvolatile acids
To maintain acid-base balance, the kidney must not only reabsorb virtually all filtered but also secrete generated nonvolatile acids
Secreted H+ titrates to CO2 ( reabsorption) and also titrates filtered buffers and endogenously produced NH3
Titration of Filtered (“ Reabsorption”)
Titration of Filtered Buffers (Titratable-Acid Formation)
Titration of Filtered and Secreted NH3 (Ammonium Excretion)
Acid-Base Transport by Different Segments of the Nephron
The nephron reclaims virtually all the filtered in the proximal tubule (~80%), thick ascending limb (~10%), and distal nephron (~10%)
The nephron generates new , mostly in the proximal tubule
Formation of Titratable Acid
Excretion
Acid-Base Transport at the Cellular and Molecular Levels
H+ moves across the apical membrane from tubule cell to lumen by Na-H exchange, electrogenic H pumping, and K-H pumping
Na-H Exchanger
Electrogenic H Pump
H-K Exchange Pump
CAs in the lumen and cytosol stimulate H+ secretion by accelerating the interconversion of CO2 and
Apical CA (CA IV)
Cytoplasmic CA (CA II)
Basolateral CA (CA IV and CA XII)
Inhibition of CA
efflux across the basolateral membrane takes place by electrogenic Na/HCO3 cotransport and Cl-HCO3 exchange
Electrogenic Na/HCO3 Cotransport
Cl-HCO3 Exchange
is synthesized by proximal tubules, partly reabsorbed in the loop of Henle, and secreted passively into papillary collecting ducts
Regulation of Renal Acid Secretion
Respiratory acidosis stimulates renal H+ secretion
Metabolic acidosis stimulates both proximal H+ secretion and NH3 production
Metabolic alkalosis reduces proximal H+ secretion and, in the CCT, may even provoke secretion
A rise in GFR increases delivery to the tubules, enhancing reabsorption (glomerulotubular balance for )
Extracellular volume contraction—via ANG II, aldosterone, and sympathetic activity—stimulates renal H+ secretion
Hypokalemia increases renal H+ secretion
Both glucocorticoids and mineralocorticoids stimulate acid secretion
Diuretics can change H+ secretion, depending on how they affect transepithelial voltage, ECF volume, and plasma [K+]
References
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Chapter 40: Integration of Salt and Water Balance
Sodium Balance
Water Balance
Control of Extracellular Fluid Volume
In the steady state, Na+ intake via the gastrointestinal tract equals Na+ output from renal and extrarenal pathways
The kidneys increase Na+ excretion in response to an increase in ECF volume, not to an increase in extracellular Na+ concentration
It is not the ECF volume as a whole, but the effective circulating volume, that regulates Na+ excretion
Decreases in effective circulating volume trigger four parallel effector pathways to decrease renal Na+ excretion
Increased activity of the renin-angiotensin-aldosterone axis is the first of four parallel pathways that correct a low effective circulating volume
Increased sympathetic nerve activity, increased AVP, and decreased ANP are the other three parallel pathways that correct a low effective circulating volume
Renal Sympathetic Nerve Activity
Arginine Vasopressin (Antidiuretic Hormone)
Atrial Natriuretic Peptide
High arterial pressure raises Na+ excretion by hemodynamic mechanisms, independent of changes in effective circulating volume
Large and Acute Decrease in Arterial Blood Pressure
Large Increase in Arterial Pressure
Control of Water Content (Extracellular Osmolality)
Increased plasma osmolality stimulates hypothalamic osmoreceptors that trigger the release of AVP, inhibiting water excretion
Hypothalamic neurons synthesize AVP and transport it along their axons to the posterior pituitary, where they store it in nerve terminals prior to release
Increased osmolality stimulates a second group of osmoreceptors that trigger thirst, which promotes water intake
Several nonosmotic stimuli also enhance AVP secretion
Reduced Effective Circulating Volume
Volume Expansion
Pregnancy
Other Factors
Decreased effective circulating volume and low arterial pressure also trigger thirst
Defense of the effective circulating volume usually has priority over defense of osmolality
References
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Section VII: The Gastrointestinal System
Chapter 41: Organization of the Gastrointestinal System
Overview of Digestive Processes
The gastrointestinal tract is a tube that is specialized along its length for the sequential processing of food
Assimilation of dietary food substances requires digestion as well as absorption
Digestion requires enzymes secreted in the mouth, stomach, pancreas, and small intestine
Ingestion of food initiates multiple endocrine, neural, and paracrine responses
In addition to its function in nutrition, the GI tract plays important roles in excretion, fluid and electrolyte balance, and immunity
Regulation of Gastrointestinal Function
The ENS is a “minibrain” with sensory neurons, interneurons, and motor neurons
ACh, peptides, and bioactive amines are the ENS neurotransmitters that regulate epithelial and motor function
The brain-gut axis is a bidirectional system that controls GI function via the ANS, GI hormones, and the immune system
Gastrointestinal Motility
Tonic and rhythmic contractions of smooth muscle are responsible for churning, peristalsis, and reservoir action
Segments of the GI tract have both longitudinal and circular arrays of muscles and are separated by sphincters that consist of specialized circular muscles
Location of a sphincter determines its function
Upper Esophageal Sphincter
Lower Esophageal Sphincter
Pyloric Sphincter
Ileocecal Sphincter
Internal and External Anal Sphincters
Motility of the small intestine achieves both churning and propulsive movement, and its temporal pattern differs in the fed and fasted states
Motility of the large intestine achieves both propulsive movement and a reservoir function
References
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Chapter 42: Gastric Function
Functional Anatomy of the Stomach
The mucosa is composed of surface epithelial cells and glands
With increasing rates of secretion of gastric juice, the H+ concentration rises and the Na+ concentration falls
The proximal portion of the stomach secretes acid, pepsinogens, intrinsic factor, bicarbonate, and mucus, whereas the distal part releases gastrin and somatostatin
Corpus
Antrum
The stomach accommodates food, mixes it with gastric secretions, grinds it, and empties the chyme into the duodenum
Acid Secretion
The parietal cell has a specialized tubulovesicular structure that increases apical membrane area when the cell is stimulated to secrete acid
An H-K pump is responsible for gastric acid secretion by parietal cells
Three secretagogues (acetylcholine, gastrin, and histamine) directly and indirectly induce acid secretion by parietal cells
The three acid secretagogues act through either Ca2+/diacylglycerol or cAMP
Antral and duodenal G cells release gastrin, whereas ECL cells in the corpus release histamine
Gastric D cells release somatostatin, the central inhibitor of acid secretion
Several enteric hormones (“enterogastrone”) and prostaglandins inhibit gastric acid secretion
