Integrated Cardiovascular Physiology

Exercise Physiology

For aerobic exercise, O2 consumed increases linearly with work load.

Trained athlete has more muscle mass with more mitochondria and capillaries. They are not more efficient at using ATP.

O2 supply = Cardiac Output X O2 Extraction

Functional Hyperemia in striated muscles allows reduction in TPR and increase in CO without an increase in MAP.

Regulation of Body Temperature

Humans use 1800 calories/day for BMR

Thermoregulatory Zone – bounded by peak sweating and heat production

Thermoneutral Zone – Core temperature maintained with no extra energy input – bounded by begining of sweating and shivering. (20-30C)

Thermal Comfort Zone – bounded by feeling too warm or too cold (26/79)

Circadian Variation: zenith at 4-6PM – 37.5, nadir in early morning (35.5)

Passive Heat Loss

• 60% – Radiation – remote
• Conduction – contact (water 25x air)
• Convection – movement of fluid (windchill) (Piloerection)
• 20% – Evaporation

Active Heat Loss

• Sweating – eccrine glands, regulated by hypothalamus autonomic, cholinergic, catecholamines. Baseline – little NaCl in sweat. Maximum – high NaCl (L/hr.). Acclimatization (2-6 weeks)(2-3 L/hr)(less NaCl loss via aldosterone)
• Vasodilation – can accommodate up to 30% of CO. Regulated by hypothalamus.

Heat Generation:

• Shivering
  • Regulated by posterior hypothalamus, inhibited by anterior hypothalamus
  • Lateral columns to anterior motor neurons, muscle spindle stretch reflex.
  • 4-5x heat production
• Nonshivering – Brown fat activated by sympathetics and thyroid. Thermogenin

Endocrine Mechanisms

Thyroid – Cooling > Sympathetics > Anterior Hypothalamus > Release TRH > Pituitary release TSH > Thyroid release T4/T3. Thyroxine increases BMR.

Adrenal – Cooling > Anterior/preoptic HT signals adrenal medulla to produce Epi/NE > Increase MR.

Temperature sensors in skin (more cold, constantly firing in response to rate of change), deep tissues (abdominal, spinal cord, great veins), and central (hypothalamus, medulla)

Anterior and Preoptic Hypothalmus – more heat receptors, sweating and vasodilation

Psoterior Hypothalamus – gets signals from periphery and anterior hypothalamus, more cold receptors, shivering.

Fever – reseting hypothalamic thermostat

• PAMPs activate leukocytes to produce cytokines (IL-1)
• Cytokines or toxins stimulate COX2 in bloo-brain barrier to make PGE2 in brain
• Stimulates preoptic anterior HT to increase temperature set point.

Antipyretics – central and peripheral

• Inhibit PGE2 via COX
• Reduced adhesion of leukocytes
• Decreased cytokine production
• Stimulation of antiinflammatory mediators (adenosine)
• Enhanced endogenous antipyretics – glucocorticoids

Fever augments host defense mechanisms

Fever may result in collateral tissue damage

Fever is very bad for the injured brain

Heat Stroke – 106-108, 41-42, high humidity, RX rapidly decrease body temperature

Malignant hyperthermia via inhalational anesthetics

Hypothermia – core temp below 35/95, Rx slow rewarming

Hemorrhage

Cerebral Ischemic Response may trigger at very low pressures, but if medulla blood flow is compromised the vaga centers iwll be activated and worsen hypotension.

Capillary pressure falls, fall in plasma oncotic pressure

Baroreceptors – vassopressin

Renal vascular pressure – angiotensin II > aldosterone

Opoids from sympathetics and CNS can depress the brain

Reticuloendothelial system is depressed, endotoxin accumulates

Work on: Fluid replacement, ion balance, naloxone to block opiods

Neonatal Circulation

Patent foramen ovale

Patent ductus arteriosus and ductus venosus

Equal R/L pressures in heart

Highly oxygenated blood to brain and myocardium, less oxygenated blood to lower body.

Only 8% goes to lungs because pulmonary resistance is high

RV pumps 2/3 of output

Ductus venosus carries 40-60% of umbilical venous blood.

Crista dividens and Eustacian valve direct blood through foramen ovale.

Little volume crosses the aortic isthmus.

At Birth

• Pulmonary resistance drops > 50% of output
•  Flow through PDA decreases
• Umbilical vessels constrict and close, peripheral resistance increases, ductus venosus closes
• Left atrial pressure increases
• Foramen ovale closes
• PDA reverses then ceases

CHD – 8/1000, 40% are VSDs

Signs:

• furrowed brow
• color
• respiratory effort – happy tachypnea
• murmur – ejection
• poor lower extremity pulses – coarctation – usually stable until PDA closes in a week.

Organ Circulations

Cardiac Circulation

Right coronary artery usually most important

Artery-Artery anastomoses called collaterals. Density lowest at epicardium.

Extraction is 13 ml/100 ml blood, 90%, so must increase CBF for more oxygen.

A decrease in supply or an increase in consumption will decrease balance.

