Highlights

The Focus box from every lecture, in book order. Click a lecture title to read the full section.

Module 1: Homeostasis and Cellular Function¶

1A · Introduction to Physiology¶

• Anatomy is structure, physiology is function, and structure dictates function.

• Six levels of organization: chemical, cellular, tissue, organ, organ system, organism. Only four tissue types: muscular, neural, epithelial, connective.

• Homeostasis is a dynamic, stable internal environment defended by negative feedback: sensor, afferent path, integrating center with set point, error signal, efferent path, effector.

• Positive feedback amplifies a departure and needs an external cutoff. Course examples: childbirth, milk ejection, ovulation, defecation, clotting.

• Gradients make things flow: concentration moves solutes, osmotic moves water, electrical moves ions, pressure moves blood and air, partial pressure moves gases.

1B · The Cell Membrane¶

• The membrane has four purposes: barrier, sensitivity, regulated exchange, structural support. It is about 50% lipid and 50% protein.

• Phosphate heads are hydrophilic, fatty acid tails hydrophobic. The bilayer forms because each end points toward the environment it prefers.

• Body water is about 60% of mass: 42 L in a 70 kg person, two thirds intracellular (28 L), one third extracellular (14 L).

• Nonpolar molecules cross the membrane freely. Polar molecules (uneven sharing, no net charge) and ions (net charge) are hydrophilic and need help.

• Receptor types: ligand-gated ion channel, G protein-coupled, catalytic, and intracellular (the only one not in the membrane).

1C · Diffusion and Membrane Transport¶

• Outside the cell: Na⁺, Ca²⁺, Cl⁻, HCO₃⁻. Inside: K⁺, Mg²⁺, proteins, phosphate.

• Diffusion is passive, down a gradient. Simple diffusion needs no protein; facilitated diffusion uses a channel (ions) or carrier (polar molecules).

• Rate rises with gradient, area, temperature, permeability; falls with thickness, molecular weight, medium density.

• Cotransporters move two solutes the same way, countertransporters opposite ways. Na⁺ usually supplies the energy.

• Pumps (ATPases) move solutes up their gradients using ATP. The Na⁺-K⁺ pump and SERCA are the two this course uses. Pumps build the gradients everything else spends.

1D · Diffusion Parameters Simulation¶

• Rate = change in concentration divided by time to equilibrium.

• Smaller solutes, higher temperature, and larger gradients all raise the rate.

• A smaller gradient can reach equilibrium sooner yet still have a lower rate, because less change is needed.

1E · Osmosis¶

• Osmosis is water diffusing toward higher solute concentration. It only happens when the solute cannot cross.

• Osmolality = molality x particles. NaCl gives 2, glucose 1. Normal range 280 to 310 mOsm/kg, target about 290.

• Van’t Hoff: pi = n C R T phi converts osmolality to mmHg so it can be compared with hydrostatic pressure.

• Infusion problems: total solute is conserved, water redistributes until every compartment has the same osmolality.

• Dilute bath: water enters and red cells hemolyze. Concentrated bath: water leaves and cells crenate.

Module 2: Excitable Membranes¶

2A · Introduction to Excitable Membranes¶

• Inside is negative relative to outside in nearly every cell.

• Non-excitable membranes sit at a steady −10 to −20 mV. Excitable membranes swing from about −90 to +30 mV and use the swing to do work.

• Depolarization is upward (positive ions in), hyperpolarization downward (positive ions out or negative ions in), repolarization the return to baseline.

• Neurons receive, produce, and propagate signals. Skeletal muscle receives and propagates. Cardiac and smooth muscle do all three.

2B · Organization of the Nervous System¶

• CNS is brain and spinal cord. Sensory (afferent) neurons carry information in; motor (efferent) neurons carry commands out.

• Receptors are visceral (organs), somatic (skin, muscle, joints), or special senses.

• Somatic motor neurons go to skeletal muscle. Autonomic motor neurons go to cardiac muscle, smooth muscle, glands, and fat.

• Sympathetic prepares for stress. Parasympathetic returns to rest and digest.

2C · Neuron Structure, Gradients, and Nernst Potentials¶

• Information flows dendrites, cell body, axon hillock, axon, axon terminals.

• For Na⁺ at rest the chemical and electrical gradients both point in and sum. For K⁺ they oppose, and the chemical gradient wins slightly.

• Electrochemical equilibrium: two nonzero gradients cancel. It is not concentration equilibrium.

• Nernst: E_X = -(61.5/z) log₁₀([X]i/[X]o). Course chart: E_K −88, E_Na +61, E_Ca +123, E_Cl −47 mV.

