1. CV Response to Exercise

Discuss the effect the autonomic nervous system (both adrenergic and cholinergic) has on the cardiac and vascular function of the CV system.

1. At rest: parasympathetic exerts most control 2. Beginning: withdrawal of vagal tone 3. As progresses: sympathetic increase 4. Recovery: immediate vagal return

Diagram and Explain the Wiggers Diagram during exercise.

1. SBP ↑, DBP remains unchanged. 2. Systole and diastole are shortened (diastole>systole). 3. EDV ↑ and ESV is decreased 4. Blood flow through aorta is increased during systole.

Putting it all together (summary of the many events involved in CV response to exercise)

1. ↑ CO. ↑ HR (↑ symp, ↓ parasym) and SV (↑ CVP, inotropy, and lusitropy). 2. ↑ MAP and pulse pressure. CO ↑s more than SVR ↓s) and ↑ SV ↑s pulse pressure. 3. ↑ Central venous pressure. venous constriction (↑ symp), muscle pump activity, abdominothoracic pump 4. ↓ SVR. metabolic vasodilation in active muscle and heart, cutaneous vasodilation ( ↓ symp), and vasoconstriction in splanchnic, nonactive muscle, and renal circulation (↑ symp)

Diagram and Explain Pacemaker APs, and how exercise can affect them through ANS Sympathetic Stimulation.

A. Pacemaker cells (group of cells located in RA's SA node) are different from nonpacemaker cells (atrial and ventricular myocytes and purkinje fibers). pacemaker cells don't really have a "true" RMP as they generate spontaneous APs. 1. Phase 4: Begins with slow, inward Na+ channels opening and creating funny currents. As membrane potential reaches -50mV, T-type Ca++ channels open and allows Ca++ into cell causing further depol. When cell reaches -40, L-type Ca++ channels open and allow Ca++. Finally when ~-35 is reached, full depol 2. Phase 0: depol is mainly caused by increased Ca++ through L-type ca++ channels that begin to open toward end of phase 4. Funny currents and T-type Ca++'s decrease bc their channels begin to close. 3. Phase 3: repol occurs as K+ channels open and increase outward directed hyperpolarizating K+ currents. At same time, L-type Ca++ close which decreases inward Ca++. Cell is completely repolarized at round -60 mV, the cycle is spontaneously repeated. During exercise, sympathetic activity is increased and vagal tone is inhibited. This does 3 things: 1) increases slope of phase 4 through NE binding to B1 adrenoceptors, stimulating Gs protein, and activating cAMP (increased chronotropy, dromotropy (velocity), and inotropy). 2) lowers threshold by increasing funny currents and earlier opening of Ca++ channels 3) increases rate of depol/repol, thus decreasing cycle length

Diagram and Explain Nonpacemaker APs, and how exercise can affect them through ANS Sympathetic Stimulation.

B. nonpacemeker cells have true resting potentials near K's equilibrium (nerns't). Their APs depend on changes in fast Na, slow Ca++, and K+ conductances. 1. Phase 4: Begins near K's equil potential (-98 mV), thus K conductance (gK+) is high, and fast sodium channels and L type slow Ca channels are closed 2. Phase 0: When cells rapidly depol to threshold of -70 by an AP in an adjacent cell, there's rapid depol (phase 0) that is caused by transient increase in fast Na+ channels. At same time, outward directed K current decreases thus moving equilibrium potential closer to Na which is +54. 3. Phases 1 and 2: Initial repol causes opening of special type of transient outward K+ channel which causes a short lived hyperpolarizing outward K current, but because the large increase in slow inward gCa++ happens at the same time, the repol is delayed and there's a plateau phase (phase 2). This inward Ca movement is through long-lasting L type ca channels that open up when membrane depols to about -40. The plateau prolongs AP duration and marks the difference between cardiac APs and nerve/muscle. 4. Phase 3: repol occurs when gK+ increases along with inactivation of Ca++ channels. 5. There's also the effective refractory period (ERP) or absolute refractory period (ARP) in which the cell does not produce a new AP for a period of time. This is due to inactivated fast sodium channels after they close in phase 1, which is protective for the heart because if it weren't the case, the heart would increase its rate and decrease fill time ultimately affecting ventricular ejection.

