Human Organ Systems Test 2, Cardiovascular

Heart Rate X Stroke Volume

Flow X Resistance

Amount of blood returned to the heart (diastolic filling)

Resistance in vasculature

Heart rate, contractility, preload, afterload

Heart --> Elastic artery --> Muscular artery --> Arteriole --> Capillaries --> Venules --> Vein --> Heart

• 15 - Heart and lungs
• 70 - Venous system
• 05 - Capillaries
• 10 - Arterial system

Epinephrine and norepinephrine increase heart rate and contractility; the increased force is gained by increases in Ca2+

Arterioles

• Fibrous outer layer made mostly of collagen
• Inner parietal layer made of mesothelial cells that secrete fluid

Made of mesothelial cells on the outer surface with connective tissue, fat, nerves and blood vessels below

Made of endothelial cells which are continuous with those of vasculature; some connective tissue is also present

• Annuli fibrosi (fibrous rings) allow for attachment of the atrioventricular valves
• Trigona fibrosi (fibrous trigones)
• Septum membranaceum (upper part of the septum)

Endothelium, connective tissue, and nerves

Fascia adherens, desmosomes, and gap junctions

Lipids, which are stored in lipid inclusions within the cardiomyocyte

Activated upon stretch, these granules found within cardiomyocytes contain atrial natriuretic factor (ANF)

Atrial natriuretic factor: Causes vasodilation (ANF is released from cardiomyocytes following stretch activation) and inhibits antidiuretic hormone, leading to diuresis and excretion of Na+

• Collagens I and III are in connective tissue septa and around blood vessels
• Collagen struts are between cells and blood vessels and prevent distortion and sliding

Mostly occurs during diastole (80%), since flow is limited in systole because of compression

Aerobic metabolism

Decreased blood flow leading to hypoxia; atherosclerosis and arteriole spasms are main causes. Ischemia is more severe in endomyocardium because arteries course transmurally from epicardium toward endocardium

Cell death caused by prolonged ischemia

Beat spontaneously, have no intercalated discs, are small, and are poorly organized

This node slows the conduction rate causing the impulse to the ventricles to be delayed

Large cells found in the endocardium that are rich in glycogen, have poor contractile proteins, conduct rapidly, and have large, round nuclei and a faint-staining cytoplasm

Pain that is felt during myocardial ischemia which is often manifested as referred pain due to sensory fibers following sympathetic nerves and synapsing

The innermost layer of blood vessels which contains the endothelium and a subendothelial space; is the site of atherosclerosis

Contains the muscular and elastic components of blood vessels and is absent in capillaries and small venules

Contains connective tissue, nerves, and, in larger vessels, vasa vasorum (microvessels) and lymphatics

Include tight and gap juctions; however, capillaries and venules have only tight juctions

• Relaxation: Nitric oxide, prostacyclin, EDHF
• Contraction: Angiotensin II, thromboxane A2, endothelin

• Anticoagulation: Prevails in normal conditions; negative charges on the lumenal surface repels platelets; anti-thrombin III inhibits thrombin
• Procoagulant: Damage to endothelial cells results in a coagulation cascade; Weibel-Palade bodies (granules) make von Willebrand factor (VWF), a anti-hemophilic

VWF is a carrier for factor VIII and is an anti-hemophilic made by Weibel-Palade bodies in endothelial cells when damage to ECs occurs

Found in capillaries and non-muscular venules (NOT arteries) that are present within the basal lamina and can differentiate into smooth muscle cells or fibrocytes

Adenosine, hypoxia, low pH, ADP, or endothelial factors (nitric oxide, prostacyclin, EDHF) which activate beta adrenergic receptors

Epinephrine or norepinephrine (sympathetic nervous system) binding to alpha adrenergic receptors (these compounds can also bind to beta receptors)

Present in terminal arterioles and allow for flow to capillaries to be completely shut off

An arteriole that transverses the capillary bed and drains directly into a venule

• Plaques form as fatty streaks, fibrosis, then calcification (which is irreversible)
• This all occurs within the tunica intima and includes macrophages, smooth muscle cells, and leukocytes
• Molecularly: LDLs are taken up by ECs and oxidized; macrophages then engulf the LDLs and become foam cells; the smooth muscle cells migrate and release collagen causing fibrosis

• Hardening of the arteries
• Atherosclerosis is technically one type of arteriosclerosis, but also has plaque development
• Major risk factors are hypertension and diabetes

Defective valves cause reversal of blood flow, causing pooling of blood in peripheral veins instead of drainage to deep veins

• Neovascularization by foration of microvessels (vascular sprouting)
• 1: Disintegration of basement membrane
• 2: Cell migration
• 3: Cell proliferation
• 4: Formation of new basement membrane

• Stem cells migrate and assemble to form new microvessel
• Occurs during development and disease states

• Continuous with numerous transport vesicles and intracellular clefts (muscle, lung, gonads, skin)
• Continuous with zonula occludens and few vesicles (CNS)
• Fenestrated with high permeability (kidney, endocrine glands, intestinal villi, exocrine pancreas)
• Sinusoidal with large gaps and phagocytic cells positioned around wall (liver, spleen, bone marrow, lymph nodes)

• Hydrostatic pressure (weight of fluid above)
• Concentration gradients
• Osmotic pressure