• If V_m is more negative than E_X a cation flows in; if less negative it flows out. Flow is proportional to |V_m - E_X|.

2D · Resting Membrane Potential¶

• At rest, voltage-gated channels are closed. K⁺ leak channels, a few Na⁺ leak channels, and the Na⁺-K⁺ pump set the resting potential.

• The pump is electrogenic: 3 Na⁺ out for 2 K⁺ in makes the inside slightly more negative.

• Chord conductance: V_m = sum of (GX/Gtotal) E_X. The ion with the most open channels pulls V_m toward its Nernst potential.

• K⁺ is the ion that most strongly sets resting potential.

2E · Graded Potentials¶

• Neurotransmitters open ligand-gated channels. Na⁺ in gives an EPSP; K⁺ out or Cl⁻ in gives an IPSP.

• Graded potentials have no threshold and no refractory period, and they decay with time and distance.

• The axon hillock sums every graded potential and fires only if threshold (about −60 to −55 mV) is met.

• Spatial summation: many synapses at once. Temporal summation: one synapse firing rapidly. Both work on EPSPs and IPSPs.

2F · Action Potentials¶

• Na⁺ channels open fast, K⁺ channels open and close slowly. That timing produces depolarization to +30 mV, repolarization, and hyperpolarization, all within about 1 ms.

• Absolute refractory: Na⁺ channels open or inactivated (activation gate open, inactivation gate closed). Relative refractory: channels resetting, a stronger stimulus works.

• Refractory membrane behind the signal makes propagation one-way.

• Electrotonic conduction 0.5 to 2 m/s; saltatory conduction on myelinated axons 10 to 150 m/s. Myelin, thicker axons, and warmth all speed conduction.

• At the terminal, voltage-gated Ca²⁺ channels open, Ca²⁺ enters, vesicles undergo exocytosis.

Module 3: Skeletal Muscle¶

3A · Skeletal Muscle Anatomy¶

• Hierarchy: whole muscle (epimysium), fascicle (perimysium), fiber, myofibril, sarcomere, filament.

• Fibers are huge: about 100 micrometers wide and up to 30 cm long. T tubules carry the action potential to the core; the SR stores Ca²⁺. A triad is one T tubule between two SR patches.

• Thick filament: titin core plus myosin. Thin filament: nebulin core plus actin, tropomyosin, troponin.

• Striations come from dark A bands (thick filaments) alternating with light I bands (thin only).

• Troponin I binds actin, troponin T binds tropomyosin, troponin C binds Ca²⁺.

3B · Electrical Stimulation at the Neuromuscular Junction¶

• The A-alpha somatic motor neuron releases acetylcholine onto nicotinic receptors on the motor end plate.

• The end plate only makes graded potentials. The action potential starts where it meets ordinary sarcolemma.

• Acetylcholinesterase clears acetylcholine and ends stimulation.

• Muscle and neural action potentials are nearly identical; muscle lasts 2 ms instead of 1.

• Targets: tetrodotoxin (Na⁺ channels), dendrotoxin (neural K⁺ channels), botulinum and tetanus toxin (ACh release), myasthenia gravis (ACh receptors), Lambert-Eaton (Ca²⁺ channels).

3C · Excitation-Contraction Coupling and the Sliding Filament Theory¶

• Excitation-contraction coupling: T tubule AP, DHPR changes shape, pulls RyR open, Ca²⁺ leaves the SR, binds troponin C, tropomyosin moves.

• Cross-bridge cycle: A.M, ATP binds and myosin detaches, hydrolysis recocks, head binds, Pi leaves, power stroke, ADP leaves.

• One ATP does two jobs: binding detaches the head, hydrolysis recocks it. No ATP means no detachment (rigor).

• Relaxation: neuron stops, ACh is cleared, SERCA pumps Ca²⁺ back, tropomyosin covers actin.

• Action potential 1 to 2 ms, twitch 10 to 100 ms. Calcium is the link between them.

3D · Muscle Metabolism and Fiber Types¶

• ATP is spent on the Na⁺-K⁺ pump, myosin detachment and recocking, and SERCA.

• Creatine phosphate: fastest, 1 ATP, about 10 s. Glycolysis: 2 ATP, under 2 min, limited by lactic acid. Oxidative: 34 ATP from glucose, 90 to 140 from fatty acids, slowest.

• Type I: slow oxidative, thin, dark red, fatigue resistant. Type IIa: fast oxidative, medium in everything. Type IIx: fast glycolytic, thick, pale, most powerful, fatigues fastest.