A meal triggers three phases of acid secretion
Basal State
Cephalic Phase
Gastric Phase
Intestinal Phase
Pepsinogen Secretion
Chief cells, triggered by both cAMP and Ca2+ pathways, secrete multiple pepsinogens that initiate protein digestion
Agonists Acting via cAMP
Agonists Acting via Ca2+
Low pH is required for both pepsinogen activation and pepsin activity
Protection of the Gastric Surface Epithelium and Neutralization of Acid in the Duodenum
Vagal stimulation and irritation stimulate gastric mucous cells to secrete mucins
Gastric surface cells secrete , stimulated by acetylcholine, acids, and prostaglandins
Mucus protects the gastric surface epithelium by trapping an -rich fluid near the apical border of these cells
Acid entry into the duodenum induces S cells to release secretin, triggering the pancreas and duodenum to secrete
Filling and Emptying of the Stomach
Gastric motor activity plays a role in filling, churning, and emptying
Filling of the stomach is facilitated by both receptive relaxation and gastric accommodation
The stomach churns its contents until the particles are small enough to be gradually emptied into the duodenum
References
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Chapter 43: Pancreatic and Salivary Glands
Overview of Exocrine Gland Physiology
The pancreas and major salivary glands are compound exocrine glands
Acinar cells are specialized protein-synthesizing cells
Duct cells are epithelial cells specialized for fluid and electrolyte transport
Goblet cells contribute to mucin production in exocrine glands
Pancreatic Acinar Cell
The acinar cell secretes digestive proteins in response to stimulation
Acetylcholine and cholecystokinin mediate the regulated secretion of proteins by pancreatic acinar cells
Ca2+ is the major second messenger for the secretion of proteins by pancreatic acinar cells
Ca2+
cAMP
Effectors
In addition to proteins, the pancreatic acinar cell secretes a plasma-like fluid
Pancreatic Duct Cell
The pancreatic duct cell secretes isotonic NaHCO3
Secretin (via cAMP) and ACh (via Ca2+) stimulate secretion by pancreatic ducts
Apical membrane chloride channels are important sites of neurohumoral regulation
Pancreatic duct cells may also secrete glycoproteins
Composition, Function, and Control of Pancreatic Secretion
Pancreatic juice is a protein-rich, alkaline secretion
In the fasting state, levels of secreted pancreatic enzymes oscillate at low levels
CCK from duodenal I cells stimulates acinar enzyme secretion, and secretin from S cells stimulates and fluid secretion by ducts
A meal triggers cephalic, gastric, and intestinal phases of pancreatic secretion
Cephalic Phase
Gastric Phase
Intestinal Phase
The pancreas has large reserves of digestive enzymes for carbohydrates and proteins, but not for lipids
Fat in the distal part of the small intestine inhibits pancreatic secretion
Several mechanisms protect the pancreas from autodigestion
Salivary Acinar Cell
Different salivary acinar cells secrete different proteins
Cholinergic and adrenergic neural pathways are the most important physiological activators of regulated secretion by salivary acinar cells
Both cAMP and Ca2+ mediate salivary acinar secretion
Salivary Duct Cell
Salivary duct cells produce a hypotonic fluid that is poor in NaCl and rich in KHCO3
Parasympathetic stimulation decreases Na+ absorption, whereas aldosterone increases Na+ absorption by duct cells
Salivary duct cells also secrete and take up proteins
Composition, Function, and Control of Salivary Secretion
Depending on protein composition, salivary secretions can be serous, seromucous, or mucous
At low flow rates, the saliva is hypotonic and rich in K+, whereas at higher flow rates, its composition approaches that of plasma
Parasympathetic stimulation increases salivary secretion
Parasympathetic Control
Sympathetic Control
References
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Chapter 44: Intestinal Fluid and Electrolyte Movement
Functional Anatomy
Both the small and large intestine absorb and secrete fluid and electrolytes, whereas only the small intestine absorbs nutrients
The small intestine has a villus-crypt organization, whereas the colon has surface epithelial cells with interspersed crypts
The surface area of the small intestine is amplified by folds, villi, and microvilli; amplification is less marked in the colon
Overview of Fluid and Electrolyte Movement in the Intestines
The small intestine absorbs ~6.5 L/day of an ~8.5-L fluid load that is presented to it, and the colon absorbs ~1.9 L/day
The small intestine absorbs net amounts of water, Na+, Cl−, and K+ and secretes , whereas the colon absorbs net amounts of water, Na+, and Cl− and secretes both K+ and
The intestines absorb and secrete solutes by both active and passive mechanisms
Intestinal fluid movement is always coupled to solute movement, and sometimes solute movement is coupled to fluid movement by solvent drag
The resistance of the tight junctions primarily determines the transepithelial resistance of intestinal epithelia
Cellular Mechanisms of Na+ Absorption
Na/glucose and Na/amino-acid cotransport in the small intestine is a major mechanism for postprandial Na+ absorption
Electroneutral Na-H exchange in the duodenum and jejunum is responsible for Na+ absorption that is stimulated by luminal alkalinity
Parallel Na-H and Cl-HCO3 exchange in the ileum and proximal part of the colon is the primary mechanism of Na+ absorption during the interdigestive period
Epithelial Na+ channels are the primary mechanism of “electrogenic” Na+ absorption in the distal part of the colon
Cellular Mechanisms of Cl− Absorption and Secretion
Voltage-dependent Cl− absorption represents coupling of Cl− absorption to electrogenic Na+ absorption in both the small intestine and the large intestine
Electroneutral Cl-HCO3 exchange results in Cl− absorption and secretion in the ileum and colon
Parallel Na-H and Cl-HCO3 exchange in the ileum and the proximal part of the colon mediates Cl− absorption during the interdigestive period
Electrogenic Cl− secretion occurs in crypts of both the small and the large intestine
Cellular Mechanisms of K+ Absorption and Secretion
Overall net transepithelial K+ movement is absorptive in the small intestine and secretory in the colon
K+ absorption in the small intestine probably occurs via solvent drag
Passive K+ secretion is the primary mechanism for net colonic secretion
Active K+ secretion is also present throughout the large intestine and is induced both by aldosterone and by cAMP
Aldosterone
cAMP and Ca2+
Active K+ absorption takes place only in the distal portion of the colon and is energized by an apical H-K pump
Regulation of Intestinal Ion Transport
Chemical mediators from the enteric nervous system, endocrine cells, and immune cells in the lamina propria may be either secretagogues or absorptagogues
Secretagogues can be classified by their type and by the intracellular second-messenger system that they stimulate
Mineralocorticoids, glucocorticoids, and somatostatin are absorptagogues
References