• Transcellular: Diffusion through cell based upon concentration gradient
• Transcytosis: Receptor-mediated endo/exocytosis
• Intercellular: In between neighboring cells
• Vesicular channels: Channels spanning the entire thickness of the cell
• Lymphatic capillaries use only intercellular while endothelial cells can use any

Occurs in liver, hematopoietic tissues, and post-capillary venules of lymph nodes

• Can be up to 100um in diameter (vascular capillaries are up to 40um)
• Have a poorly developed basal lamina and are supported by anchoring filaments

Found near the right atrium, a group of cells make up the sino-atrial node, and any one of them can assume the role of the normal cardiac pacemaker

Atrial muscle tissue oriented to promote preferential conduction from the SA node to the AV node

The atrio-ventricular node is normally the only electrical conduction pathway between the atria and the ventricles due to the dense fibrous rings around the AV valves

Important for ventricular conduction, these left/right and anterior/posterior bundles sit just below the AV node

Large-diametered cells (70-80um) with many Na channels that have the fastest conduction velocity (4m/s)

Conduction spreads from the endocardium out to the epicardium via myocytes (10-15um diameter, 1m/s conduction velocity)

• The V_m (resting membrane potential) is maintained by the sodium-potassium pump (3 Na⁺ out of the cell and 2 K⁺ inside) which is responsible for the slightly negative (-30mV) V_m, the high intracellular [K] and the high extracellular [Na⁺].
• The V_m is dependent on the flux of all ions through ion channels.

• Flux for each ion can be calculated by:
• G stands for conductance, which is the ease at which ions flow through a channel
• In cardiac myocytes at rest, K channels are 100 times more permeable (leaky) than other ion channels, meaning that the resting membrane potential is very close to E_K.
• The outward leak current of potassium is called the inward rectifier (I_K) and the smaller Na leak current is the I_{Na background}

• An I_f (funny) current of cations moving inward slowly occurs due to HCN (hyperpolarization-activated, cyclic necleotide gated) channels
• I_Ca occurs by mainly transient Ca channels (Ca is flowing inward all the time)
• I_K occurs by an outward flow of K, but the conductance (or ease of which K flows through the channels) decreases during diastolic depolarization, causing a depolarization

• SA node: 60-100 beats/min
• AV node/bundle of His: 40-50 beats/min
• Ventricular myocytes: less than 40 beats/min
• This makes sense because the SA node cells depolarize more rapidly and send an AP to the other cells before they can depolarize themselves

• The velocity is influenced by the voltage difference of the two cells and the resistance between them
• (Ohm's Law)
• The difference in voltage can be altered by the amplitude and rate of rise of APs and the resting membrane potential
• The resistance can be altered by the number of gap junctions and the fiber diameter (the larger the fiber, the faster the velocity)

• Effective refractory periods are where NO AP can be conducted due to all fast Na channels being inactivated
• Relative refractory periods are where is is difficult to initiate an action potential because some Na channels are still inactivated, but not all of them are

• SA/AV node: Small-diametered cells with few intercellular connections and weak contractile activity
• Atrial/ventricular muscle: Medium-diametered cells with many intercellular connections and strong contractile activity
• His bundle/bundle branch/Purkinje cells: Large-diametered cells with many intercellular connections and weak contractile activity

The horizontal time axis has large boxes that represent .2 sec and the vertical voltage scale has large boxes that represent .5mV

• P wave: Atrial depolarization
• QRS complex: Ventricular depolarization
• T wave: Ventricular repolarization
• ST segment: Time between completion of ventricular depolarization and before ventricular repolarization; nearly all ventricular myocytes are depolarized
• PR interval: Pause between atrial and ventricular depolarization (.12-.2 sec) due to slow conduction of AV node
• QRS interval: Total length of time necessary to depolarize the entire ventricular muscle (indicative of His-Purkinje system) (.07-.12 sec)
• QT interval: Correlates closely with mean AP duration of ventricular myocytes (~.4 sec)

Heart rate (bpm) = 60(sec/min) / R-R interval (sec/beat)

The T wave is positive because it is a repolarization in the opposite direction of the electrode. Therefore, it can appear the same (positive direction) as the depolarization (QRS complex) heading in the direction of the electrode

• Lead I: Right arm (negative electrode) to left arm (positive electrode)
• Lead II: Right arm (negative elctrode) to left foot (positive electrode)
• Lead III: Left arm (negative electrode) to left foot (positive electrode)

• aVR: Sum of left arm and leg (negative electrodes) to right arm (positive electrode)
• aVL: Sum of right arm and leg (negative electrodes) to left arm (positive electrode)
• aVF: Sum of left and right arms (negative electrodes) to left foot (positive electrode)

• The axis is in the normal range if both leads I and II have a positive QRS. The normal range is from -30 to +90 degrees (lead I is 0 and lead II is 60)
• The mean axis can be determined by the isoelectric method; an isoelectric lead (one where there are equal positive and negative deflections) is chosen because the axis is perpendicular to it and the direction is determined by the lead with a great positive deflection

• Physiological abnormality: The heart may be positioned at an alternate angle; affected by posture and body build
• Pathological abnormality: Ventricular hypertrophy, myocardial damage, or bundle branch block may be present