3E · Modulation of Force Production¶

• Three ways to change force: resting length, stimulation frequency, motor unit recruitment.

• Length-tension is a bell curve. Too long gives too little overlap; too short crushes filaments against the Z and M lines.

• Frequency: 5 Hz separate twitches, 10 Hz summation, about 25 Hz unfused tetanus, about 50 Hz fused tetanus.

• Size principle from I = CV: smaller cells have lower capacitance, need less current, and are recruited first.

3F · Dynamics of Skeletal Muscle Contraction¶

• Concentric: force greater than load, shortens, accelerates. Eccentric: force less than load, lengthens, decelerates. Isometric: force equals load, no length change, stabilizes.

• Heavier loads give a longer isometric phase, less shortening, and lower shortening velocity.

• Force-velocity: maximum velocity at zero load, zero velocity at maximum force. Fast-twitch curves sit higher.

• Power = force x velocity. It peaks near one third of maximum force; fast twitch gives 2 to 3 times the power of slow twitch.

Module 4: Smooth and Cardiac Muscle¶

4A · Introduction to Smooth Muscle¶

• Smooth muscle: spindle-shaped, 5 to 10 micrometers thick, no striations, dense bodies instead of Z discs, caveolae instead of T tubules, no troponin.

• Phasic muscle rests and contracts on demand (esophagus). Tonic muscle stays contracted and relaxes on demand (sphincters, vessels).

• Single-unit cells are coupled by gap junctions and fire together; most smooth muscle is single-unit. Multi-unit (eye) cells are independent.

• Autonomic innervation is involuntary and mixed: sympathetic contracts most vessels but relaxes airways, GI, urinary, and vessels in exercising muscle.

4B · Smooth Muscle Function¶

• Five-step template for all muscle: stimulus raises Ca²⁺, Ca²⁺ binds a regulator, cross-bridges form; Ca²⁺ falls, tension falls.

• Smooth muscle depolarizes with Ca²⁺ influx and shows slow waves, pacemaker potentials, summed APs, and ligand responses with no voltage change.

• Ca²⁺ rises two ways: voltage-gated channels plus CICR through the RyR, or GPCR, phospholipase C, IP3, IP3 receptor.

• Ca²⁺ binds calmodulin, which activates MLCK. MLCK phosphorylates myosin, the activated state. Regulation is on the thick filament.

• Relaxation: SERCA (most), NCX, PMCA lower Ca²⁺; MLCK shuts off and MLCP dephosphorylates myosin unopposed.

4C · Modulation of Smooth Muscle Contraction and Relaxation¶

• MLCK is the gas, MLCP the brake. More force: raise MLCK or lower MLCP. Less force: the reverse.

• Gq (M3, alpha-1) raises IP3 and rho kinase. Gi (alpha-2) lowers cAMP. Gs (beta-2) raises cAMP, which inhibits MLCK.

• Nitric oxide raises cGMP, which raises MLCP and relaxes smooth muscle. Losing NO is the first sign of vascular dysfunction.

• Higher MLCP shifts the Ca²⁺-contraction curve right (desensitization); lower MLCP shifts it left (sensitization).

4D · Introduction to Cardiac Muscle¶

• Heart wall: pericardium (about 1 mm), myocardium (up to 9 mm), endocardium (about 0.5 micrometers).

• Cardiac cells are branched, striated, 50 to 100 micrometers long, joined by intercalated disks with desmosomes and gap junctions.

• Shared with skeletal: sarcomeres, troponin, T tubules (dyad, not triad). Shared with smooth: involuntary, automaticity, autonomic innervation, coupling, long waveforms.

• Pacemaker cells fire about 100 times per minute. Autonomic nerves modulate rate and force; they do not start the beat.

4E · Cardiac Muscle Function¶

• Cardiac AP (about 200 ms): phase 0 Na⁺ in, 1 brief K⁺ out, 2 plateau with K⁺ out balanced by Ca²⁺ in, 3 K⁺ out, 4 rest.

• Phase 2 Ca²⁺ influx (about 20%) triggers CICR from the SR (about 80%). Ca²⁺ binds troponin C.

• Ca²⁺ removal: SERCA about 70%, NCX about 28%, PMCA about 2%.

• Frank-Starling: more stretch gives more force, apparently through filament proximity raising Ca²⁺ sensitivity.

• More stretch (preload) shifts the force-velocity curve up and right.

4F · Modulation of Cardiac Muscle Contraction and Relaxation¶

• Sympathetic: NE, beta-1, cAMP up, PKA up. PKA phosphorylates the Ca²⁺ channel and RyR (stronger contraction) and phospholamban and troponin I (faster relaxation).