Myocardium has little preference for substrate. Glucose uptake is stimulated during hypoxia – sympathetics.

Autoregulation is excellent in coronary circulation. Blood pressure usually remains constant.

Flow in ventricle decreases markedly with each systole, especially in the endocardium. But these vessels are more numerous and more dilated. So average flow is equal. Reduction in transmural pressure below normal will decrease end/epi ratio below 1.

Hypoxia is most potent stimulator of dilation. Adenosine released by parenchymal cells.

Sympathetics can produce dilation and parasympathetics barely.

Skeletal Muscle Circulation

Muscle mass is 43% of body weight.

Blood flow can vary from 250-12500 ml/min.

Huge contributor of peripheral resistance, blood pressure in toto.

In exercise – skeletal muscles can increase both flow and extraction

At rest – 25% of total, during exercise – 90%

Flow regulation at arteriole level. 1.5-150 w/ exercise.

Also metabolic dilation.

Local control overrides neural control during exercise. Ignore sympathetics. Functional sympatholyasis

Cerebral Circulation

Very weak sympathetic control

As intracranial pressure rises, transmural pressure falls, and vessels tend to collapse. Collapse leads to myogenic and metabolic dilation and flow is autoregulated up to a point.

When flow falls to a critical level, a massive sympathetic discharge is triggered and the arterial pressure begins to rise in parallel with the rise intracranial pressure. Called Cushing Response.,

Regional metabolic control. Adenosine, K and H

Cutaneous Circulation

Low resting flow. Range from 50-2800.

Arteries and arterioles control perfusion of subdermal venous plexuses and capillary loops

Capillary loops run perpendicular to skin surface.

Subcutaneous venous plexus, secondary route for heat exchange, large volume, run parallel, core temperature regulation, prevent freezing, filling controlled by A-V anastomoses.

When warm, open shunts, venous plexus is major surface for heat loss to regulate core temperature.

Countercurrent: superficial arteries and veins are separated, deep vessels run parallel. When cold, superficial vessels contract. Blood in deep arteries runs next to blood in deep veins and exchange.

CNS role: preoptic region of anterior hypothalamus is major control. Temperature receptors are both in skin and hypothalamus, initiate reflex to change sympathetic tone

Kinin system: Heat > sympathetic cholinergic signal to sweat glands > kallikrein acts on kininogen to form bradykinin. Dilates and opens A-V anastomoses.

White reaction – due to vasoconstriction, not neural

Triple response – red line (vessel trauma), flare or red blush (axon reflex from mechanical stimulation via histamine), wheal (increased capillary permeability followed by fluid and protein leaks.

Intestinal

Supply to muscularis and mucosa

Capillary loops with countercurrent flow to facilitate absorption of Na and H2o and shunting of o2

Neural control is exclusively sympathetic

Local control: autoregulation is poorly developed, functional hyperemia is well developed, glucose and FA are mediators along with gastrin and chol.

Hepatic Blood Flow

Large flow – 25% of CO at rest

75% inflow from portal vein

25% O2 inflow via portal vein (Mean pressure is 10mmHg), 75% from hepatic artery (Mean pressure is 90).

Low O2 and high substrate from gut

Paired arteriole and venule pass in parallel with bile ductule into hepatic acinus. Then to hepatic sinusoids (capillaries)

Blood leaves liver via hepatic venules.

Blood enters lobule with same pressure, thus pressure drop in arterioles is large

Elevation of pressure causes filtration out of sinusoids and into peritoneal cavity.

Local control is well developed, sensitive to O2

Sympathetic innervation, most important as volume reservoir, contains 15% of volume.

Coupling of the Heart and Great Vessels

With infinite reservoir, output of heart is dependent on preload, afterload, and ionotropic state. Otherwise, the output is determined by how much blood can flow into the atria during diastole.

Ionotropic state and output of heart determine right atrial pressure. Right atrial pressure determines preload.

Mean circulatory filling pressure – Pmc – estimate of cardiovascular volume. Use central venous pressure, arterial pressure and cardiac output. Pressure in system is determined by capacitance and volume. Venous capacitance is 19X the arterial.

Only if you have pumping will there be a difference in volume between the two sides. If you decrease pumpin, you increase venous pressure.

Pressure is reduced as blood flows through the system.

Decreased vascular resistance causes greater cardiac output for any given filling pressure.

Combine vascular function and starling curve.

Increased resistance will lower venous return and cardiac output and central venous pressure. But it also raises the blood pressure (afterload) causing cardiac output to fall. The net result is decreased CO with little change in central venous pressure.

Cardiac failure will cause your body to increase volume, which will increase central venous pressure and CO.

Change in HR will decrease preload, increase afterload and increase contractility.

Negative pressure breathing will increase CO.

The Peripheral Vasculature

Local, Humoral, and Neural control of resistance.

Changes in resistance control filtration, flow, diffusion.

Bleeding causes neurally mediated constriction of blood vessels.

Blood-Brain barrier protects it from vasoconstrictor stimuli.

VSM capable of graded contraction.