Explain what happens to low-moderate epinephrine released during exercise. What happens during high epi concentrations?

Binds a1, a2, B1, and B2. Has a higher affinity for B than a. With low to moderate levels of epinephrine, there is increased HR, inotropy, dromotropy via B1 adrenoceptor, and small artery and arteriole vasodilation via B2 adrenoceptor During high, epi binds both a and b and further stims vasoconstriction of vascular smooth muscle leading to increased SVR and CO (SVxHR), ultimately leading to increased BP.

Discuss the G-protein coupled and cGMP-coupled pathways for vascular smooth muscle and heart! (just discuss

• Things that affect both: ntms, circulating hormones, paracrine substances •2 different mechanisms that affect state of vascular tone: 1) G protein coupled pathway and 2) nitric oxide-cGMP pathway • Similar to heart, Gs protein coupled pathway stims adenylyl cyclase whcih catalyzes cAMP. Unlike heart, increased cAMP in vascular smooth muscle causes reduced contraction due to ca-calmodulin activating MLCK in vascular smooth muscle which phosphorylates myosin and causes contraction, however, MLCK is inhibited by cAMP. In heart, Gs stims increased cAMP doesn't increase intracellular Ca. Gs also coupled with receptors: B2 adrenoceptors (binds EP), a2 (binds adenosine), and IP receptors (binds prostacylin/PGi2). • Gi proteins in vascular smooth muscle are coupled to a2 adrenoceptors (binds NE) causes reduction in cAMP which leads to smooth muscle contraction. • Gq proteins are coupled to a1 adrenoceptors (bind NE, EPI), ETa (bind endothelin1), AT1 (bind angiotensin II), V1 (vasopressin), M3 (ACh). 2 signal pathways are linked to Gq: phospholipase C (makes Ip3), and Rho-kinase. IP3 stims SR release of Ca and activates PKC via formation of DAG which stims contraction. Rho-kinase inhibits MLC phosphatase, which enhances contraction. • NOTE: EPI binding to Gs coupled B2 adrenoceptor vs Gq coupled a1 adrenoceptor is concentration dependent, B2 adrenoceptor have higher affinity for EPI than a1. At low [EPI], vasodilation occurs. At high [EPI], vascontriction dominates! • cGMP coupled signal transduction regulates vascular smooth muscle tone. vascular endothelial cells make NO which diffuses from endothelial cells to adjacent smooth msucle cells where it activates guanylyl cyclase leading to increased formation of cGMP and vasodilation. cGMP can activate cGMP dependent protein kinase, inhibit Ca entry into vascular smooth muscle, activate K+ channels (causing hyperpolarization) and decrease Ip3. ACh binds M3 on vascular endothelium (also on vascular smooth muscle cells) and stims the formation and release of NO.

Discuss how Heart Rate responds to exercise: 1. How does exercise induces tachycardia from rest? 2. How does an increase in HR affect the ventricle? Explain this mechanism. 3. How does HR differ between trained and untrained? Explain why they differ.

•1. HR responds linearly and proportionally to exercise intensity. At the start of exercise, HR increases as a result of decreased parasympathetic/vagal tone. The withdrawal begins to increase HR but not enough to for max exercise, the main increase comes from sympathetic tone because it releases catecholamines (epi/norepi) into blood stream that bind to cardiocytes. The Bainbridge reflex also contributes to increased HR; an increase in atrial pressure (due to filling) results in increased HR. •2. Increase HR increases the contractility of the ventricle which is known as "Bowditch staircase effect, Treppe effect, Positive inotropic effect of activation, or the force-frequency relationship." The mechanism is that during rapid stimulation of the heart, there's a significant increase in Na and Ca in the cardiomyocyte leading to Na overload in cell. Na overload increases activity of sodium-calcium exchanger which increases calcium into cell (3 Na are exchanged for 1 Ca). increased intracellular Ca allows it to bind to contractile proteins which leads to increase in force of contraction (inotropy). •3. Trained has lower resting HR, and lower HR at any given intensity while max HR is same as untrained, and trained reaches higher max at higher intensities. There are 3 main reasons why relating to ANS, stroke volume, and CO: a) ANS: Training increases parasympathic tone (more ACh released at heart) and decreases sympathetic tone (less epi/norepi release, sensitivity, and their receptors in the heart) b) SV (read below) c) CO (read below)