• Phospholamban brakes SERCA; phosphorylating it releases the brake.

• Parasympathetic: ACh, M2, cAMP down, everything reversed, and the effect is weak.

4G · Summary: Muscle Tissue Comparisons and Contrasts¶

• Size: skeletal about 100 micrometers by up to 30 cm, cardiac 10 to 20 by 50 to 100, smooth 5 to 10 by 30 to 200 micrometers.

• Twitch: skeletal 10 to 100 ms, cardiac about 400 ms, smooth about 5 s.

• Skeletal and smooth muscle can be tetanized; cardiac cannot, because a tetanized heart is a stopped heart.

• Cardiac and smooth muscle rely almost entirely on oxidative ATP and resist fatigue.

Module 6: Cardiac Electrophysiology¶

6A · General Electrophysiology Concepts: Review¶

• Nernst potential: the membrane potential where an ion’s concentration and electrical gradients balance. E_K −94 to −84 mV, E_Na +59 to +71 mV, E_Ca +123 to +125 mV.

• Chord conductance and GHK both weight each Nernst potential by how freely the ion crosses at rest, so K⁺ dominates resting potential.

• Cardiac V_m runs from about −90 to +30 mV, always below E_Na and E_Ca and above E_K. Na⁺ and Ca²⁺ always flow in, K⁺ always flows out. A bigger V_m - Ex gap means a bigger current.

• The heart has eight named currents: I_Na and I_f (Na⁺), I_CaL and I_CaT (Ca²⁺), and I_K1, I_to, I_Kr, I_Ks (K⁺). I_f flows through the new HCN channel.

6B · Introduction to Heart Anatomy¶

• Atria on top, ventricles below. Left and right are the patient’s. RA thin, RV moderately thick, LA thin, LV very thick. Valves: tricuspid, pulmonary, mitral, aortic.

• Atria contract and depolarize top down; ventricles contract and depolarize bottom up.

• Excitatory tissue (pacemaker, slow AP), conductive tissue (fast conduction, little contraction, fast AP), contractile tissue (myocardium, slower conduction, fast AP).

• Path: SA node, internodal tracts, atrial muscle, AV node, bundle of His, bundle branches, Purkinje fibers, ventricular muscle.

• Velocities: atria 0.5, AV node 0.05, bundle branches 2, Purkinje 4, ventricles 0.5 m/s. Conduction velocity is proportional to AP amplitude and phase 0 dV/dt.

6C · Slow-Response Cardiac Action Potential¶

• The slow AP has only phases 4, 0, 3. Phase 4 creeps from the maximum diastolic potential (about −60 mV) to threshold (about −40 mV) on its own: the pacemaker potential, source of autorhythmicity.

• Phase 4 currents in order: falling K⁺ efflux, then I_f (Na⁺ through HCN, opened by hyperpolarization), then I_CaT, then I_CaL. Phase 0 is Ca²⁺-driven through L-type channels. Phase 3 is K⁺ efflux.

• T-type is tiny and transient (pA). L-type is large and long-lasting (nA).

• SA node: posterior right atrium, dV/dt about 2 V/s, fires every 0.6 s for an intrinsic rate of 100 bpm.

• Chronotropy changes phase 4 duration three ways: slope (I_f and I_Ca via cyclic AMP, both branches), maximum diastolic potential (parasympathetic I_K-ACh only), threshold (I_Ca).

• AV node: the only route to the ventricles. Delays about 0.1 s at 0.05 m/s (dV/dt 5 V/s, amplitude 70 mV). Backup pacemaker at 40-50 bpm, normally held by overdrive suppression. Dromotropy changes AV conduction through I_CaL.

6D · Fast-Response Cardiac Action Potential¶

• Fast AP: dV/dt 150-800 V/s, amplitude 110-120 mV, conduction 0.5-4 m/s.

• Phase 4 I_K1 at −80 to −90 mV. Phase 0 I_Na. Phase 1 I_to notch from about +30 mV. Phase 2 plateau near 0 mV, I_Kr and I_Ks out balanced by I_CaL in. Phase 3 I_Kr, I_Ks, then I_K1, with NCX, PMCA, and SERCA clearing Ca²⁺.

• Plateau Ca²⁺ triggers contraction through troponin C and CICR, then closes its own channels by calcium-dependent channel inactivation, leaving K⁺ efflux unopposed.

• Absolute refractory period while Na⁺ channels are open or inactivated (phases 0 to early 3). Relative refractory period from about −50 mV until rest, when a stronger-than-normal stimulus can fire the cell.