• V1 through V6 are positive electrodes which record in the horizontal plane; they are compared to the negative electrode which is the sum of leads I, II, and II (the middle of the heart)
• Can determine the mean vector in the transverse plane, which is towards the left ventricle
• 

• Late Phase 1: Inflow; mitral valve open but little flow into ventricle since ventricles are nearly full; atria contract and contribute <20% to ventricular volume
• Phase 2: Isovolumetric contraction; beginning of systole; mitral valve closes; ventricular volume remains the same because the aortic valve has not yet opened and the ventricular pressure is lower than aortic pressure
• Phase 3: Outflow; ventricular pressure exceeds aortic pressure and aortic valve opens allowing for rapid ejection followed by decreased ejection, during which aortic pressure exceeds ventricular, but outflow continues because of the inertia of the blood flow
• Phase 4: Isovolumetric relaxation; blood flow into aorta ceases and closure of aortic valve occurs because of slight reversal of blood flow; this closure results in a slight increase in aortic pressure (dicrotic notch); ventricular pressure is still greater than atrial, so mitral valve has not yet opened (ventricular volume same)
• Early phase 1: Inflow; rapid ventricular filling because ventricular pressure falls below that of atria and mitral valve opens

• Initiated by AP from adjacent cardiomyocyte
• T tubules are invaginations of sarcolemma near Z discs and the sarcoplasmic reticulum contains large amounts of Ca
• Ca entry occurs during an AP through L-type Ca channels; this Ca entry causes ryanodine receptors to release Ca from the SR (L-type Ca channels and RyR are not mechanically coupled)
• Intracellular Ca levels spike and contraction occurs just as skeletal muscle

• Relaxation happens when Ca dissociates from troponin C, and Ca is extruded by a Na-Ca exchanger and a Ca pump
• SERCA2 causes reuptake of Ca into sarcoplasmic reticulum
• Phospholamban is a protein that regulates SERCA2: when PLB is phosphorylated, it cannot inhibit SERCA2
• Some Ca is also sequestered by mitochondria

• Passive: Cardiac muscle has greater levels of titin, allowing it to be less distensible than skeletal muscle, which results in a steeper length/tension slope
• Active: Cardiac muscle does not have overstretch due to high levels of titin; the resting length of cardiac muscle also modulates Ca binding to the contractile proteins, causing cardiac muscle to be activated in a much narrower sarcomere length range

• The X-axis is the end diastolic volume which represents the sarcomere length; it is the volume in the left ventricle just before contraction
• The Y-axis is the stroke volume (or cardiac output, since it equals SV times heart rate), representing the force, load, or tension

• Preload: The amount of blood returned to the heart; it is the same as the initial sarcomere length; an increase in preload results in an increase in stroke volume (A to C)
• Afterload: The resistance in the vasculature, or the force that the contracting myocardium must overcome; a decrease in afterload results in an increase in stroke volume and a decrease in end diastolic volume (A to D)
• Intrinsic contractility: An increase in contractility causes a shift in the curve upwards and to the left (A to D)

• Increasing afterload results in slower shortening
• Increasing preload results in faster shortening

• Right ventricle: The free wall moves towards the septum (not efficient to generate high pressure)
• Left ventricle: The chamber constrics in a twisting movement due to circular oriented fibers

• A: Mitral valve closes (beginning of contraction)
• B: Opening of aortic valve
• C: Closure of aortic valve
• D: Opening of mitral valve

The maximal isovolumetric pressure (theoretical--think about what would happen if aortic valve was sealed shut) is proportional to the end-systolic pressure (the strength from contraction), both of which are good measures of intrinsic contractility. In other words, the ESPVR is the intrinsic contractility.

Increased contractility results in the heart emptying to a lower volume (stroke volume increased)

Increased preload results in greater stroke volume due to greater filling of the ventricles

Increased afterload results in the ventricles reaching a higher pressure during isovolumetric contraction (the increased afterload results in greater aortic blood pressure that must be overcome before opening of aortic valve) and stroke volume is decreased

The area within the loop (W=P*ΔV)

• E = P*V + 1/2mv² + k*T*Δt
• PV equals work
• 1/2mv² equals kinetic energy (or the speed at which the heart ejects blood)
• Work and kinetic energy equal the total external work
• kTΔt equals tension heat, which is the energy required to generate tension during isovolumetric contraction
• The tension heat is the major determinant of the total energy requirement of the heart

When heart rate increases, contractility/strength of contraction does also due to increase in intracellular Ca (the increase in number of AP leads to more Ca influx and an increased inward Ca current per AP)

A higher preload leads to an increased force of contraction and an increase in stroke volume

• The premature beat has a lower volume due to less time to fill and the post-extrasystolic contraction has a longer time to fill and increase its end-diastolic volume
• Less calcium is available for the extrasystolic contraction, resulting in a less strong beat (and a stronger post-extrasystolic beat)

• The autonomic nervous system regulation of heart rate and ventricular contraction
• Hormones

• Sympathetic: Postganglionic fibers arise from the stellate ganglion and innervate the SA node, atria, the AV node, and the ventricles
• Parasympathetic: Preganglionic fibers are found in the vagus nerve and synapse onto postganglionic fibers in the SA node, atria, AV node, and to a lesser extent, the ventricles