Discuss the Cardiac Output response to exercise: 1. Discuss why CO is important for determining aerobic exercise capacity. 2. Describe the relationship between CO and VO2, and how training affects that relationship. 3. Explain how CO begins and changes during the start of exercise. 4. Describe Cardiovascular Drift.

•1. Measures CV system by VO2max through the Fick Equation VO2max = (HRmax) (SVmax) (a-vO2 diffmax). The ability to increase O2 extraction is limited so the most influential factor of VO2max is CO which depends on HR and SV. •2. Its a linear relationship, for every increase in oxygen consumption of 1L, there's a 5-6L increase in CO! The relationship is not affected by training since there's a direct relationship between CO and work performed. For both trained and untrained, a given intensity will have the same CO, the difference is that the trained will have a lower HR because their SV is higher. Trained will also reach max CO at higher absolute VO2. •3. Beginning of exercise, increases in CO are the result of both HR and SV but at 50% VO2max and beyond, increases in CO are due to HR bc SV is sustained. •4. CD is when prolonged submax exercise results in slow increase in HR and thus slow CO which is caused from decreased blood volume or body temp (loss of water), resulting in decr venous return and preload, and ultimately SV in which HR has to pick up.

Discuss how Stroke Volume responds to exercise: 1. Diagram how exercise affects SV and explain why this happens. 2. Explain how exercise affects affects Ejection Fraction.

•1. SV increases fast with early phase of exercise, then reaches max around 50% of VO2max, with little to no increase after (flattens). This is because SV is influenced by cardiac filling and emptying, which are affected during high VO2max. From rest to heavy, then max exercise, EDV will rapidly rise but then slowly decline because heart is "less full" during max exercise than light exercise. This decreases filling time. ESV changes little from rest to light exercise, then slowly declines at heavy and max because inotropy is increasing but preload is decreasing. It's important to note that decrease in ESV is offset by decrease in EDV thus SV remains unchanged. •2. EF is %blood in left ventricle that's ejected with each heart beat and is normally 60-70%. It's used to indicate ventricular function. Exercise increases it by 30% from resting values due to Starling's Law and circulating catecholamines.

Discuss how Blood Volume changes during different modes of exercise (acute, chronic), the time it takes for these changes to occur from chronic exercise and why these changes are beneficial, and how blood component changes as well. Draw a diagram to help explain chronic changes.

•Acute: loss of body fluids which reduces plasma volume, which decreases oxygen transport capacity (lowers Vo2max). Decrease in BV is called hypovolemia, and increase in BV is hypervolemia. •Chronic: increases blood volume (15-20% increase) can happen in as little as 24 hours. Hypervolemia can plateau in 10-14 days, which PV being the primary component in increased BV. Afterwards, PV will decrease and RBCs will increase while maintaining the increased BV. This is good because 1) increased BV decreases HR at given intensity, and 2) increased BV increases central venous pressure which increases ventricular filling pressure in heart, thus increasing preload, and finally, Cardiac Output through Starling's Law. •Component changes from endurance training: There will be absolute changes in Hct and Hb in which trained will have a higher absolute value for both RBCs and Hb, but no differences in relative Hct and Hb between trained and untrained individuals. Generally, normal Hb for men is 14-18 g/dL and women is 12-16 g/dL. Normal Hct is 40-50% in men and 36-44% in women. So that means trained men and women will have more Hct and Hb but their percentages of Hct and Hb will remain the same.