• Internodal pathways: 1-1.5 m/s, not insulated, depolarize atria top down. His-Purkinje: 2-4 m/s, insulated, depolarize ventricles from the apex up.

6E · Introduction to the Electrocardiogram (ECG)¶

• The ECG detects summed depolarization and repolarization of the atria and ventricles, which have enough mass to be seen outside the body.

• P wave: atrial depolarization. QRS: ventricular depolarization, with atrial repolarization hidden inside it. T wave: ventricular repolarization.

• SA node, AV node, bundle of His, bundle branches, and Purkinje network are too small to appear. The PR segment is His-Purkinje transit.

• Phase 0 lines up with the P wave (atria) or QRS (ventricles); phase 3 with the QRS (atria) or T wave (ventricles). The ST segment is the ventricular phase 2 plateau.

• 12 leads: I (RA to LA), II (RA to LL), III (LA to LL) form Einthoven’s triangle; aVR, aVL, aVF are calculated; V1-V6 view the transverse plane. Lead II gives the most iconic waveform.

6F · The Electrocardiogram: A Two-Cell Model¶

• Guest lecture. Burdon-Sanderson and Page (1883) reduced the EKG to two cells: A (endocardium, first to depolarize) and B (epicardium, second).

• V_ECG = V+ - V- = Vs,B - Vs,A = V_m,A - V_m,B. The EKG is the first region’s action potential minus the second’s, which behaves like a time derivative.

• Frog T wave is downward. The human T wave is upright because the epicardium has the shorter action potential: depolarization runs endo to epi, repolarization epi to endo.

• Hyperkalemia: tall peaked T. Hypokalemia: flat T. Hypercalcemia: short QT. Hypocalcemia: long QT. Quinidine: wide QRS and long QT.

• Endocardial ischemia gives ST depression; epicardial ischemia gives ST elevation.

• AV block: first degree PR over 0.2 s; second degree some P waves without a QRS; third degree P waves and QRS complexes fully independent.

6G · The Electrocardiogram: Geometry and Electrical Axis¶

• Guest lecture. Lead geometry matters: the QRS on a lead is the projection of the cell A to cell B arrow onto the line between the electrodes.

• Frontal leads: I, II, III and the augmented aVR, aVL, aVF with a phantom negative electrode. Precordial V1-V6 use a phantom negative at the heart’s center.

• Geometric method: mark QRS heights from two leads on the circle of axes, draw perpendiculars, connect the center to their intersection.

• Inspection method: find the isoelectric lead, the axis is perpendicular to it, then a second lead picks the direction. aVL (−30 degrees) isoelectric with lead II positive gives +60 degrees.

• Normal 0 to 90 degrees. Right axis 90 to 180 (right ventricular hypertrophy). Mild left 0 to −30 (obesity, ascites). Severe left −30 to −120 (left ventricular hypertrophy, left bundle branch block).

Module 7: Heart as a Pump¶

7A · Heart Anatomy¶

• Four valves act as passive one-way doors with no muscle. A valve opens when P1 upstream exceeds P2 downstream and closes when P1 falls below P2.

• AV valves (tricuspid right, mitral or bicuspid left) are ventricular inlets. Semilunar valves (pulmonary right, aortic left) are outlets.

• Papillary muscles pull on the chordae tendineae to keep the AV valves from prolapsing, like the cords on a parachute.

• Valve disease is mostly left-sided. Stenosis narrows a calcified valve (healthy 3 to 5 cm2, severe under 1 cm2). Regurgitation lets blood flow backward.

• Arteries always carry blood away from the heart, veins always toward it. The pulmonary trunk is an artery carrying deoxygenated blood.

• Typical pressures in mmHg: RA 4, RV 26/3, pulmonary trunk 25/10, LA 8, LV 121/7, aorta 120/80.

7B · Virtual Reality Lab: Heart Chambers¶

• VR walkthrough of an MRI scan of a 97-year-old heart.

• Pectinate muscles are ridges on the atrial wall that add muscle without much thickness or weight.

• Both ventricles take blood in from the top and eject it out the top.

• The right ventricle has three groups of papillary muscles. The left has two, anterior and posterior, matching the two mitral flaps.

• The left atrium sits behind the aorta and pulmonary trunk and runs along the back of the heart.

7C · Virtual Reality Lab: Heart Valves and Great Vessels¶

• In this heart the inferior vena cava enters the back of the right atrium, not the bottom.

• Valve flaps are very thin and not muscular. Tricuspid, pulmonary, and aortic valves each have three flaps; the mitral has two.

• The pulmonary trunk moves backward and splits into left and right pulmonary arteries.