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Chapter 45: Nutrient Digestion and Absorption
Carbohydrate Digestion
Carbohydrates, providing ~45% of total energy needs of Western diets, require hydrolysis to monosaccharides before absorption
Luminal digestion begins with the action of salivary amylase and finishes with pancreatic amylase
“Membrane digestion” involves hydrolysis of oligosaccharides to monosaccharides by brush-border disaccharidases
Carbohydrate Absorption
SGLT1 is responsible for the Na+-coupled uptake of glucose and galactose across the apical membrane
The GLUT transporters mediate the facilitated diffusion of fructose at the apical membrane and of all three monosaccharides at the basolateral membrane
Protein Digestion
Proteins require hydrolysis to oligopeptides or amino acids before absorption in the small intestine
Luminal digestion of protein involves both gastric and pancreatic proteases, and yields amino acids and oligopeptides
Brush-border peptidases fully digest some oligopeptides to amino acids, whereas cytosolic peptidases digest oligopeptides that directly enter the enterocyte
Protein, Peptide, and Amino-Acid Absorption
Absorption of whole protein by apical endocytosis occurs primarily during the neonatal period
The apical absorption of dipeptides, tripeptides, and tetrapeptides occurs via an H+-driven cotransporter
Amino acids enter enterocytes via one or more group-specific apical transporters
At the basolateral membrane, amino acids exit enterocytes via Na+-independent transporters and enter via Na+-dependent transporters
Lipid Digestion
Natural lipids of biological origin are sparingly soluble in water
Dietary lipids are predominantly TAGs
Endogenous lipids are phospholipids and cholesterol from bile and membrane lipids from desquamated intestinal epithelial cells
The mechanical disruption of dietary lipids in the mouth and stomach produces an emulsion of lipid particles
Lingual and gastric (acid) lipase initiate lipid digestion
Pancreatic (alkaline) lipase, colipase, milk lipase, and other esterases—aided by bile salts—complete lipid hydrolysis in the duodenum and jejunum
Lipid Absorption
Products of lipolysis enter the bulk water phase of the intestinal lumen as vesicles, mixed micelles, and monomers
Lipids diffuse as mixed micelles and monomers through unstirred layers before crossing the jejunal enterocyte brush border
The enterocyte re-esterifies lipid components and assembles them into chylomicrons
The enterocyte secretes chylomicrons into the lymphatics during feeding and secretes VLDLs during fasting
Digestion and Absorption of Vitamins and Minerals
Intestinal absorption of fat-soluble vitamins follows the pathways of lipid absorption and transport
Dietary folate (PteGlu7) must be deconjugated by a brush-border enzyme before absorption by an anion exchanger at the apical membrane
Vitamin B12 (cobalamin) binds to haptocorrin in the stomach and then to intrinsic factor in the small intestine before endocytosis by enterocytes in the ileum
Ca2+ absorption, regulated primarily by vitamin D, occurs by active transport in the duodenum and by diffusion throughout the small intestine
Mg2+ absorption occurs by an active process in the ileum
Heme and nonheme iron are absorbed in the duodenum by distinct cellular mechanisms
Nonheme Iron
Heme Iron
Nutritional Requirements
No absolute daily requirement for carbohydrate or fat intake exists
The daily protein requirement for adult humans is typically 0.8 g/kg body weight but is higher in pregnant women, postsurgical patients, and athletes
Minerals and vitamins are not energy sources but are necessary for certain enzymatic reactions, for protein complexes, or as precursors for biomolecules
Minerals
Vitamins
Excessive intake of vitamins and minerals has mixed effects on bodily function
References
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Chapter 46: Hepatobiliary Function
Overview of Liver Physiology
The liver biotransforms and degrades substances taken up from blood and either returns them to the circulation or excretes them into bile
The liver stores carbohydrates, lipids, vitamins, and minerals; it synthesizes carbohydrates, protein, and intermediary metabolites
Functional Anatomy of the Liver and Biliary Tree
Hepatocytes are secretory epithelial cells separating the lumen of bile canaliculi from the fenestrated endothelium of sinusoids
The liver contains endothelial cells, macrophages (Kupffer cells), and stellate cells (Ito cells) within the sinusoidal spaces
The liver has a dual blood supply, but a single venous drainage system
Hepatocytes can be thought of as being arranged as classic hepatic lobules, portal lobules, or acinar units
Periportal hepatocytes specialize in oxidative metabolism, whereas pericentral hepatocytes detoxify drugs
Bile drains from canaliculi into small terminal ductules, then into larger ducts, and eventually, via a single common duct, into the duodenum
Uptake, Processing, and Secretion of Compounds by Hepatocytes
An Na-K pump at the basolateral membranes of hepatocytes provides the energy for transporting a wide variety of solutes via channels and transporters
Hepatocytes take up bile acids, other organic anions, and organic cations across their basolateral (sinusoidal) membranes
Bile Acids and Salts
Organic Anions
Bilirubin
Organic Cations
Neutral Organic Compounds
Inside the hepatocyte, the basolateral-to-apical movement of many compounds occurs by protein-bound or vesicular routes
Bile Salts
Bilirubin
In phase I of the biotransformation of organic anions and other compounds, hepatocytes use mainly cytochrome P-450 enzymes
In phase II of biotransformation, conjugation of phase I products makes them more water soluble for secretion into blood or bile
In phase III of biotransformation, hepatocytes excrete products of phase I and II into bile or sinusoidal blood
The interactions of xenobiotics with nuclear receptors control phase I, II, and III
Hepatocytes secrete bile acids, organic anions, organic cations, and lipids across their apical (canalicular) membranes
Bile Salts
Organic Anions
Organic Cations
Biliary Lipids
Hepatocytes take up proteins across their basolateral membranes by receptor-mediated endocytosis and fluid-phase endocytosis
Bile Formation
The secretion of canalicular bile is active and isotonic
Major organic molecules in bile include bile acids, cholesterol, and phospholipids
Canalicular bile flow has a constant component driven by the secretion of small organic molecules and a variable component driven by the secretion of bile acids
Bile Acid–Independent Flow in the Canaliculi
Bile Acid–Dependent Flow in the Canaliculi
Secretin stimulates the cholangiocytes of ductules and ducts to secrete a watery, -rich fluid
The gallbladder stores bile and delivers it to the duodenum during a meal
The relative tones of the gallbladder and sphincter of Oddi determine whether bile flows from the common hepatic duct into the gallbladder or into the duodenum
Enterohepatic Circulation of Bile Acids
The enterohepatic circulation of bile acids is a loop consisting of secretion by the liver, reabsorption by the intestine, and return to the liver in portal blood for repeat secretion into bile