Spontaneous tone due to high leak of Ca

Agonist tone via neural (NE) or humoral (Epi)

Stretch induced – myogenic response

Endothelial cell cooperation: Mechanical, Electrical, Chemical (paracrine factors)

No is produced from arginine, activates GC to produce cGMP which reduces intra Ca and desensitizes myosin to Ca. Phosphodiesterase 5 removes the cGMP (Viagra inhibitsP5)

Endothelium derived hyperpolarizing factor (EDHF) – dilates, with secondary reduction in Ca

Arachidonic Acid metabolites

Endothelin – constriction peptide, potent, hypertension.

Intrinsic control at precapillary vasculature. Pre dilation accompanied by post dilation.

Reactive hyperemia – excess flow that follows reduced flow. Recovery depends on contration of VSM.

Autoregulation stabilizes blood flow and capillary pressure in the face of changing arterial blood pressure.

Functional hyperemia – increased flow with increased metabolic activity.

Myogenic mechanism very important in autoregulation and reactive hyperemia.

Look at flow to metabolic rate ratio to determine myogenic vs. metabolic component.

Vasomotor Center – CNS control from dorsal medulla

• Regulates cardiac function with SNS and PNS
• Vascular regulation only by SNS
• Sympathetic tone
• Traube Herring Waves – cyclical pressure changes associated with respiration

Depressor Area – Ventromedial and caudal medulla

• Dilation through vasomotor and spinal pathways

Hypothalamus

• stimulation of anterior causes decreased blood pressure, vasodilation, and bradycardia
• stimulation of posterolateral causes tachycardia and vasoconstriction
• cutaneous thermal receptors induce vasodilation or vasoconstriction in response to temperature.

Cerebral Cortex

• blushing and fainting
• connections to vasculature via hypothalamus

Cardiovascular sensors

• Peripheral Blood Gas – carotid and aortic, glossopharangeal and vagus nerves
  • Control respiration
  • cardiac acceleration and vasoconstriction
• Central Blood Gas – vasomotor
• Blood Pressure Sensors – carotid and aorta
  • work through vasomotor via intermediate inhibitory nucleus
  • sensitive to both mean and pulse pressure
  • increased sympathetic activation of VSM in artery increases sensitivity of sinus
  • rapidly adapting
  • stretch receptors work through glosspharangeal and vagus nerves to inhibit vassomotor center
    • inhibits sympathetics
    • increased parasympathetic flow – HR
• Blood Pressure Sensors – low pressure side – atria, ventricles, pulmonary artery
  • Atrial A receptors are stimulated by contraction, B stimulated by distension
  • Important in blood volume control
  • Stimulation inhibits release of angiotensin, aldosterone, vasopressin
• Enteric Sensors
• Cutaneus Receptors – Superficial produce constriction, deep produce vasodilation

• Sympathetic Adrenergic Fibers – NE, ATP , NPY

• receptors in blood vessels
  • alpha – contraction of smooth muscle (DOMINANT with NE)
  • beta – relaxation of smooth muscle
• Epi is a more potent beta stimulator at low doses, at high doses alpha are stimulated
• Arterioles and venules are both innervated but NOT capillaries

Extracellular fluid compartment is divided between interstitial fluid and plasma.

If venous pressure rises, more fluid is filtered from capillaries. The initial change in tissue weight is due to the expansion of the vessels.

Driving pressure is Arterial pressure – Venous pressure. This affects flow.

Sympathetic stimulation constricts arterioles more than venules, so the capillary pressure falls.

Contraction of veins shifts blood from the periphery to the central circulation, called venous volume mobilization. Happens during hemorrhage.

Skin is the most sensitive to sympathetic stimulation, brain is the least.

Sympathetic cholinergic fibers use ACh to induce active vasodilation. Not major. These fibers are not tonically active and do not innervate capacitance vessels. They are activated by emotion and anticipation of exercise.

Parasympathetic Dilator Fibers use ACh. Fibers of cranial origin supply the head and viscera. Sacral origin serve pelvis.

Salivary glands: parasympathetic discharge > dilation of glands > formation of kallikrein > formation of bradykinin from plasma proteins > vasodilation

Bradykinin also formed in sweat glands and is involved in cutaneous vasodilation.

NO at work in penis for vasodilation.

Cutaneous sensory neurons release substance P which degranulates mast cells and increases capillary permeability.

Adrenal Medullary Hormone – Epi – Release is stimulated by lots of things including baraoreceptor, works on muscle and skin.

Adrenal cortical hormones

• Corticosterone – permissive role
• Aldosterone – Major action in the kidney, increases salt and water retention, elevates BP.

Angiotensin II – formation initiated by low NaCl and low BP in kidney. Vasoconstrictor. ACE inhibitors

Antidiuretic Hormone – ADH – Vasopressin – released by posterior pituitary – vasoconstrictor – hemorrhage.

Histamine – released by mast cells – dilates arterioles, constricts venules, increases capillary permeability.

Prostas from AA – synthesized on demand, release associated with injury.