• Two pulmonary veins come from each lung into the left atrium.

• The aortic valve shows small white spots of calcification. Transcatheter valve replacement reaches it by going retrograde up the aorta.

7D · The Cardiac Cycle¶

• Cardiac cycle duration (s/beat) = 60 / HR (beats/min). Diastole takes the bigger share unless heart rate is very high.

• Systole and diastole are named for the ventricles, so atrial systole falls during diastole.

• Diastole: isovolumic relaxation (P art > P vent > P atria, all valves closed), then filling (P art > P atria > P vent), passive and then the active atrial kick, ending at EDV.

• Systole: isovolumic contraction (isometric-like, all valves closed), then ejection (P vent > P art > P atria, isotonic concentric-like), ending at ESV.

• Some residual ESV always remains after ejection, and its size varies.

7E · The Wiggers Diagram¶

• The Wiggers diagram tracks left atrial, left ventricular, and aortic pressure plus left ventricular volume over one cycle.

• Each valve event is where two pressure tracings cross: mitral closes, aortic opens, aortic closes, mitral opens.

• Filling has three sub-stages: 1A rapid (passive), 1B reduced (passive), 1C atrial kick (active).

• Isovolumic phases show a fast pressure change with a flat volume tracing. Ejection shows high pressure with falling volume.

• Stroke volume is the vertical drop from EDV to ESV.

7F · Cardiac Output¶

• CO = HR x SV (mL/min) and SV = EDV - ESV. The SNS and PSNS set heart rate.

• Preload (stretch, set by volume) is proportional to SV. Surrogates are LV EDV, LV end-diastolic pressure, and atrial pressures. A preload change moves the operating point along the Starling curve.

• Positive lusitropy (faster, more complete relaxation via SNS, PKA on troponin I and SERCA) raises preload. Negative lusitropy lowers it.

• Afterload (set by pressure) is inversely related to SV. Higher afterload means longer isovolumic contraction, less ejection time, and more residual ESV. The surrogate is mean arterial blood pressure.

• Contractility, or inotropy, is load-independent and set by intracellular Ca²⁺ (chemicals). EF gets two thumbs down, dP/dt max one down, ESPVR three up.

• Positive inotropes: beta-1 agonists, blocking cAMP degradation, inhibiting the Na⁺-K⁺ pump. Negative: inhibiting the SNS in the brain, beta-1 antagonists, blocking L-type Ca²⁺ channels.

7G · Left Ventricular Pressure-Volume Loops¶

• The P-V loop drops time and plots LV pressure against LV volume. Read it counterclockwise.

• The right vertical side is isovolumic contraction, the top is ejection, the left vertical side is isovolumic relaxation, and the bottom is diastolic filling.

• The lower right corner gives EDV and preload, the upper left gives ESV, and loop width is stroke volume. The height of the upper right corner approximates afterload.

• Compliance = dV/dP. Elastance, or stiffness, = dP/dV, which is what slopes on a P-V graph show.

• ESPVR joins the end-systolic corners. Its slope, E_ES, is active stiffness and the gold standard for contractility.

• EDPVR joins the end-diastolic corners and shows passive stiffness, or ease of filling. A counterclockwise rotation of either line means more stiffness.

Module 8: The Circulation¶

8A · Vascular Anatomy¶

• Each circulation is plumbed in parallel, so every capillary bed gets the same blood at the same driving pressure. The two circulations are in series, so the whole cardiac output passes through both.

• Arterial side diverges, venous side converges. Large arteries distribute, arterioles provide resistance, capillaries exchange, veins return blood and act as capacitance.

• Three tunicas: intima (endothelium, basement membrane, internal elastic membrane), media (smooth muscle, external elastic membrane), externa (mostly collagen). Veins lack the elastic membranes; capillaries are endothelium plus basement membrane.

• Elastic tissue matters most in the aorta, smooth muscle in small arteries and arterioles, collagen in the largest vessels. Veins have thinner walls, larger lumens, and valves.

• Resting cardiac output of 5.0 L/min: cerebral 14%, coronary 4%, splanchnic 27%, renal 20%, skeletal muscle 21%, cutaneous 5%, other 9%. Gut and kidneys are overperfused because they clean and filter the blood.

8B · Vascular Hemodynamics: An Overview¶

• Ohm’s law for flow: Q = delta P / R. Flow is like current, delta P like voltage difference, R like electrical resistance.

• Hagen-Poiseuille: Q = delta P x pi x r^4 / (8 x eta x l). Rearranged, R = 8 x eta x l / (pi x r^4).

• Flow also equals mean velocity times cross-sectional area (Q = v x A). Compliance in pressure form: delta P = delta V / C.