Efficient intestinal conservation of bile acids depends on active apical absorption in the terminal ileum and passive absorption throughout the intestinal tract
The Liver as a Metabolic Organ
The liver can serve as either a source or a sink for glucose
The liver synthesizes a variety of important plasma proteins (e.g., albumin, coagulation factors, and carriage proteins) and metabolizes dietary amino acids
Protein Synthesis
Amino-Acid Uptake
Amino-Acid Metabolism
The liver obtains dietary triacylglycerols and cholesterol by taking up remnant chylomicrons via receptor-mediated endocytosis
Cholesterol, synthesized primarily in the liver, is an important component of cell membranes and serves as a precursor for bile acids and steroid hormones
Synthesis of Cholesterol
The liver is the central organ for cholesterol homeostasis and for the synthesis and degradation of LDL
The liver is the prime site for metabolism and storage of the fat-soluble vitamins A, D, E, and K
Vitamin A
Vitamin D
Vitamin E
Vitamin K
The liver stores copper and iron
Copper
Iron
References
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Journal Articles
Section VIII: The Endocrine System
Chapter 47: Organization of Endocrine Control
Principles of Endocrine Function
Chemical signaling can occur through endocrine, paracrine, or autocrine pathways
Endocrine Glands
Paracrine Factors
Hormones may be peptides, metabolites of single amino acids, or metabolites of cholesterol
Hormones can circulate either free or bound to carrier proteins
Immunoassays allow measurement of circulating hormones
Hormones can have complementary and antagonistic actions
Endocrine regulation occurs through feedback control
Endocrine regulation can involve hierarchic levels of control
The anterior pituitary regulates reproduction, growth, energy metabolism, and stress responses
The posterior pituitary regulates water balance and uterine contraction
Peptide Hormones
Specialized endocrine cells synthesize, store, and secrete peptide hormones
Peptide hormones bind to cell-surface receptors and activate a variety of signal-transduction systems
G Proteins Coupled to Adenylyl Cyclase
G Proteins Coupled to Phospholipase C
G Proteins Coupled to Phospholipase A2
Guanylyl Cyclase
Receptor Tyrosine Kinases
Tyrosine Kinase–Associated Receptors
Amine Hormones
Amine hormones are made from tyrosine and tryptophan
Amine hormones act via surface receptors
Steroid and Thyroid Hormones
Cholesterol is the precursor for the steroid hormones: cortisol, aldosterone, estradiol, progesterone, and testosterone
Steroid hormones bind to intracellular receptors that regulate gene transcription
Thyroid hormones bind to intracellular receptors that regulate metabolic rate
Steroid and thyroid hormones can also have nongenomic actions
References
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Chapter 48: Endocrine Regulation of Growth and Body Mass
Growth Hormone
GH, secreted by somatotrophs in the anterior pituitary, is the principal endocrine regulator of growth
GH is in a family of hormones with overlapping activity
Somatotrophs secrete GH in pulses
GH secretion is under hierarchical control by GH–releasing hormone and somatostatin
GH-Releasing Hormone
GHRH Receptor
Ghrelin
Ghrelin Receptor
Somatostatin
SS Receptor
Both GH and IGF-1 negatively feed back on GH secretion by somatotrophs
GH has short-term anti-insulin metabolic effects as well as long-term growth-promoting effects mediated by IGF-1
GH Receptor
Short-Term Effects of GH
Long-Term Effects of GH via IGF-1
Growth-Promoting Hormones
IGF-1 is the principal mediator of the growth-promoting action of GH
IGF-2 acts similarly to IGF-1 but is less dependent on GH
Growth rate parallels plasma levels of IGF-1 except early and late in life
Thyroid hormones, steroids, and insulin also promote growth
Thyroid Hormones
Sex Steroids
Glucocorticoids
Insulin
The musculoskeletal system responds to growth stimuli of the GHRH–GH–IGF-1 axis
Regulation of Body Mass
The balance between energy intake and expenditure determines body mass
Energy expenditure comprises resting metabolic rate, activity-related energy expenditure, and diet-induced thermogenesis
Hypothalamic centers control the sensations of satiety and hunger
Leptin tells the brain how much fat is stored
Leptin and insulin are anorexigenic (i.e., satiety) signals for the hypothalamus
POMC Neurons
NPY/AgRP Neurons
Secondary Neurons
Ghrelin is an orexigenic signal for the hypothalamus
Plasma nutrient levels and enteric hormones are short-term factors that regulate feeding
References
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Chapter 49: The Thyroid Gland
Synthesis of Thyroid Hormones
T4 and T3, made by iodination of tyrosine residues on thyroglobulin, are stored as part of thyroglobulin molecules in thyroid follicles
Follicular cells take up iodinated thyroglobulin, hydrolyze it, and release T4 and T3 into the blood for binding to plasma proteins
Peripheral tissues deiodinate T4 to produce T3
Action of Thyroid Hormones
Thyroid hormones act through nuclear receptors in target tissues
Thyroid hormones can also act by nongenomic pathways
Thyroid hormones increase basal metabolic rate by stimulating futile cycles of catabolism and anabolism
Carbohydrate Metabolism
Protein Metabolism
Lipid Metabolism
Na-K Pump Activity
Thermogenesis
Thyroid hormones are essential for normal growth and development
Hypothalamic-Pituitary-Thyroid Axis
TRH from the hypothalamus stimulates thyrotrophs of the anterior pituitary to secrete TSH, which stimulates T4/T3 synthesis
Thyrotropin-Releasing Hormone
TRH Receptor
Thyrotropin
TSH Receptor
T3 exerts negative feedback on TSH secretion
References
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Chapter 50: The Adrenal Gland
The Adrenal Cortex: Cortisol
Cortisol is the primary glucocorticoid hormone in humans
Target Tissues
Actions
The adrenal zona fasciculata converts cholesterol to cortisol
Cortisol binds to a cytoplasmic receptor that translocates to the nucleus and modulates transcription in multiple tissues
Corticotropin-releasing hormone from the hypothalamus stimulates anterior pituitary corticotrophs to secrete ACTH, which stimulates the adrenal cortex to synthesize and secrete cortisol
Corticotropin-Releasing Hormone
CRH Receptor
Arginine Vasopressin
Adrenocorticotropic Hormone
ACTH Receptor
Cortisol exerts negative feedback on CRH and ACTH secretion, whereas stress acts through higher CNS centers to stimulate the axis
Feedback to the Anterior Pituitary
Feedback to the Hypothalamus
Control by a Higher CNS Center
The Adrenal Cortex: Aldosterone
The mineralocorticoid aldosterone is the primary regulator of salt balance and extracellular volume
The glomerulosa cells of the adrenal cortex synthesize aldosterone from cholesterol via progesterone
Aldosterone stimulates Na+ reabsorption and K+ excretion by the renal tubule
Angiotensin II, K+, and ACTH all stimulate aldosterone secretion
Angiotensin II
Potassium
Adrenocorticotropic Hormone