Diagram and explain: 1. Cardiomyocyte autonomic receptors and neurotransmitters 2. Signal transduction pathways and effects from exercise.

•Cardiomyocyte has mainly B1 adrenoceptors, as well as B2, a1, m2. •B1 (and B2) bind NE released from sympathetic adrenergic nerves, and coupled with Gs protein which activates adenylyl cyclase to form cAMP from ATP. More cAMP activates PKA that phosphorylates L-type Ca channels which causes increased Ca into cell (increases chronotropy, inotropy). PKA also phosphorylates sites on sarcoplasmic reticulum which lead to enhanced release of Ca through RYR providing more Ca for TnC and thus enhancing further inotropy. Finally, PKA can phosphorylate myosin light chains, which may contribute to positive inotropic effects. *fun note: beta adrenoceptor antagonists (beta-blocker) will block NE and EPI from binding B1 and B2!

Diagram and Explain the PV Loop during exercise.

•From rest to max exercise (basically SV and SBP changes): 1. at 50% of max exercise, ↑ SV from ↑ EDV, through Starling's law, not contractility 2. at 80% of max ex, ↑ SV from ↑ EDV, minimally on contractility 3. at max ex, SV relies on ↑ in both EDV and contractility, and so 80% max = 100% max 4. Systolic pressure ↑s proportionally to exercise intensity 5. Diastolic pressure remains unchanged

Discuss how Blood Flow changes during different modes of exercise (acute, chronic, and progressive), compared to at rest. Define: dynamic & steady-state exercise.

•REST: 20% of total blood flow (5800 ml/min) is to the muscle with most directed to the visceral organs. •1. Acute: single bout of exercise -> At rest, light/heavy/max exercise, the only organ that maintains absolute rate of BF is brain (750 ml/min). Organs that increase with intensity are the heart and muscle in which they increase in proportion to intensity level. The heart will experience absolute BF increase 4 fold, but BF% remains the same (3.5% and 4%). The skin is different, blood flow increases with light and heavy exercise, but drops at max exercise (600 ml/min vs 1500 and 1900 ml/min) because blood will be directed to muscle for the exercise to continue. The kidneys and visceral organs will decrease as exercise intensity increases •2. Chronic: repeated bouts over time (training). Adaptations will occur... •3. progressive: single bout increased from rest to max, will follow acute, with 90% of blood flow will go to muscle and other organs will be compromised •4. Dynamic: repetitive movements of large muscle groups (running/cycling) •5. SS: exercise maintained at submax

Discuss the Blood Pressure response to exercise, and how training affects it.

•Systolic: linear increase for every MET increase because ↑ CO exceeds decrease in SVR/TPR (BP = CO x SVR). Training lowers it a bit but no difference in max BP. •Diastolic: doesn't change during exercise because the ↑ in CO is equal to decrease in SVR during the diastolic phase of the cardiac cycle (BP = CO x SVR). Training slightly lowers it.

Draw and explain the Pressure Volume Loop. Discuss

•The ventricular PV loop describes the relationship between pressure and volume in the cardiac cycle. •To make the PV loop for the LV, LVP is on Y axis and LVV is on the X axis. There are 4 basic phases to the cardiac cycle on this diagram: a) ventricular filling in diastole. "1" shows pressure and volume at end of diastole, and represent the end diastolic pressure and EDV for the ventricle. Filling occurs along this end diastolic pressure volume relationship or passive filling curve for the ventricle. b) isovolumetric contraction in diastole. As the ventricle begins to contract isovolumetrically, the mitral valve closes and LV pressure increases but the LV volume remains unchanged resulting in a vertical line (all valves are closed). c) ejection in systole. Once LV pressure > aortic pressure, aortic valve opens "2" and ejection begins. During this phase, the LV volume decreases as LV pressure peaks (peak systolic pressure) then decreases as the ventricle begins to relax. When aortic valve closes "3", ejection stops and ventricle relaxes isovolumetrically (LV pressure falls but the LV volume remains unchanged thus the line is vertical - all valves are closed). The max pressure that can be developed by the ventricle at any given LV volume is defined by the end systolic pressure volume relationship ESPVR, which represents the inotropic state of the ventricle. d) isovolumetric relaxation in diastole. The LV volume at this time is ESV. When LV pressure falls below LA pressure, mitral valve opens "4" and the ventricle begins to fill. LV pressure continues to fall as the ventricle fills bc the ventricle is still relaxing until the LV pressure increases and LV volume increases. •Width of loop represents the difference between EDV and ESV, or SV.