Norepinephrine acts on β₁-adrenergic receptors (β₁ARs)

Acetylcholine acts on muscarinic (M₂) receptors

• They are both G protein-coupled receptors
• β₁ARs are coupled to G_s which activates adenylate cyclase to increase levels of cAMP, which activates PKA that phosphorylates specific proteins. M₂ receptors are coupled to G_i which inhibits the cAMP-PKA pathway

• Follow parasympathetics via vagus nerve with cell bodies in nodose ganglion and integrate into the CNS via the nucleus tractus solitarii
• Follow sympathetics with cell bodies in DRG

• Increase contractility and decrease duration of contraction by β1AR activation of cAMP-PKA pathway
• This pathway leads to (1) phosphorylation of PLB which stops inhibition of SERCA2 which allows faster reuptake of Ca (and a faster contraction) (2) phosphorylation of L-type Ca channels causing them to open easier and allow more Ca inside the cell (3) phosphorylation of trponin I which facilitates quicker dissociation of Ca from troponin C (increased speed of relaxation)

• Increase in peak pressure
• Decrease in ventricular diastolic pressure
• Decrease in end-systolic ventricular volume
• Increase in the velocity of contraction
• Shortened systole and lengthened diastole

Decreased contractility and increased duration of contraction by M₂ inhibition of the cAMP-PKA pathway

• When we gave a M₂ blocker (atropine) and a β₁AR blocker (propanolol), we see that parasympathetics influence the base heart rate drastically (keep HR at 62bpm instead of 100bpm)
• 

• M₂ activation causes release of a βγ subunit that opens the inward-rectifier K channels (GIRK) which makes the V_m more negative, taking longer to depolarize
• I_f, or the pacemaking influx of Ca, is also reduced, resulting in lower levels of intracellular Ca and a higher level of threshold
• Slowed conduction velocity through the AV node
• All of these changes result in a slower heart rate

• They do not play as large of a role as parasympathetics for resting heart rate, but take over during exercise or stress
• The rate of effect on heart rate is slower than the rapid effect caused by parasympathetic stimulation
• I_f and I_Ca are both increased which increases the steepness of phase 4 (the pacemaker activity) and lowers the threshold for AP generation

• Activated by an increase in sympathetic nerve activity or a decrease in cardiac output
• Renin cleaves angiotensinogen to make antiotensin I. ACE converts Ang-I into Ang-II.
• Ang-II: Causes an increase in vascular resistance (vasoconstriction), increased Na retention, and production and release of aldosterone from adrenal gland
• Aldosterone: Increases Na resorption and water retention, increases salt and water intake, and therefore increases total fluid volume
• All these effects occur by AT₁ Receptors
• Angiotensin and aldosterone affect cardiac hypertrophy, oxidative stress, apoptosis, and extracellular fibrosis

• Released from the adrenal medulla during stress and exercise
• Causes increase in HR and contractility via activation of β₁AR

S1 is caused by closure of the mitral and tricuspid valves and S2 is caused by closure of the aortic and and pumonic valves

• S3 is caused by sudden tensing of the chordae tendinae and the AV ring (opening of the mitral valve) during the rapid phase of ventricular filling
• It is normal in children and young adults, but can be indicative of congestive heart failure
• Ken-Tuck-Y

• S4 is the audible pressure wave generated by atrial contraction which is heard when the heart wall is stiff or noncompliant (ventricular hypertrophy or atrial hypertension)
• It is not a normal finding
• Ten-nes-see

• Aortic stenosis: Begins after S1 at ejection due to a nozzle effect of high velocity flow
• Mitral regurgitation: Begins at the onset of S1 (holosystolic murmur)

• Mitral stenosis: Often creates an opening snap (S3) followed by a low-pitch rumbling diastolic murmur
• Aortic regurgitation: This type of murmur diminishes through diastole as the pressure gradient becomes less

• Opening: The pulmonary valve opens slightly before the aortic because the right ventricle has to generate less pressure than the left ventricle (pulmonary versus systemic circulation) and therefore has a shorter period of isovolumetric contraction
• Closure: The aortic valve closes before the pulmonary because the downstream pressure in the aorta is higher, allowing left ventricular pressure to drop below it faster; the right ventricle contraction also lasts longer, keeping the pulmonary valve open

The mitral valve closes slightly before the tricuspid because the left ventricle contracts slightly before the right

Inspiration, because the negative intrathoracic pressure facilitates venous return to the right heart, causing a larger preload which postpones the closing of the pulmonary valve

The pulmonary valve closes earlier than noral due to conditions such as pulmonary hypertension

• a peak: Caused by contraction of atria
• av minimum: Relaxation of atria and closure of AV valves
• c peak: Bulging of AV valves into atria caused by early ventricular contraction
• x descent: Shortening of the ventricles during ejection causes elongation of atria and veins, lowering their pressure
• v peak: Filling of atria against a closed AV valve
• y descent: Fall in atrial pressure as AV valve opens and rapid ventricular filling occurs

Right atrial pressure, right ventricular pressure, and pulmonary capillary wedge pressure, which is the same as the pulmonary veins or the left atrium, since all upstream influences are blocked