Aldosterone exerts indirect negative feedback on the renin-angiotensin axis by increasing effective circulating volume and by lowering plasma [K+]
Renin-Angiotensin Axis
Potassium
Role of Aldosterone in Normal Physiology
Role of Aldosterone in Disease
The Adrenal Medulla
The adrenal medulla bridges the endocrine and sympathetic nervous systems
Only chromaffin cells of the adrenal medulla have the enzyme for epinephrine synthesis
Catecholamines bind to α and β adrenoceptors on the cell surface and act through heterotrimeric G proteins
The CNS-epinephrine axis provides integrated control of multiple functions
References
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Chapter 51: The Endocrine Pancreas
The islets of Langerhans are endocrine and paracrine tissue
Insulin
Insulin replenishes fuel reserves in muscle, liver, and adipose tissue
β cells synthesize and secrete insulin
The Insulin Gene
Insulin Synthesis
Secretion of Insulin, Proinsulin, and C Peptide
Glucose is the major regulator of insulin secretion
Metabolism of glucose by the β cell triggers insulin secretion
Neural and humoral factors modulate insulin secretion
Exercise
Feeding
The insulin receptor is a receptor tyrosine kinase
High levels of insulin lead to downregulation of insulin receptors
In liver, insulin promotes conversion of glucose to glycogen stores or to triacylglycerols
Glycogen Synthesis and Glycogenolysis
Glycolysis and Gluconeogenesis
Lipogenesis
Protein Metabolism
In muscle, insulin promotes the uptake of glucose and its storage as glycogen
In adipocytes, insulin promotes glucose uptake and conversion to TAGs for storage
Glucagon
Pancreatic α cells secrete glucagon in response to ingested protein
Pancreatic α Cells
Intestinal L Cells
Glucagon, acting through cAMP, promotes the synthesis of glucose by the liver
Glucagon promotes oxidation of fat in the liver, which can lead to ketogenesis
Somatostatin
Somatostatin inhibits the secretion of growth hormone, insulin, and other hormones
References
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Journal Articles
Chapter 52: The Parathyroid Glands and Vitamin D
Calcium and Phosphate Balance
The gut, kidneys, and bone regulate calcium balance
The gut, kidneys, and bone also regulate phosphate balance
Physiology of Bone
Dense cortical bone and the more reticulated trabecular bone are the two major bone types
The extracellular matrix forms the nidus for the nucleation of hydroxyapatite crystals
Bone remodeling depends on the closely coupled activities of osteoblasts and osteoclasts
Parathyroid Hormone
Plasma Ca2+ regulates the synthesis and secretion of PTH
PTH Synthesis and Vitamin D
Processing of PTH
Metabolism of PTH
High plasma [Ca2+] inhibits the synthesis and release of PTH
The PTH receptor couples via G proteins to either adenylyl cyclase or phospholipase C
In the kidney, PTH promotes Ca2+ reabsorption, phosphate loss, and 1-hydroxylation of 25-hydroxyvitamin D
Stimulation of Ca2+ Reabsorption
Inhibition of Phosphate Reabsorption
Stimulation of the Last Step of Synthesis of 1,25- Dihydroxyvitamin D
In bone, PTH can promote net resorption or net deposition
Bone Resorption by Indirect Stimulation of Osteoclasts
Bone Resorption by Reduction in Bone Matrix
Bone Deposition
Vitamin D
The active form of vitamin D is its 1,25-dihydroxy metabolite
Vitamin D, by acting on the small intestine and kidney, raises plasma [Ca2+] and thus promotes bone mineralization
Small Intestine
Kidney
Bone
Calcium ingestion lowers—whereas phosphate ingestion raises—levels of both PTH and 1,25-dihydroxyvitamin D
Calcium Ingestion
Phosphate Ingestion
Calcitonin and Other Hormones
Calcitonin inhibits osteoclasts, but its effects are transitory
Sex steroid hormones promote bone deposition, whereas glucocorticoids promote resorption
PTHrP, encoded by a gene that is entirely distinct from that for PTH, can cause hypercalcemia in certain malignancies
References
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Section IX: The Reproductive System
Chapter 53: Sexual Differentiation
Genetic Aspects of Sexual Differentiation
Meiosis occurs only in germ cells and gives rise to male and female gametes
Fertilization of an oocyte by an X- or Y-bearing sperm establishes the zygote’s genotypic sex
Genotypic sex determines differentiation of the indifferent gonad into either an ovary or a testis
The testis-determining gene is located on the Y chromosome
Endocrine and paracrine messengers modulate phenotypic differentiation
Differentiation of the Gonads
Primordial germ cells migrate from the yolk sac to the primordial gonad
The primitive testis develops from the medulla of the primordial gonad
The primitive ovary develops from the cortex of the primordial gonad
Development of the Accessory Sex Organs
The embryonic gonad determines the development of the internal genitalia and the external sexual phenotype
Embryos of both sexes have a double set of embryonic genital ducts
In males, the wolffian ducts become the epididymis, vas deferens, seminal vesicles, and ejaculatory duct
In females, the müllerian ducts become the fallopian tubes, the uterus, and the upper third of the vagina
In males, development of the wolffian ducts requires testosterone
In males, antimüllerian hormone causes regression of the müllerian ducts
Differentiation of the External Genitalia
The urogenital sinus develops into the urinary bladder, the urethra, and, in females, the vestibule of the vagina
The external genitalia of both sexes develop from common anlagen
Endocrine and Paracrine Control of Sexual Differentiation
The SRY gene triggers development of the testis, which makes the androgens and AMH necessary for male sexual differentiation
Testosterone Production
Androgen Receptor
DHT Formation
Antimüllerian Hormone
Androgens direct the male pattern of sexual differentiation of the internal ducts, the urogenital sinus, and the external genitalia
Differentiation of the Duct System
Differentiation of the Urogenital Sinus and External Genitalia
Androgens and estrogens influence sexual differentiation of the brain
Puberty
Puberty involves steroid hormones produced by the gonads and the adrenals
Hypothalamic gonadotropin-releasing hormone secretion controls puberty
Multiple factors control the timing of puberty
Androgens and estrogens influence secondary sex characteristics at puberty
Males
Females
The appearance of secondary sex characteristics at puberty completes sexual differentiation and development
References
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Chapter 54: The Male Reproductive System
Hypothalamic-Pituitary-Gonadal Axis
The hypothalamus secretes GnRH, which acts on gonadotrophs in the anterior pituitary
Under the control of GnRH, gonadotrophs in the anterior pituitary secrete LH and FSH
LH stimulates the Leydig cells of the testis to produce testosterone
FSH stimulates Sertoli cells to synthesize hormones that influence Leydig cells and spermatogenesis
The hypothalamic-pituitary-testicular axis is under feedback inhibition by testicular steroids and inhibins
Testosterone
Leydig cells convert cholesterol to testosterone
Adipose tissue, skin, and the adrenal cortex also produce testosterone and other androgens