Microcirculation

Collagen in arteries ages and become less elastic.

Precapillary sphincters present only in few tissues like liver. Dominated by local control.

A-V Anastomoses have large smooth muscle fraction. Mainly in skin. Involved in body temperature regulation.

In capillary wall:

• Tight junctions
• Fenestrations – capillaries and postcapillary venules, large molecules
• Vesicles – can carry fluid and solute
• Fused chains of vesicles – path for large solutes

Collecting capillaries – leakage site for macromolecules, major site for WBC adherance

Venules – regulate distribution of blood in circulation, mainly neural control

Law of Laplace – small vessel can withstand pressure more easily than large vessels because tension is less. T=PxR. 12 vs. 200dynes. Or S=Pxr/w

Ficks first law of diffusion: Flux = Permeability x Area x Concentration Difference

Area depends on molecule and endothelial cell

Vant Hoff and Oncotic Pressure: Pi = RT(deltaC)

Starling balance of forces: 1) flow can be induced by hydrostatic or oncotic pressure difference.

Filtration = K[(Pp-Pt)-(Pip-Pit)]

K also called the CFC, it is proportional to the size and number of pores and number of capillaries perfused. Pp runs from 32 > 15. Pt is 0. Pip is 25. Pit is 3.

Net filtration over length of capillary is 3mmHg

Proteins are not very permeable in the capillaries and the situation approaches that for an ideal osmotic system.

Reflection coefficient describes deviation from ideality.

Any force producing filtration will be positive.

Decrease in proteins causes increase in permeability.

Histamine, TNFalpha, analphylatoxins, free radicals all increase permeability.

Electrocardiography

Voltage produced when charges are in motion.

Two types of leads – bipolar and unipolar (+)

12 Lead ECG has 3 bipolar leads (I, II, III) and 9 unipolar leads (aVR, aVL, aVF) and (V1-V6). 10 electrodes

Bipolar leads (limb leads) record potential difference between 2 electrodes. 4th electrode on right leg serves as an electrical ground. Positive poles of these leads lie inferiorly and to the left.

6 leads: limb leads (I, II, III) and augmented leads (aVR, aVL, aVF) are in coronal plane and are derived from the four limb electrodes.

Augmented leads fill gaps between limb leads. Lead aVR stands opposite from others, superior and to the right.

The precordial leads (V1-V6) are in horizontal plane. They point positively towards the chest. add 3D.

A positive vector towards a positive lead will have a positive deflection on ECG.

Cardiac repolarization is opposite of cellular depolarization (positive T wave). Due to repolarization delay (out to in) away from positive electrode.

Charge reverse in endocardium

PR interval is time between beginning of P wave and beginning of QRS complex. Time through AV node (0.2 sec in adult)

QRS Complex – (0.08 sec)

Initial negative = Q

Initial positive = R

Negative after R = S

ST segment – no signature – phase 2 – very important.

T wave is repolarization. Beginning of QRS complex to T wave is QT interval, a measure of AP duration (.44 sec) (should be less than 1/2 RR interval). T wave abnormalities are common.

SAN depolarization gives positive deflection in I and aVF

As it passes from left ventricle to right ventricle, you get negative Q wave in lead I and a positive R wave in aVF.

Endocardium > Epicardium gives a positive R wave in I and aVF

Depolarization of left lateral wall is last, gives R wave in I and negative S wave in aVF

Repolarization is superior and to the right giving T wave a positive deflection in I and avF

Thin lines are .04 sec, thick lines are .20 seconds (25mm/sec). Each lead displayed for 2.5 seconds.

Right Ventricle is tough to see.

• Inferior wall of left ventricle – II, III, aVF
• Lateral – I, aVI, V5, V6
• Anterior – V1-V4
• Posterior – V1, V2, V8, V9
• Right Ventricular – RV1-RV6

The Large Vessels

Damping – reduction in pulsatility – accomplished by placing resistance and capacitance in system.

Capacitance is larger in arteries compared to arterioles.

Capacitance is ability to distend.  Change in volume/Change in pressure

Capacitance is less at high pressure than at low pressure and decreases with aging and disease.

Veins have large capacitance.

Venous blood volume is variable. Passive postural change. When you stand, transmural pressure increases in abdomen and legs. Almost 1L of blood can be displaced into legs.

Intrathoracic pressure increases during exhalation.

Skin, liver, lungs and spleen are important blood reservoirs because they undergo substantial venoconstriction.

Mean Pressure – 100mmHg = Pd + (Ps-Pd)/3

Pressure = Flow x Resistance

Flow = Cardiac Output

So systemic pressure = CO x R = SV x HR x R

Pulsatile pressure – Stroke volume and arterial capacitance are key determinants

When mean pressure rises with nonlinear capacitance, elevation of systolic pressure is greater than diastolic pressure.

Pressure pulse of radial artery. Velocity varies inversely with capacitance. High frequency components tend to be damped out. Systolic portions are more pronounced.

Regulation of Cardiac Function

Stroke Volume can vary from 5-40L/min.