• Right atrium: 2 (mean)
• Right ventricle: 25/6
• Pulmonary artery: 25/8
• Left atrium: 8 (mean)
• Left ventricle: 120/8
• Aorta: 120/70

• With a Swan-Ganz catheter
• Right ventricle: RV end-diastolic pressure/right atrial pressure is preload and the mean pulmonary artery pressure is afterload
• Left ventricle: Pulmonary capillary wedge pressure (balloon inflated) is preload and mean systemic arterial pressure is afterload

• Fick method: Concentrations of a specific indicator (such as oxygen) are measured before entering the cardiac system and after leaving the cardiac system (C_in and C_out) and consumption of the indicator (V, which is the difference of indicator inhaled and indicator exhaled per time). Then, the rate of the flow of the heart is: 
• Indicator-dilution method: Inject an indicator into a systemic vein and measure its mean concentration and duration it is present downstream of the heart. Determine the amount of dilution. Concentration versus time is used
• A temperature versus time can be used also to measure CO or SV, by injecting cold saline into the right atrium and measuring the temperature in the pulmonary artery.

Decrease, since the blood is moving faster through the capillaries, meaning that there is a lesser amount of time for oxygen extraction

• Aka hydraulic filter, the Windkessel effect refers to the reduction of pulsatility of arterial pressure and flow caused by compliance (distensibility) and elasticity
• When the aorta is distended during systole, ventricular wall tension and cardiac workload are reduced since the aortic pressure rise is limited
• Elastic recoil limits the drop in pressure of the aorta, maintaining pressure and blood flow to the tissues

Arterioles, because they have thick muscular walls and a narrow radius

• Defines the determinants of the flow of fluid through a nondistensible tube
• Flow is proportional to the inlet pressure (mean arterial pressure) minus the outlet pressure (venous pressure, which is often near zero and can be deleted; right atrial pressure for systemic resistance) and is inversely proportional to the resistance
• 
• Similar to Ohm's Law for electricity (I=V/R)

• Arterioles are the major site of vascular resistance
• 
• Radius (r): The most important factor! Resistance is altered in the cardiovascular system by changing the radius of blood vessels at key control points
• Tube length (L): Resistance is proportional to length
• Viscosity (n): Resistance is proportional to the viscosity of the fluid; viscosity is the lack of slipperiness between adjacent layers of fluid; living at higher altitudes can result in a higher hematocrit, higher viscosity, and higher resistance

• Since , for systemic circulation (TPVR stands for total peripheral vascular resistance)
• Since RAP is near zero, CO can be approximated to
• Therefore:

Total peripheral vascular resistance and cardiac output

• HR: 55-80bpm
• SV: 70-80ml/heart beat
• CO: 4.0-5.5L/minute
• MAP: 85-95mmHg

• Series: Total resistance is the sum of all
• Parallel: Reciprocal of the total resistance is the sum of the reciprocolas of the individual resistances--total resistance is much less than each of the individual resistances

• Laminar flow: Streamlined; outer layers are slowed by viscous drag, and the fastest flow is found at the center of the vessel (shaped like a parabola)
• Turbulent flow: Disorganized; high fluid velocity and density, large diameter, and low fluid viscosity all promote turbulent flow. These are all proportional to Reynold's number

Representative of turbulent flow, N_R, or Reynold's number, is proportional to the velocity, density, and diameter of the blood vessel and is inversely proportional to the viscosity

• Distal to stenoses due to high velocity and an increase in diameter
• During exercise, when fluid velocity is high
• When patients are anemic, because fluid viscosity is lowered
• Turbulent flow predisposes to development of atherosclerosis and thrombus

True: This is because diastole is longer than systole. MAP is approximately equal to the diastolic pressure plus 1/3 of the pulse pressure, which is the difference between the systolic and diastolic pressures

• The change in volume that occurs in response to a change in pressure (the slope of the pressure-volume relationship)
• Decreases with aging and in patients with vascular disease, due to increased collagen, sympathetic nerve activity, or renin-angiotensin system; endothelial dysfunction; or decreased elastin

140/90

• Pressure at the bottom of a column of fluid is equal to the force of gravity x the density of the fluid x the height of the column
• We eliminate this confounding by measuring blood pressure at the level of the heart

• The difference between systolic and diatolic pressures of the arteries
• Affected by stroke volume and arterial compliance

• A law defining the wall tension of a vessel or the ventricular wall stress/tension
• It is useful in describing why capillaries are resistant to aneurism
• Tension=Pressure x Radius
• Capillaries have both low pressure and small radii

• Thin walled endothelium
• Large surface area in total
• Structure and permeability vary among different vascular beds
• Large total cross-sectional area and low velocity of blood flow

• Exchange of nutrients and waste products between cells and blood
• Filtration and reabsorption of fluid
• Metabolic and paracrine functions of endothelium

• Fick's law:
• J: Quantity of substance moved per unit time
• D: Diffusion coefficient for a molecule (inverse to molecular weight)
• A: Surface area of the diffusion pathway
• C₁-C₂: Concentration gradient across the capillary membrane
• T: Thickness of the wall

• Regulate blood flow and arterial pressure by:
• Angiotensin I conversion into angiotensin II by ACE (angiotensin converting enzyme) which causes vasoconstriction
• L-arginine conversion into nitric oxide by NOS (nitric oxide synthase) which causes smooth muscle relaxation