Testosterone acts on target organs by binding to a nuclear receptor
Metabolism of testosterone occurs primarily in the liver and prostate
Biology of Spermatogenesis and Semen
Spermatogenesis includes mitotic divisions of spermatogonia, meiotic divisions of spermatocytes to spermatids, and maturation to spermatozoa N54-7
The Sertoli cells support spermatogenesis
Sperm maturation occurs in the epididymis
Spermatozoa are the only independently motile cells in the human body
The accessory male sex glands—the seminal vesicles, prostate, and bulbourethral glands—produce the seminal plasma
Male Sex Act
The sympathetic and parasympathetic divisions of the autonomic nervous system control the male genital system
Sympathetic Division of the ANS
Parasympathetic Division of the ANS
Visceral Afferents
Erection is primarily under parasympathetic control
Parasympathetic Innervation
Sympathetic Innervation
Somatic Innervation
Afferent Innervation
Emission is primarily under sympathetic control
Motor Activity of the Duct System
Secretory Activity of the Accessory Glands
Ejaculation is under the control of a spinal reflex
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Chapter 55: The Female Reproductive System
Female reproductive organs include the ovaries and accessory sex organs
Reproductive function in the human female is cyclic
Hypothalamic-Pituitary-Gonadal Axis and Control of the Menstrual Cycle
The human menstrual cycle coordinates changes in both the ovary and endometrium
Follicular/Proliferative Phase
Ovulation
Luteal/Secretory Phase
Menses
The hypothalamic-pituitary-ovarian axis drives the menstrual cycle
Neurons in the hypothalamus release GnRH in a pulsatile fashion
GnRH stimulates gonadotrophs in the anterior pituitary to secrete FSH and LH
The ovarian steroids (estrogens and progestins) feed back on the hypothalamic-pituitary axis
Negative Feedback by Ovarian Steroids
Positive Feedback by Ovarian Steroids
Ovaries produce peptide hormones—inhibins, activins, and follistatins—that modulate FSH secretion
Negative Feedback by the Inhibins
Positive Feedback by the Activins
Modulation of gonadotropin secretion by positive and negative ovarian feedback produces the normal menstrual rhythm
Ovarian Steroids
Starting from cholesterol, the ovary synthesizes estradiol, the major estrogen, and progesterone, the major progestin
Estrogen biosynthesis requires two ovarian cells and two gonadotropins, whereas progestin synthesis requires only a single cell
Estrogens stimulate cellular proliferation and growth of sex organs and other tissues related to reproduction
The Ovarian Cycle: Folliculogenesis, Ovulation, and Formation of the Corpus Luteum
Female reproductive life span is determined by the number of primordial follicles established during fetal life
Primary Oocytes
Primordial Follicles
Primary Follicles
Secondary Follicles
Tertiary Follicles
Graafian Follicles
The oocyte grows and matures during folliculogenesis
FSH and LH stimulate the growth of a cohort of follicles
Each month, one follicle achieves dominance
Estradiol secretion by the dominant follicle triggers the LH surge and thus ovulation
After ovulation, theca and granulosa cells of the follicle differentiate into theca-lutein and granulosa-lutein cells of the corpus luteum
Growth and involution of the corpus luteum produce the rise and fall in estradiol and progesterone during the luteal phase
The Endometrial Cycle
The ovarian hormones drive the morphological and functional changes of the endometrium during the monthly cycle
The Menstrual Phase
The Proliferative Phase
The Secretory Phase
The effective implantation window is 3 to 4 days
Female Sex Act
The female sex response occurs in four distinct phases
Excitement
Plateau
Orgasm
Resolution
Both the sympathetic and the parasympathetic divisions control the female sex response
The female sex response facilitates sperm transport through the female reproductive tract
Menopause
Only a few functioning follicles remain in the ovaries of a menopausal woman
During menopause, levels of the ovarian steroids fall, whereas gonadotropin levels rise
References
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Chapter 56: Fertilization, Pregnancy, and Lactation
Transport of Gametes and Fertilization
Cilia and smooth muscle transport the egg and sperm within the female genital tract
The “capacitation” of the spermatozoa that occurs in the female genital tract enhances the ability of the sperm cell to fertilize the ovum
Fertilization begins as the sperm cell attaches to the zona pellucida and undergoes the acrosomal reaction, and it ends with the fusion of the male and female pronuclei
Implantation of the Developing Embryo
The presence of an embryo leads to decidualization of the endometrium
Uterine secretions nourish the preimplantation embryo, promote growth, and prepare it for implantation
The blastocyst secretes substances that facilitate implantation
During implantation, the blastocyst apposes itself to the endometrium, adheres to epithelial cells, and finally invades the stroma
Apposition
Adhesion
Invasion
Physiology of the Placenta
At the placenta, the space between the fetus’s chorionic villi and the mother’s endometrial wall contains a continuously renewed pool of extravasated maternal blood
Maternal Blood Flow
Fetal Blood Flow
Gases and other solutes move across the placenta
O2 and CO2 Transport
Other Solutes
The placenta makes a variety of peptide hormones, including hCG and human chorionic somatomammotropin
The Maternal-Placental-Fetal Unit
During pregnancy, progesterone and estrogens rise to levels that are substantially higher than their peaks in a normal cycle
After 8 weeks of gestation, the maternal-placental-fetal unit maintains high levels of progesterone and estrogens
Response of the Mother to Pregnancy
Both maternal cardiac output and blood volume increase during pregnancy
Increased levels of progesterone during pregnancy increase alveolar ventilation
Pregnancy increases the demand for dietary protein, iron, and folic acid
Less than one third of the total maternal weight gain during pregnancy represents the fetus
Parturition
Human birth usually occurs at around the 40th week of gestation
Parturition occurs in distinct stages, numbered 0 to 3
Stage 0—Quiescence
Stage 1—Transformation/Activation
Stage 2—Active Labor
Stage 3—Involution
Reciprocal decreases in progesterone receptors and increases in estrogen receptors are critical for the onset of labor
Signals from the fetus may initiate labor
PGs initiate uterine contractions, and both PGs and OT sustain labor
Prostaglandins
Oxytocin
Relaxin
Mechanical Factors
Positive Feedback
Lactation
The epithelial alveolar cells of the mammary gland secrete the complex mixture of sugars, proteins, lipids, and other substances that constitute milk
PRL is essential for milk production, and suckling is a powerful stimulus for PRL secretion
OT and psychic stimuli initiate milk ejection (“let-down”)
Suckling inhibits the ovarian cycle
References
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Chapter 57: Fetal and Neonatal Physiology
Biology of Fetal Growth