• Delta P is the force that promotes flow, R the force that opposes it (friction), and Q is cardiac output, delivering O2 and nutrients and picking up CO2 and waste.

8C · VR Systemic Vasculature Tour¶

• The first branches off the aorta are the coronary arteries, leaving from the aortic sinuses just behind the valve cusps.

• The left coronary artery splits into the left anterior descending artery (the widow maker) and the circumflex artery. Cardiac veins drain via the great cardiac vein into the coronary sinus, which empties into the right atrium.

• Three branches leave the aortic arch: brachiocephalic trunk, left common carotid, left subclavian. Lower branches feed the gut, kidneys, and, via the iliac and femoral arteries, the legs.

• Veins track the arteries in reverse. Sister arteries and veins run side by side, and the vein always has the larger lumen, most strikingly at the kidney.

8D · Vascular Pressures (P)¶

• Systemic driving pressure is MAP - CVP, pulmonary is pulmonary artery pressure - left atrial pressure. The steepest drop and the loss of pulsatility occur across the arterioles.

• Wall tension is proportional to P x r. Arteries limit it with elastic tissue and thick walls (wall stress is proportional to P x r / h).

• MAP = 1/3 SBP + 2/3 DBP, or MAP = CO x SVR with CVP rounded to 0. Pulse pressure = SBP - DBP and rises with arterial volume and stiffness.

• Arteries hold about 15% of blood volume (about 750 mL of 5 L) at high pressure with low-but-sufficient compliance. Aortic elasticity stores volume in systole and recoils to drive flow in diastole.

• Veins hold about 65% of blood volume at 18 down to 2-3 mmHg. Venous compliance is 20 to 30 times arterial at low pressure.

• Compliance is the slope of the volume-pressure curve; capacitance is the volume held at a given pressure. High capacitance makes veins a blood reservoir.

8E · Vascular Flow (Q)¶

• Flow starts as cardiac output and is driven by MAP. MAP depends on blood volume, flow into the arteries (cardiac output), and flow out (resistance).

• Flow is conserved, so Q = v x A means velocity varies inversely with aggregate cross-sectional area. Velocity is lowest in the capillaries.

• Laminar flow has concentric layers and a parabolic profile, and is required for the flow equations. Re = v x 2r x density / viscosity; below 2,000 is laminar, above 3,000 turbulent.

• Turbulent flow is blunt, chaotic, noisy, and high-resistance. It produces murmurs and Korotkoff sounds and damages endothelium and red cells.

• Viscosity is stickiness, mostly from red blood cells. It rises with hematocrit (normally about 45%) and falls with higher shear rate.

8F · Vascular Resistance (R)¶

• Resistance comes from friction. Viscosity and length contribute but are not regulated; radius is the only regulated variable and carries the fourth power.

• Doubling radius cuts resistance 16-fold, because more laminae flow without touching the wall.

• Arterioles are the resistance vessels. Their resistance sets upstream pressure (MAP) and decides where downstream flow goes, as when muscle dilates and gut, kidney, and skin constrict during a run.

• Vasodilation is mostly intrinsic and local: metabolites, histamine, prostacyclin, bradykinin, myogenic response to lower pressure, nitric oxide and other endothelial factors. Extrinsic dilation is passive withdrawal of sympathetic tone, plus minor epinephrine at beta-2.

• Vasoconstriction is mostly extrinsic and systemic: sympathetic norepinephrine at alpha-1 and alpha-2 in all beds, angiotensin II, vasopressin. It maintains SVR and MAP.

8G · Capillary Function¶

• Capillaries are about 5 micrometers across, endothelium plus basement membrane. Precapillary sphincters control flow into each bed.

• Continuous capillaries (most) pass only water and small solutes; fenestrated (kidney, intestine, choroid plexus) pass more volume; sinusoidal (liver, marrow, spleen) pass proteins and cells.

• Small solutes diffuse by Fick’s law, Jx = Px x ([Xc] - [Xif]). Proteins need slow vesicles, so most capillaries are functionally protein impermeable.

• Pc pushes water out and Pif pushes it in; pi c pulls water in and pi if pulls it out. NFP = (Pc - Pif) - (pi c - pi if); positive filters, negative reabsorbs.

• With 35 vs 25 mmHg at the arterial end (NFP +10) and 18 vs 25 at the venous end (NFP −7), we filter 24 L/day and reabsorb 20.4 L/day.

• Lymphatics return the remaining 3.6 L/day to the veins near the neck. If they are overwhelmed, edema forms; cerebral and pulmonary edema can be life-threatening.