• 
• k: Filtration coefficient for the capillary membrane
• P_c: Capillary hydrostatic pressure (intraluminal blood pressure); usually from 15 to 32 mmHg
• n_i: Interstitial colloid osmotic pressure (pressure due to proteins); usually from 0.1 to 5 mmHg
• P_i: Interstitial hydrostatic pressure; close to 0 mmHg
• n_c: Capillary colloid osmotic pressure; usually around 25 mmHg and is relatively constant (except for kidney)
• Filtration is favored by: P_c and n_i
• Resorption is favored by: P_i and n_i

High arterial pressure, venous pressure, and venous resistance and low arteriolar resistance raise capillary hydrostatic pressure

• Return fluid and protein to circulation via subclavian veins
• Lymphatics have valves that prevent fluid accumulation
• Lymphatics can contract along with skeletal muscle to facilitate movement of fluid back to circulation

• Low pressure
• High compliance (distensibility)

• Increased vascular tone in veins which decreases compliance (distensibility)
• Skeletal muscle contraction
• Integrity of valves
• Negative intrathoracic pressure during inspiration
• Posture/gravity

• The phenomenon by which certain vascular beds are able to maintain blood flow nearly constant despite changes in arterial (perfusion) pressure
• Usually increases local resistance (not peripheral!) in response to an increase in pressure and vice versa
• Metabolic mechanisms: Blood flow is governed by metabolic activity of the tissue via vasodilator metabolites (high pressure washes them away, so vasoconstriction occurs to move blood flow back towards baseline)
• Myogenic mechanisms: Vascular smooth muscle is stretched when pressure increases, causing an increase in [Ca] in vascular smooth muscle and contraction to move blood flow back towards baseline

• Hyperemia, or increased blood flow, occurs when vasodilator metabolites enable blood flow to be matched to metabolic demand
• Active hyperemia: An increase in tissue activity leads to greater production of vasodilator metabolites
• Reactive hyperemia: An obstruction in blood flow leads to accumulation of vasodilator metabolites because reduced blood flow is not enough to wash the substances away from tissue. This results in vasodilation following occusion

• Neural control of blood flow is strong in skin, resting skeletal muscle, kidneys, and visera
• It is weak in brain, heart, and exercising skeletal muscle

Diastolic aortic pressure, because extravascular compression of coronary arteries occurs in systole due to ventricular contraction

Thermoregulation, which is mainly controlled by neural mechanisms (local control not as important)

They are often structural changes, such as the development of collateral vessels in ischemic heart disease or angiogenesis

• A change in the metabolic demand of a tissue (exercising skeletal muscle)
• Obstruction of blood flow to tissue (atherosclerotic lesion in large artery)
• Changes in arterial blood pressure

Include: Potassium ion, adenosine, prostaglandins, nitric oxide, and hydrogen peroxide

• A vasodilator metabolite released by endothelial cells
• Made from L-arginine by nitric oxide synthase (NOS) in response to acetylcholine or serotonin in the blood or shear stress caused by high blood flow (flow-mediated vasodilation)
• Tonic vasodilation is maintained by NO in resistance vessels (arterioles)
• Platelet activation is inhibited

• A vasodilator metabolite released by endothelial cells (and others)
• Inhibits platelet activation

A powerful vasoconstrictor released by endothelial cells

• Serotonin: Causes vasoconstriction and platelet activation while also evoking opposing vasodilation by stimulating release of NO
• Thromboxane: Causes vasoconstriction and platelet activation

• Norepinephrine: Binds to alpha adrenergic receptors in the vasculature to cause vasoconstriction and to beta-1 receptors in the heart to increase heart rate and contractility; also inhibits additional release of norepinephrine to limit vasoconstriction through alpha receptors
• Neuropeptide Y (NPY): Causes vasoconstriction
• ATP: Causes vasoconstriction

Epinephrine and norepinephrine into systemic circulation

• Increased vascular tone on both arterial and venous blood vessels by increasing vascular resistance and decreasing compliance
• This vasoconstriction is regionally selective in order to redistribute blood away from the skin, visceral organs, resting skeletal muscle, and kidneys to the heart, brain, and exercising skeletal muscle

Parasympathetics excessively innervate the heart but have limited innervation of the vasculature and have nearly no influence on total peripheral vascular resistance

• Parasympathetics use acetylcholine as their primary neurotransmitter
• ACh binds to muscarinic cholinergic receptors
• Causes a decrease in heart rate, a decrease in contractility, a decrease in the speed of atrio-ventricular conduction, and vasodilation in a few specific vascular beds

• Norepinephrine: Released from adrenal medulla in response to sympathetic stimulation; causes vasoconstriction by binding to alpha receptors; causes increased heart rate and contractility by binding to beta-1 receptors
• Epinephrine: Released from the adrenal medulla; increase heart rate and contractility by binding to beta-1 receptors; when in low-moderate concentrations, causes vasodilation in skeletal muscle by beta-2 receptors; when in high concentrations, will bind to alpha receptors and cause vasoconstriction
• Angiotensin II: Released as a paracrine factor from endothelial cells; causes vasoconstriction in response to renin which is released when arterial pressure is low
• Vasopressin (antidiuretic hormone): Released in response to decreased arterial pressure or blood volume or increased plasma osmolarity and causes vasoconstriction