Two distinct circulations—fetoplacental and uteroplacental—underlie the transfer of gases and nutrients
Growth occurs by hyperplasia and hypertrophy
Growth depends primarily on genetic factors during the first half of gestation and on epigenetic factors thereafter
Increases in placental mass parallel periods of rapid fetal growth
Insulin, the insulin-like growth factors, and thyroxine stimulate fetal growth
Glucocorticoids and Insulin
Insulin-Like Growth Factors
Epidermal Growth Factor
Thyroid Hormones
Peptide Hormones
Many fetal tissues produce red blood cells early in gestation
The fetal gastrointestinal and urinary systems excrete products into the amniotic fluid by midpregnancy
A surge in protein synthesis, with an increase in muscle mass, is a major factor in the rapid fetal weight gain during the third trimester
Fetal lipid stores increase rapidly during the third trimester
Development and Maturation of the Cardiopulmonary System
Fetal lungs develop by repetitive branching of both bronchial and pulmonary arterial trees
An increase in cortisol, with other hormones, triggers surfactant production in the third trimester
Fetal respiratory movements begin near the end of the first trimester but wane just before birth
The fetal circulation has four unique pathways—placenta, ductus venosus, foramen ovale, and ductus arteriosus—to facilitate gas and nutrient exchange
Placenta
Ductus Venosus
Foramen Ovale
Ductus Arteriosus
Cardiopulmonary Adjustments at Birth
Loss of the placental circulation requires the newborn to breathe on its own
Mild hypoxia and hypercapnia, as well as tactile stimuli and cold skin, trigger the first breath
At birth, removal of the placenta increases systemic vascular resistance, whereas lung expansion decreases pulmonary vascular resistance
Removal of the Placental Circulation
Increase in Pulmonary Blood Flow
Closure of the ductus venosus within the first days of life forces portal blood to perfuse the liver
Closure of the foramen ovale occurs as left atrial pressure begins to exceed right atrial pressure
Closure of the ductus arteriosus completes the separation between the pulmonary and systemic circulations
Neonatal Physiology
Although the newborn is prone to hypothermia, nonshivering thermogenesis in brown fat helps to keep the neonate warm
The neonate mobilizes glucose and FAs soon after delivery
Carbohydrate Metabolism
Fat Metabolism
Metabolic Rate
Breast milk from a mother with a balanced diet satisfies all of the infant’s nutritional requirements during the first several months of life
The neonate is at special risk of developing fluid and acid-base imbalances
Humoral and cellular immune responses begin at early stages of development in the fetus
Fetus
Neonate
In premature newborns, immaturity of organ systems and fragility of homeostatic mechanisms exacerbate postnatal risks
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Section X: Physiology of Everyday Life
Chapter 58: Metabolism
Forms of Energy
Energy Balance
Energy input to the body is the sum of energy output and storage
The inefficiency of chemical reactions leads to loss of the energy available for metabolic processes
Free energy, conserved as high-energy bonds in ATP, provides the energy for cellular functions
Energy Interconversion From Cycling between 6-Carbon and 3-Carbon Molecules
Glycolysis converts the 6-carbon glucose molecule to two 3-carbon pyruvate molecules
Gluconeogenesis converts nonhexose precursors to the 6-carbon glucose molecule
Reciprocal regulation of glycolysis and gluconeogenesis minimizes futile cycling
Allosteric Regulation
Transcriptional Regulation
Cells can convert glucose or amino acids into FAs
The body permits only certain energy interconversions
Energy Capture (Anabolism)
After a carbohydrate meal, the body burns some ingested glucose and incorporates the rest into glycogen or TAGs
Liver
Muscle
Adipose Tissue
After a protein meal, the body burns some ingested amino acids and incorporates the rest into proteins
After a fatty meal, the body burns some ingested FAs and incorporates the rest into TAGs
Energy Liberation (Catabolism)
The first step in energy catabolism is to break down glycogen or TAGs to simpler compounds
Skeletal Muscle
Liver
Adipocytes
The second step in TAG catabolism is β-oxidation of FAs
The final common steps in oxidizing carbohydrates, TAGs, and proteins to CO2 are the citric acid cycle and oxidative phosphorylation
Citric Acid Cycle
Oxidative Phosphorylation
Ketogenesis
Oxidizing different fuels yields similar amounts of energy per unit O2 consumed
Integrative Metabolism During Fasting
During an overnight fast, glycogenolysis and gluconeogenesis maintain plasma glucose levels
Requirement for Glucose
Gluconeogenesis versus Glycogenolysis
Gluconeogenesis: The Cori Cycle
Gluconeogenesis: The Glucose-Alanine Cycle
Lipolysis
Starvation beyond an overnight fast enhances gluconeogenesis and lipolysis
Enhanced Gluconeogenesis
Enhanced Lipolysis
Prolonged starvation moderates proteolysis but accelerates lipolysis, thereby releasing ketone bodies
Decreased Proteolysis
Decreased Hepatic Gluconeogenesis
Increased Renal Gluconeogenesis
Increased Lipolysis and Ketogenesis
References
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Chapter 59: Regulation of Body Temperature
Heat and Temperature: Advantages of Homeothermy
Homeotherms maintain their activities over a wide range of environmental temperatures
Body core temperature depends on time of day, physical activity, time in the menstrual cycle, and age
The body’s rate of heat production can vary from ~70 kcal/hr at rest to 600 kcal/hr during exercise
Modes of Heat Transfer
Maintaining a relatively constant body temperature requires a fine balance between heat production and heat losses
Heat moves from the body core to the skin, primarily by convection
Heat moves from the skin to the environment by radiation, conduction, convection, and evaporation
Radiation
Conduction
Convection
Evaporation
When heat gain exceeds heat loss, body core temperature rises
Clothing insulates the body from the environment and limits heat transfer from the body to the environment
Active Regulation of Body Temperature by the Central Nervous System
Thermoreceptors in the skin and temperature-sensitive neurons in the hypothalamus respond to changes in their local temperature
Skin Thermoreceptors
Hypothalamic Temperature-Sensitive Neurons
The CNS thermoregulatory network integrates thermal information and directs changes in efferent activity to modify rates of heat transfer and production
Thermal effectors include behavior, cutaneous circulation, sweat glands, and skeletal muscles responsible for shivering
Hypothermia, Hyperthermia, and Fever
Hypothermia or hyperthermia occurs when heat transfer to or from the environment overwhelms the body’s thermoregulatory capacity
Exercise raises heat production, which is followed by a matching rise in heat loss, but at the cost of a steady-state hyperthermia of exercise
Fever is a regulated hyperthermia
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Chapter 60: Exercise Physiology and Sports Science