Increased tension produced from a fixed preload is called positive contractility or positive inotropy. (NE)

Ventricles are not well innervated with parasympathetics, so the PNS is more important for HR.

For same internal pressure a larger sphere has greater wall stress. During isovolumetric phase, wall tension increases 25X. Increases to 50x during systole.

Treppe or Staircase phenomenon describes rate induced regulation. Increase HR and you increase force due to cytoplasmic Ca.

Bainbridge Reflex and atrial receptors, stretch induced, ensure inflow and outflow are equal. Increase in venous return will accelerate HR.

Thyroid Hormone increases HR and cardiac output. Also influences myosin ATPase in cardiac cells.

Hypoxia – modest reduction – causes increase in HR and contractility.

Marked reduction causes depressed function

Alkalosis – mild decrease in Co2 – augments cardiac function via effects on myocardium

Acidosis – mild increase in Co2 – depresses heart function

Adrenergic fibers from lower cervical and upper thoracic ganglia. Right nerves work on SA node to increase HR. Left nerve increases contractility via ventricles.

Activation of cAMP dependent kinases phosphorylate Ca channels and phospholamban.

Cannot regulate heart on beat to beat basis, slow fx

B-blocker propanolol

Phosphodiesterase inhibitors slow down removal of Ca, but increase myocardial oxygen need.

Parasympathetics. Right works on SA node to slow HR. Left slows the AV node. Acts on muscarinic receptor, opens K channels, slows phase 4 depolarization.

Blocked by atropine

Fast effects. Keeps HR down at 70 when at rest. Exercise increases vagal tone and decreases HR. This can also happen with increased intracranial pressure.

Thalamic and medullary centers are critical in the control of vasculature

Frontal lobes and orbital cortex have input

Baroreceptor reflex: High BP causes vagal firing and inhibits sympathetics. Receptors in aortic arch and carotid sinus. Acute hypertension may cause bradycardia.

Sinus arrhythmia: HR varies with breathing, increases with inspiration. Due to increased sympathetic firing  due to parallels to phrenic nerve>vasomotor center and increases venous return/Bainbridge reflex. HR decreases during expiration due to increased parasympathetics, decreased venous return.

Chemoreceptor reflex – low o2 or high co2 have small effects on lungs and heart, but bigger effects on vaculature.

Ventricular Receptor Reflex – sensory receptor in wall of ventricle may slow the HR and lower peripheral vascular resistance when stimulated. Mechanical or chemical.

Hemodynamics

P = specific gravity x g x h

Specific gravity of Hg = 13.6 g/cm3

Normal blood pressure will support 130cm of water, 10cm/100mm Hg

760mmHg used as 0.

Perfusion pressure = difference between input and output.

Transmural pressure = pressure across walls.

Flow = Area x Velocity = Q

Potential Energy = Pressure x Volume

Kinetic Energy = 1/2 x density x volume x velocity squared

Friction results in decrease in pressure.

When area is halved, velocity doubles, and pressure decreases .

Calculating hydrostatic pressure in head standing up. 39cmH20 > 390mmH20/13.6 = 29mmHg. Then you subtract that value from 99 and get 70mmHg. For feet you add 96mmHg to 98mmHg.

Newtonian/Streamline Flow: Velocity is 0 and the wall of the tube where the fluid wets the surface. Velocity is 2x mean in center of tube.

Turbulence increases with velocity, density, and area of tube (inertial forces).

Turbulence decreases with viscosity.

Reynolds Number = ratio of inertial forces to the viscous forces. Above 3 000 turbulence occurs. Sounds of Korotkoff.

Blood flows in proportion to perfusion pressure and inverse proportion to resistance. Q=PP/R. This equation can be used to predict a pressure gradient required to drive fluid through tube.

Resistance = Hindrance x Viscosity

H = 8L/Pi(r)4

Viscosity = (F/A)/Shear Rate. Water = 1 centipoise

Shear Rate is greatest at the walls and least at the center. Wall shear stress can cause atherosclerosis. T = (4 x viscosity x Q)/Pr3

Poiseuille-Hagen Equation describes flow in ideal situation

As number of R’s in parallel increases, the total R decreases. Rt=R/n

Hematocrit can vary from 15-75%

Fahraeuas-Lindqvist Effect – when tube approaches size of blood cell, the hematocrit falls. 1)Exclusion phenomenon, cell poor layer near walls. 2) Axial accumulation, cells tend to curve towards center.

At low flow rates, shear rate important due to interactions in plasma (fibro)

Cardiac Electrophysiology

Phases of Cardiac Depolarization

• 0 – rapid depolarization
• 1 – early repolarization
• 2 – plateau
• 3 – repolarization
• 4 – resting potential

For Fast: Early Refractory Period (ERP) lasts from 0-2, Relative Refractory Period lasts 3.

For Slow : ERP lasts from 0-3, RRP lasts from 3-4.

The duration of contraction is determined by the duration of the AP (it persists after repolarization).

Slow conduction in nodes:

• smaller and slower phase 0
• no phase 1
• unstable phase 4

Speed of conduction is proportional to rate of change of membrane potential.