• Fick's Law: MVO₂ = Coronary flow x (Arterial - Venous O₂ difference)
• The oxygen consumption depends on the cardiac work, which is determined by heart rate, aortic pressure, myocardial contractility, and ventricular wall stress (Tension=Pressure*Radius of Ventricle/Thickness of ventricle wall; Law of LaPlace)
• Cardiac work can also be estimated from the pressure-rate product (systolic arterial pressure x heart rate)

They show enhanced vasoconstrictor responses

Coronary vasodilation in normal regions of the heart in response to increased cardiac work may reduce blood flow to regions distal to a coronary stenosis

• Mainly regulated by local mechanisms such as autoregulation
• Small changes in carbon dioxide levels can cause large changes in cerebral vascular resistance and blood flow; therefore, ventilation can alter cerebral vascular resistance and blood flow by changing PCO₂
• The CNS can affect cerebral blood flow indirectly when ischemia activates sympathetic nerves that cause vasoconstriction in other vascular beds, thereby increasing arterial pressure

• At rest, neural and myogenic control prevail, and the muscle is receiving low blood flow due to vasoconstriction via alpha receptors
• During exercise, local control prevails, and the muscle receives more blood flow due to vasodilation following accumulation of vasodilator metabolites (active hyperemia)
• This decreased vascular resistance to skeletal muscle could result in a drop in blood pressure, but sympathetic nerve activity (stimulated by "exercise pressor reflex" due to contracting skeletal muscle) maintains arterial pressure and redistributes blood flow to exercising muscle by vasocontricting in resting skeletal muscle and viscera

• Under resting conditions, the liver receives about 25% of the cardiac output and has about 15% of the total blood volume
• Influenced by both local and neural mechanisms
• Increased sympathetic nerve activity results in vasoconstriction and decreases venous compliance
• Food intake can result in increased splanchnic flow by release of GI hormones

• Arterioles: Controlled mainly by sympathetic nervous system; are also capable of autoregulation and reactive hyperemia
• Arteriovenous anastomoses: Controlled only by sympathetic nervous system (not local mechanisms)
• Both of these vessels function to regulate temperature

Carotid sinus (CN IX) and aortic arch (CN X), both of which synapse in the nucleus tractus solitarius (NTS) of the medulla oblongata

• Major function: Oppose/buffer changes in BP as a negative feedback mechanism
• Increased blood pressure causes increased baroreceptor activity that triggers inhibition of sympathetic nerve activity (inhibition of vasoconstriction results in decreased vascular resistance), an increase in parasympathetic nerve activity (decreases atrial contractility and heart rate by decreasing AV node conduction rate), and inhibition of release of vasopressin (AVP) and renin (inhibition of water retention and vascular resistance) --> Reducing BP back towards control

• Mean arterial BP
• Rate of change in pressure
• Large artery compliance
• Remember: The rate of baroreceptor activity is increased by deformation caused by increased diameter of the carotid sinus and aortic arch
• Adaptation: After sustained changes in BP, baroreceptor activity goes back towards normal (the baroreceptor function curve is shifted to higher or lower BP)

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• Pressure threshold: Minimum pressure at which baroreceptors fire APs (40-60mmHg)
• Sensitivity or gain: The slope of the pressure-activity relationshiop (the maximum slope/sensitivity usually occurs near teh resting baseline level of arterial BP)
• Saturation pressure: The pressure above which the arterial baroreceptors no longer increase their firing rate with an increase in pressure (180mmHg)

Baroreceptor tonically inhibits SNA (and inhibits vasoconstriction) and activates paraSNA

• Chronic hypertension, atherosclerosis, myocardial ischemia, heart failure, diabetes mellitus, and obesity, in addition to aging
• This decreased baroreflex sensitivity promotes high sympathetic nerve activity, low parasympathetic nerve activity, and increased BP variability
• Arrhythmias and sudden cardiac death are more likely

Sensory nerve endings in the heart detect changes in central blood volume and myocardial ischemia and cause stimulation or inhibition of cardiac vagal afferents, vasodilation/constriction, increased/decreased sodium in kidney, and water excretion/retention

• Vagal afferents follow the vagus nerve/parasympathetics to medullary cardiovascular centers. These regulate most of the normal reflex control of blood volume
• Sympathetic spinal afferents follow sympathetics back to spinal cord. They play a small role in healthy humans and are often activated in disease

Increased blood volume is sensed by mechanoreceptors in the heart and vagal afferents are stimulated. This causes reflex inhibition of sympathetic nerve activity, vasodilation, and increased renal sodium and water excretion

• Paradoxical activation of vagal afferents innervating the left ventricle can occur because of vigorous contraction of under-filled ventricles (our baroreceptors fired less, so we had less paraSNA, so HR and contractility increased)
• This activation of paraSNA can lead to decreased HR and decreased TPVR, leading to severe hypotension and fainting
• This is called the Bezold Jarisch reflex
• Fainting due to this reflex is called vasovagal or neurocardiogenic syncope
• Emotional stimuli can also cause this increase in paraSNA