Motor Units and Muscle Function
The motor unit is the functional element of muscle contraction
Muscle force rises with the recruitment of motor units and an increase in their firing frequency
Compared with type I motor units, type II units are faster and stronger but more fatigable
As external forces stretch muscle, series elastic elements contribute a larger fraction of total tension
The action of a muscle depends on the axis of its fibers and its origin and insertion on the skeleton
Fluid and energetically efficient movements require learning
Strength versus endurance training differentially alters the properties of motor units N60-3
Conversion of Chemical Energy to Mechanical Work
ATP and PCr provide immediate but limited energy
Anaerobic glycolysis provides a rapid but self-limited source of ATP
Oxidation of glucose, lactate, and fatty acids provides a slower but long-term source of ATP
Oxidation of Nonmuscle Glucose
Oxidation of Lactate
Gluconeogenesis
Oxidation of Nonmuscle Lipid
Choice of Fuel Sources
Muscle Fatigue
Fatigued muscle produces less force and has a reduced velocity of shortening
Changes in the CNS produce central fatigue
Impaired excitability and impaired Ca2+ release can produce peripheral fatigue
High-Frequency Fatigue
Low-Frequency Fatigue
Fatigue can result from ATP depletion, lactic acid accumulation, and glycogen depletion
ATP Depletion
Lactic Acid Accumulation
Glycogen Depletion
Determinants of Maximal O2 Uptake and Consumption
Maximal O2 uptake by the lungs can exceed resting O2 uptake by more than 20-fold
O2 uptake by muscle is the product of muscle blood flow and O2 extraction
O2 delivery by the cardiovascular system is the limiting step for maximal O2 utilization
Limited O2 Uptake by the Lungs
Limited O2 Delivery by the Cardiovascular System
Limited O2 Extraction by Muscle
Effective circulating volume takes priority over cutaneous blood flow for thermoregulation
Sweating
Eccrine, but not apocrine, sweat glands contribute to temperature regulation
Eccrine sweat glands are tubules comprising a secretory coiled gland and a reabsorptive duct
Secretion by Coil Cells
Reabsorption by Duct Cells
The NaCl content of sweat increases with the rate of secretion but decreases with acclimatization to heat
Flow Dependence
Cystic Fibrosis
Replenishment
Acclimatization
The hyperthermia of exercise stimulates eccrine sweat glands
Endurance (Aerobic) Training
Aerobic training requires regular periods of stress and recovery
Aerobic training increases maximal O2 delivery by increasing plasma volume and maximal cardiac output
Maximizing Arterial O2 Content
Maximizing Cardiac Output
Aerobic training enhances O2 diffusion into muscle
Aerobic training increases mitochondrial content
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Chapter 61: Environmental Physiology
The Environment
Voluntary feedback control mechanisms can modulate the many layers of our external environment
Environmental temperature provides conscious clues for triggering voluntary feedback mechanisms
Room ventilation should maintain , , and levels of toxic substances within acceptable limits
Acceptable Limits for and
Measuring Room Ventilation
Carbon Monoxide
Threshold Limit Values and Biological Exposure Indices
Tissues must resist the G force produced by gravity and other mechanisms of acceleration
The partial pressures of gases—other than water—inside the body depend on Pb
Diving Physiology
Immersion raises Pb, thereby compressing gases in the lungs
SCUBA divers breathe compressed air to maintain normal lung expansion
Increased alveolar can cause narcosis
Increased alveolar can lead to O2 toxicity
Using helium to replace inspired N2 and O2 avoids nitrogen narcosis and O2 toxicity
After an extended dive, one must decompress slowly to avoid decompression illness
High-Altitude Physiology
Pb and ambient on top of Mount Everest are approximately one third of their values at sea level
Everest Base Camp
Peak of Mount Everest
Air Travel
Up to modest altitudes, arterial O2 content falls relatively less than Pb due to the shape of the Hb-O2 dissociation curve
During the first few days at altitude, compensatory adjustments to hypoxemia include tachycardia and hyperventilation
Long-term adaptations to altitude include increases in hematocrit, pulmonary diffusing capacity, capillarity, and oxidative enzymes
Hematocrit
Pulmonary Diffusing Capacity
Capillary Density
Oxidative Enzymes
High altitude causes mild symptoms in most people and acute or chronic mountain sickness in susceptible individuals
Symptoms of Hypoxia
Acute Mountain Sickness
Chronic Mountain Sickness
Flight and Space Physiology
Acceleration in one direction shifts the blood volume in the opposite direction
“Weightlessness” causes a cephalad shift of the blood volume and an increase in urine output
Space flight leads to motion sickness and to decreases in muscle and bone mass
Exercise partially overcomes the deconditioning of muscles during space flight
Return to earth requires special measures to maintain arterial blood pressure
References
Books and Reviews
Journal Articles
Chapter 62: The Physiology of Aging
Concepts in Aging
During the 20th century, the age structure of populations in developed nations shifted toward older individuals
The definition, occurrence, and measurement of aging are fundamental but controversial issues
Aging is an evolved trait
Human aging studies can be cross-sectional or longitudinal
Cross-Sectional Design
Longitudinal Design
Whether age-associated diseases are an integral part of aging remains controversial
Cellular and Molecular Mechanisms of Aging
Oxidative stress and related processes that damage macromolecules may have a causal role in aging
Reactive Oxygen Species
Glycation and Glycoxidation
Mitochondrial Damage
Somatic Mutations
Inadequacy of repair processes may contribute to the aging phenotype
DNA Repair
Protein Homeostasis
Autophagy
Dysfunction of the homeostasis of cell number may be a major factor in aging
Limitations in Cell Division
Cell Removal
Aging of the Human Physiological Systems
Aging people lose height and lean body mass but gain and redistribute fat
Aging thins the skin and causes the musculoskeletal system to become weak, brittle, and stiff
Skin
Skeletal Muscle
Bone
Synovial Joints
The healthy elderly experience deficits in sensory transduction and speed of central processing
Sensory Functions
Motor Functions
Cognitive Functions
Aging causes decreased arterial compliance and increased ventilation-perfusion mismatching
Cardiovascular Function
Pulmonary Function
Exercise
Glomerular filtration rate falls with age in many but not all people
Aging has only minor effects on gastrointestinal function
Aging causes modest declines in most endocrine functions
Insulin
Growth Hormone and IGF-1
Adrenal Steroids
Thyroid Hormones
Parathyroid Hormone
Gonadal Hormones
Aging Slowly
Caloric restriction slows aging and extends life in several species, including some mammals
Genetic alterations can extend life in several species
Proposed interventions to slow aging and extend human life are controversial
References
Books and Reviews
Journal Articles