Single channel current = single channel conductance x (membrane potential – potential for channel)

Membrane Na conductance is = (# of channels)(probability open)(single channel current)

K moves out of cell, leaving negatively charged ions behind, producing negative intracellular potential. Resting potential of -90mV is slightly less negative than expected because membrane is permeable to other ions.

Opening and closing of K channels is regulated by transmembrane potential and chemical signals (ACh)

Effects of ions in combination described by chord conductance equation

Na and Ca drive membrane potential positive

Resting potential very sensitive to changes in K compared to Na

Upon depolarization to -65mV, Fast Na Channels open (tetrodotoxin channels, puffer). This makes cell very sensitive to changes in extracellular Na. Lidocaine, Rx arrhythmias, blocks these channels.

Activation Gate – m gate – makes channel more permeable as Em becomes less negative

Inactivation gate – h gate – closes channel as Em becomes more negative

Reversal of membrane polarity from positive to negative is the overshoot of the cardiac AP.

Rate of change of voltage determines the rate of spread of of membrane potential across the heart and thus the speed of contraction.

As soon as membrane potential goes in positive direction, the h gates begin to close, ending the upstroke. H gates remain closed until the cell partially repolarizes in phase 3.

Throughout AP, chemical force remains virtually constant, and only electrostatic force changes.

Phase 0: Inward rectifier current Ik1. At onset of AP, this conductance decreases. Inward rectification means K flux high at negative value, low at positive values. Between -70 and -30mV chemical forces K currents are directed outward.

Phase 1: brief repolarization due to Transient Outward Current Channel (Ito).

Phase 2: plateau due to Ca influx vs. K efflux, 20mV

• L-type Ca channels opened by depolarization from Na, keeps membrane potential positive, long lasting. T-type Ca channel also opened.
• At -30mV/-40mV, Ik1 channel allows K to flow out
• iK channels are activated late in phase 2 and accelerate repolarization, slow or rapid type determines AP duration.

Phase 3: Final Repolarization, efflux of K exceeds influx of Ca

• Ito and Ik initiate repolarization, determine duration of plateau.
• Ik1 contribute to rate of repolarization in phase 3

Phase 4: Restoration of Ionic Concentrations

• Na accumulation eliminated by 3NA/2K ATPase
• Ca accumulation eliminated by 3Na/Ca exchanger, and Ca pump

Catecholamines enhance Ca conductance via B receptors and are major means of regulating contractility. Work through Gs>AC>cAMP>L-type

ACh binds to muscarinic receptors and inhibits AC to regulate heart rate (not really contractility).

Ca channel antagonists inhibit L-type channels. Verapamil, Diltiazem. Paradoxically diminish contractile strength and thus work of heart. They also cause vasodilation. Rx congestive heart failure.

Depolarization in SA/AV nodes due to Ca influx rather than Na.

Because there are so many T-type Ca channels they mute the Ito channels and the plateau is absent.

Repolarization is due to inactivation of Ca channels and conductance of iK channels. iK efflux diminishes through phase 4. Ik1 channels are not found in the nodes (means less negative membrane potential)!

Em affects conduction velocity because the less negative the Em, the more h gates are closed, leaving fewer to be activated by depolarization. This can be caused by increased extracellular K. At K above 10mM, all fast Na channels are inactivated.

In coronary artery disease, the Na/K ATPase is compromised. Potential source of arrhythmia because slow responses are more likely to be blocked.

Threshold potential for slow response is about -40mV. Conduction velocity 0.1m/s vs. 1-4m/s.

ERP or ARP lasts until about -50mV. Duration is determined by time for m and h channels to reset.

With premature depolarizations early in the RRP, reentry can occur leading to ventricular fibrillation, arrhythmia. For reentry to occur you need unidirectional block

In slow response fiber the RRP extends beyond phase 3, called postrepolarization refractoriness. This can lead to conduction blocks in the AV node.

As Heart Rate increases, AP duration diminishes, this is mediated by iK and Ito. Each AP tends to occur earlier in inactivation period of iK of previous AP.

70BPM in SA node compared to 40BPM in AV node.

SA node generates a slow depolarization phase 4. Mediated by 2 currents.

• iF is activated near end of repolarization, inward Na current. Activated at values more negative than -50mV.
• iCa activated near end of phase 4 around .55mV. Ca influx.

Autonomics don’t normally alter the threshhold of the node. However quinidine and procainaminde do raise threshold and lower HR.

Frequency of pacemaker determined by autonomics changing slope of slow diastolic depolarization. Vasovagal syncope in response to pain is extreme example.

Adrenergics affect iF, iCa and iK, enhance all?

Cholinergics depress iF and iCa via Gi opening of iKACh channels and inhibition of AC

Overdrive suppression describes diminishing automaticity at high frequencies. Results from inbalance produced by Na/K ATPase, essentially hyperpolarizes cell. This can happen to SA node after an ectopic foci effect.

Interatrial myocardial band (Bachmann Bundle) conducts impulse from SA node to LA.