Module 9: Regulation and Integration of the Cardiovascular System¶

9A · Autonomic Innervation of the Cardiovascular System¶

• Parasympathetic: long-short, ACh on nicotinic at the ganglion, ACh on muscarinic at the target. Sympathetic: short-long, ACh on nicotinic, then norepinephrine on adrenergic receptors.

• The adrenal medulla route releases about 80% epinephrine (alpha-1, beta-1, beta-2) and 20% norepinephrine (alpha-1, alpha-2, beta-1) as hormones that reinforce and prolong sympathetic effects.

• SA and AV nodes have balanced dual innervation: beta-1 speeds heart rate and AV conduction, M2 slows both. Myocardium, arteries, and veins are mostly sympathetic.

• Venoconstriction lowers venous volume and compliance, raises venous pressure, and raises venous return and preload.

• MAP = CO x SVR and R = 8(viscosity)(length)/(pi r^4). Sympathetic stimulation raises pressure through heart rate, lusitropy, venous return, contractility, and vasoconstriction. Parasympathetic lowers it through heart rate.

9B · The Baroreflex¶

• The baroreflex defends arterial pressure. Baroreceptors in the carotid sinus (CN IX) and aortic arch (CN X) sense wall stretch as a surrogate for pressure.

• Firing rises with pressure: almost none at very low pressure, nearly continuous at very high pressure.

• Rising pressure: solitary nucleus and tract stimulates the nucleus ambiguus (parasympathetic to SA node) and the CVLM, which inhibits the RVLM and withdraws sympathetic outflow.

• Falling pressure: baroreceptors go quiet, parasympathetic outflow stops, the RVLM is disinhibited, and heart rate, contractility, venoconstriction, and vasoconstriction all rise.

• 500 mL hemorrhage: intact reflex holds MAP at 99 mmHg (HR 77 to 106). Without it MAP falls from 100 to 65 mmHg.

9C · Elements of the Atrial Stretch Reflex: The Bainbridge Reflex¶

• The atrial stretch reflex defends blood volume. Low-pressure cardiopulmonary baroreceptors (atria, vena cava junction, pulmonary vessels, right ventricle) read stretch as volume, via CN X.

• Bainbridge reflex: more venous return stretches the atria, parasympathetic drive to the SA node falls and sympathetic drive rises, and heart rate increases to match outflow to inflow.

• Venous return changes with blood volume, posture, microgravity, and breathing. Breathing in raises venous return and heart rate; breathing out lowers both (respiratory sinus arrhythmia).

• A rise in venous return drives the baroreflex to slow the heart and the Bainbridge reflex to speed it.

• The baroreflex dominates when volume is low (protecting arterial pressure). The Bainbridge reflex dominates when volume is high (protecting the heart from overfilling).

9D · Elements of the Atrial Stretch Reflex: Endocrine Reflexes¶

• Neural reflexes are instant, short-lived band-aids. Endocrine reflexes start in a minute or more, last hours to weeks, and often fix the root cause.

• Vasopressin (ADH) fixes low BP and BV: hypothalamus to posterior pituitary, powerful vasoconstriction plus renal water retention.

• Renin-angiotensin system: low renal pressure or sympathetic input releases renin. Renin makes angiotensin I, ACE in the lungs makes angiotensin II.

• Angiotensin II raises thirst, vasoconstricts through AT1 receptors, raises sympathetic activity, and releases vasopressin and aldosterone. Aldosterone retains Na⁺, and water follows.

• ANP fixes high BP and BV: released by stretched atrial myocytes, it vasodilates, causes natriuresis, and suppresses renin. It mirrors vasopressin and aldosterone.

9E · Integration of Cardiac and Vascular Function¶

• Heart rate and contractility are intrinsic. Preload and afterload are extrinsic. Afterload is the only one inversely related to cardiac output.

• Venous return drives right atrial pressure, which drives cardiac output. Preload couples inflow to outflow, and at steady state they are equal.

• Cardiac function curve: cardiac output against right atrial pressure. Up with more contractility, heart rate, or less afterload; down with the reverse.

• Pump experiment: baseline 5 L/min, 102 and 2 mmHg. No flow gives a mean systemic filling pressure of 7 mmHg. Venous compliance is about 20 times arterial (95 vs 5 mmHg change).

• Volume or compliance changes shift the venous return curve in parallel and move mean systemic filling pressure. Resistance changes pivot the slope: vasodilation steeper, vasoconstriction flatter.

• The curves cross at the operating point, normally 2 mmHg and 5 L/min. Heart failure moves it right and down; added volume moves it right and up.