• Myocardial ischemia is sensed by chemosensitive nerve endings in response to prostaglandins, adenosine, bradykinin, serotonin, ROS, or protons
• Both sympathetic and vagal afferents are stimulated to cause the Bezold Jarisch reflex via vagal afferents (decrease in BP, HR, and TPVR) and an increase in BP, HR, and TPVR via SNA
• The stimulation of cardiac sympathetic afferents elicit chest pain also

• Sensors: Glomus cells in carotid and aortic bodies (carotid body innervated by CN IX)
• Stimuli: These cells can be depolarized by hypoxia, hypercapnia (too much CO2), or decreased pH, causing increased activation of these sensory nerves
• Reflex response: Increased ventilation is our main goal, and when it is increased the following effects are minimized due to negative feedback from ventilation. However, if our ventilation does not increase or we have apnea, we have pronounced increased SNA (vasoconstriction--we want to keep our BP up so that our head and heart get blood) and increased paraSNA to heart to decrease heart rate.

• Pulmonary stretch receptors are stimulated by lung inflation and cause inhibition of paraSNA to the heart, which causes increased heart rate during inspiration and inhibition of SNA to vasculature causes vasodilation
• Respiratory sinus arrhythmia

Immersion of the face in water stimulates trigeminal receptors that result in apnea accompanied by parasympathetic-mediated brachycardia and sympathetic-mediated vasoconstriction (we want to keep our BP high to perfuse the heart and brain)

High frequency heart rate variability synchronized to respiration via the lung inflation reflex

Spectral analysis measures high frequency HR variability (respiratory sinus arrhythmia) which reflects cardiac parasympathetic modulation and low frequency HR variability that is strongly dependent on sympathetic modulation

The low frequency heart rate variability over the high frequency heart rate variability

• Beta-1 receptors: Norepinephrine and epinephrine can bind; found in the heart; cause increased heart rate and contractility
• Beta-2 receptors: Epinephrine at low-moderate concentrations can bind in skeletal muscle; causes vasodilation

• SNA: Increases
• Myocardial ischemia: Decreases
• Heart failure: Decreases
• Acidosis: Decreases (chemoreceptor reflex results in increased SNA and paraSNA, but paraSNA prevails in heart, resulting in decreased contractility)
• Cardiac glyosides: Increases
• Cardiotoxic drugs: Increases

• Increased blood volume: Increases
• Increased vascular tone of veins: Increases
• Change from supine to upright posture: Decreases
• Skeletal muscle contraction: Increases
• Inspiration: Increases
• Aortic regurgitation: Increases

• Remember, afterload is the resistance in the vasculature, or the force the contracting myocardium must overcome
• Increased peripheral vascular resistance: Increases
• Increased arterial pressure: Increases
• Decreased large artery compliance: Decreases
• Increased radius of left ventricle: Increases
• Aortic stenosis: Increases

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• Right atrial pressure (RAP) is on the X-axis and cardiac output on the Y-axis
• We can see that when RAP is increased, our cardiac output is decreased because more blood has been shifted to the venous side and vice versa (an increase in cardiac output shifts blood flow to the arterial side of circulation)

• Blood volume: An increase in blood volume results in an increased CO and RAP
• Venous compliance: An increase in venous compliance results in decreased RAP and CO
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• TPVR: Vasoconstriction will decrease CO and increase RAP; it will have less of an effect on RAP when CO is low, decreasing the slope
• 

• Circulatory shock is a state of inadeuate tissue perfusion and oxygenation, usually associated with low arterial blood pressure
• Hypovolemic: Low blood volume (hemorrhage)
• Cardiogenic: Low CO (myocardial infarction)
• Hypermetabolic: Low TPVR (sepsis)
• Neurogenic: Low TPVR (spinal cord injury)

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• Decreased blood volume, preload (end-diastolic pressure), stroke volume (due to Frank-Starling mechanism), cardiac output, and possibly arterial blood pressure
• Compensatory mechanisms work to restore BP and cardiac output by increasing TPVR, heart rate, myocardial contractility, and blood volume

• Cardiopulmonary vagal afferents (blood volume/cardiac filling pressure)
• Arterial baroreceptors (blood pressure)
• Juxtaglomerular (JG) cells in the kidneys (decreases in renal perfusion pressure; release renin and increase renal SNA)

• Cardiopulmonary and baroreceptor reflexes: Both increase SNA and vasopressin release
• Reflex inhibition of parasympathetic activity
• Reabsorption of fluid from interstitium into capillaries
• Increased Na and water resorption in kidneys mediated by SNA, Ang-II, aldosterone, and vasopressin
• Increased sodium and water intake

Sustained hypotension and inadequate blood flow occurs due to loss of sympathetic vasomotor tone/vascular responsiveness, acidosis, intravascular thrombosis, decreased myocardial contractility, and increased vascular permeability

• Definition: Failure of the heart to pump enough blood to satisfy the needs of the body at normal cardiac filling pressures
• Causes: Myocardial ischemia, chronic hypertension, valvular heart disease, pulmonary hypertension, arterio-venous shunts, and cardiomyopathy

• Activation of SNA
• Activation of renin-angiotensin-aldosterone system
• However, these mechanisms become maladaptive in decompensated heart failure, contributing to increased cardiac afterload, fluid retention, and deterioration of cardiac function