3 regions of AV node: AN – N – H > Bundle of His

Conduction velocity only .05m/s causes delay. Seen in delay between P and QRS complex

Wolff-Parkinson-White syndrome is a congenital disturbance involving an accessory pathway. Can result in supraventricular tachycardia. Rx with adenosine or increasing vagal activity through carotid sinus.

Ca channel antagonists depress AV conduction time.

Abnormal prolongation of AV conduction time is called 1st degree block.

Second degree block is essential frequency screening by AV node.

Sympathetics decrease AV conduction time.

Weak vagal activity can prolong AV conduction time.  Strong vagal activity can cause 3rd degree block.

Coronary artery disease can cause blocks in His bundles. Bundle Branch Block vs. Hemiblock.

Purkinje fibers have no T-tubule system.  They have long refractory period. ERP varies inversely with HR. (In AV node the ERP increases with higher HR, thus it serves as protector).

IV septum and papillary muscles are the first to be excited.

The Heart as a Pump

Overlapping filaments in A Band. I Band contains only thin filaments.

Intercalated discs connect cells

• Desmosomes – mechanical connections
• Gap junctions – electrical connections, connexin 43

Cardiac cells can consume lactic acid.

Cardiac APs are long compared to skeletal muscle

Na dominates phase 0, K dominates phase 1, Ca and K share phase 2, K dominates phase 3.

Depolarization opens L-type Ca channels in sarcolemma. Ca flows into cell. Also opens Dihydropyridine receptor in T-tubules. Ca enters space next to terminal cisternae SR.

Rhyanodyne receptor activated. Ca release from SR. CICR.

Ca increases from 0.1um > 100um

Troponin T connects troponin complex to tropomyosin.

Ca binds to Troponin C, weakening bond between Tropinin I and Actin. Unblocking.

Control of Ca release is determined by phosphorylation of:

• L-type Ca Channel – increases release, contraction
• Phospholamban – reduced inhibition of SR pump has effect of accelerating relaxation and increasing amount of Ca in SR for next beat.

Protein Kinase A (PKA) phosphorylates Troponin I, reducing Ca affinity for troponin C, which increases the rate of relaxation.

Decrease in phosphodiesterase activity (milrinone) will increase cAMP > phosphorylation > contractility.

Sympathetic stimulation > B receptors > phosphorylation cascade

• Diastolic Filling
• Isovolumetric Contraction – Fiber length does not change, pressure up
• Ejection
• Isovolumetric Relaxation – Fiber length does not change, pressure down

Precontraction fiber length is the End Diastolic Volume (EDV) or Preload

Afterloaded – preload determines fiber length and afterload is weight that has to be lifted.

A larger afterload means less shortening

Starling Law of Heart – Relates Length and Force

• preload determines length of fibers
• End Diastolic Pressure (EDP) used to estimate Preload or EDV
• preload expressed as volume, afterload as a pressure

Contractility is change in force without change in resting fiber length. Estimated by pressure rise at beginning of systole (dP/dt)

Fick prinicple used to measure Cardiac Output by determining flow rate from substance removal. Oxygen Consumption / Amount of Oxygen removed from blood from PA>PV.

MRI, ECG, Thermodilution and dyes also used to determine Cardiac Output

Flow is 5L/min. > 20L/min. everywhere

Pressures (mm Hg)

• Right Atrial End Diastolic – 5
• Right Ventricular – 25/5
• Pulmonary Artery – 25/15
• Pulmonary Wedge – 15 (Approximates Left Ventricle from catheter in PA)
• Pulmonary Vein – 18
• Left Atrial End Diastolic – 15
• Left Ventricular End Systolic – 0
• Left Ventricular – 120/15
• Aortic 120/80
• Mean Arterial Pressure – Diastolic + 1/3 pulse pressure (empirical average)

Introduction to Cardiovascular System

Velocity decreases from arteries to capillaries and rises again to veins.

Cardiac Output = Heart Rate x Stroke Volume

Blood Pressure = Cardiac Output x Vascular Resistance

Arterial system has higher resistance than venous system. Resistance increases from arteries to arterioles. Wall/Lumen ratio increases from arteries to arterioles then decreases to veins.

Pressure in left side of heart 4x right side.

Flow must be equal on left and right sides of heart.

Histology of Blood and Blood Vessels

Pressure and speed of flow decrease from arteries to veins.

Capillaries have the highest permeability and regenerative ability.

Elastic substance decreases from artery to capillary and then increases to vein.

Muscle increases from artery to arteriole and from venule to vein.

Vaso Vasorum present in arteries, venules, and veins.

Total area greatest in capillaries.

Tunics of Blood Vessel:

• Tunica Intima – longitudinal – squamous + smooth muscle cells
  • Internal elastic lamina -well developed in muscular arteries
• Tunica Media – helical – smooth muscle
  • External elastic lamina – well developed in muscular arteries
• Tunica Adventitia – lonigitudinal – fibroblasts + collagenous + elastic

In large vessels, media and adventitia are supplied by vaso vasorum.

Principle tunic in arteries is media.

• Tunica media of elastic arteries has fenestrated sheets of elastin interspersed with smooth muscle. These arteries have thin adventitia with abundant vaso vasorum.
• Tunica media of muscular arteries is relatively thinner and sooth muscle predominates, also remember the prominent internal elastic lamina.
• Tunica media of arterioles has 1-6 layers of smooth muscle. (1/3 mm in diameter)

Capillaries (10um diameter)

• Endothelia surrounded by basal lamina and occasional pericytes.
  • Pericytes contain actin, myosin, tropomyosin
• Three Types
  • Continuous – Muscle and Brain
    • Continuous endothelia joined by tight junctions
    • Diffusable by hydrophilic molecules
    • Other molecules transported by transcytosis
  • Fenestrated – Intestines and Kidneys
    • pores allow rapid exchange of water and small molecules
  • Sinusoidal – Liver, Bone Marrow, Endocrine Glands
    • Smaller irregular channels make both endothelium and basal lamina discontinuous.
    • Allow slow circulation of blood.

Principle layer in veins is adventitial.

• Postcapillary Venules – similar to capillaries (20um)
• Medium veins contain valves

Lymphatic Vessels

• Capillaries are blind ended irregular tubes with loosely joined cells and a complete basal lamina. Anchoring filaments provide structure
• Vessels are thinner walled than veins. They have valves.

Vasculogenesis – angioblasts come together to form loose chords of cells which differentiate into endothelia.

Angiogenesis – sprouting, growth factors released by tumors or inflammatory cells, ECM remodeling.

• role in metastases and tumorigenesis
• inhibitors often prevent adhesion of endothelial cells

Plasma contains fibrinogen, immunoglobulins, complement proteins, lipoproteins, albumin

• Albumin gives blood colloid osmotic pressure.

Erythrocytes – 90% of formed elements (7um)

• packed with hemoglobin, glycolysis enzymes, bicarbonate converting enzymes
• Unique cytoskeleton

Leukocytes

• Diapedesis – migrate between endothelial cells.
• Granulocytes
  • Neutrophils (70%) alsoPMNs
    • multi-lobed single nucleu
    • lack of staining
    • Stimulated by inflammation to migrate and phagocytose bacteri (kamikaze)
  • Eosinophils (5%)
    • bilobed nucleus
    • eosin staining granules in cytoplasm
    • stimulated by mast cells and granulocytes to sites of inflammation
    • phagocytose AA complex and exocytose substances that inactivate inflammatory signals
    • fight worm infections
  • Basophils (1%)
    • s-shaped nuclei
    • large basophilic granules contain heparin, histamine, chemotactic factors
    • Similar to mast cells
    • express IgE receptors, crosslinking of IgE by antigen results in degranulation and release of histamine
• Agranulocytes
  • Lymphocytes (20%)
    • 3 polulations
      • T-Lymphocytes – cell mediated response
      • B-Lymphocytes – differentiate into plasma cells which produce antibodies
      • Null Cells – NK cells and stem cells
  • Monocytes (3-8%)
    • Largest of blood cells
    • Deeply indented nucleus
    • Leave blood stream and mature to macrophages which can be APC
  • Platelets – anucleate fragments (2-4um)
    • produced in megakaryocytes in marrow

Tubular Function

Na gradient powers the reabsorption of solutes

In first half of the PT, reabsorption of Na and secretion of H power reabsorption of HCO3

Reabsorption of water and solutes via tight junctions

Second half of PT, Na/H and Cl/anion exchangers result in secretion of HA and reabsorption of NaCl. Organic cations are secreted in exchange for H

Cl and Na also reabsorbed via leaky tight junctions

TAL – NKCC transporter , special cation transport mechanisms in tight juncitons.

Bartter’s syndrome, type 1, mutation inactivates NKCC

First part of distal tubule – coupled Na/Cl transporter, blocked by thiazides

Gitelman’s syndrome – inactivating mutation of NaCl cotransporter

Late distal tubule and cortical collecting tubule

Two cell types:

1. Prinicpal – reabsorb Na and secrete K
   1. ENaC channel makes lumen electronegative, drives secretion of K
   2. Liddle Syndrome – increased ENaC – hypertension
2. Intercalated – Secrete H, usually reabsorb K and HCo3

Kidney produces Nh3 and NH4

PT cells metabolize glutamine to HCo3 and Nh4

NH4 secreted into lumen in exchange for Na

NH4 reabsorbed in the LoH and accumulates in medullary interstitium

NH3 and NH4 in equilibrium, pka=9.3

When fluid in collecting tubule is acidic, NH4 accumulates there

Nh3 can diffuse, NH4 cannot, diffusion trapping,

NH3 is important buffer that allows secretion of H

Tuboglomerular balance – helps keep PT absorption constant, Pi and P

SNS stimulates reabsorption of NaCl in all nephron segments

Angiotensin II stimulates reabsorption of NaCl and water in PT, but this is inhibited by renal dopamininergic neurons