Diagram and explain: 1. Vascular smooth muscle autonomic receptors and neurotransmitters 2. Signal transduction pathways and effects from exercise. 3. What happens to the muscarinic receptors?

•Vascular smooth has 2 types of a-adrenoceptors, a1 and a2. Others include B2, m2, m3, and others AT1 and V1 -a1 are more predominant. a1 is linked to Gq protein that activates contraction through phospholipase C pathway (which forms Ip3). Ip3 stimulates SR release of Ca and activates PKC, which both lead to contraction. -a2 are linked to Gi protein which reduces cAMP, leading to smooth muscle contraction. *also! angiotensin binds AT1, vasopressin binds V1, and ACh binds M3 receptors, leading to v.smooth muscle contraction. *funfact: a adrenoceptor antagonists (alpha blockers) block a1 and a2 binding leading to sympatholytics. Muscarinic receptors: When under parasympathetic activation, ACh binds to m2 receptors primarily on SA and AV nodes. They are coupled to Gi protein which decreases cAMP leading to decreased firing rate (negative chrono and dromo)

Discuss factors that affect Cardiac Output. Explain these factors in terms of Preload and Afterload, and the factors that affec these.

•Well, anything that affects HR and SV can affect CO. •1. Anything that affects Preload (LV wall stress at End Diastole (when LV just finished filling up with blood)): a) ↑CO: ↑s VR = ↑ preload b) posture: EDV is greatest in supine, then sitting, then erect c) sympath stim: venoconstriction ↑s VR = ↑ preload d) ↑BV e) atrial priming via inotropy f) muscle and respiratory pumps in which muscle acts as a pump propelling blood back to heart to ↑preload, and negative pressure in the thorax expands large thoracic veins which "suck" blood toward heart and ↑s preload. •2. Anything that affects Afterload (LV wall stress during Ejection, afterload is proportional to pressure): a) sympath/parasym stimulation in which SYM ↑SVR which ↑ arterial BP, and PARASYM is the opposite b) isometric exercise: ...static can impede BF ↑ TPR/SVR = ↑ arterial BP c) Valsalva: closing the airways while expiring to ↑ thoracic pressure. This will ↑ BP due to pressure on aorta, and then BP will drop because venous pressure will impede venous return, which affects both afterload and preload, and will decrease CO •3. Contractility and 4. HR: a) FFR b) sympath and parasympath c) circulating catecholamines •5. ventricular compliance which determines EDV...less compliant will result in less fill

Draw and explain the Wiggers Diagram, discussing all 7 phases.

•When explaining each phase, explain the major anatomical parts and what they're doing, and these 4 things: atrial/ventricular pressures, aortic BF, ventricular volume, and ECG. •1. Atrial systole. Mitral valve is open, atrial and ventricular pressures are below 10 mmHg, there is no flow through aorta and aortic BP is ↓, and there's a slight increase in ventricular volume from this atrial kick. P wave. •2. Isovolumetric contraction. This signals the beginning of ventricular systole. It is the interval between closure of mitral valve and opening of aortic valve, iso "same" volume because the ventricle is contracting but ventricular volume remains unchanged. This phase starts RIGHT after the QRS complex (ventricular depolarization). Once the ventricle begins to contract, ventricular pressure rapidly increases and when it exceeds atrial pressure, the mitral valve will close, but the pressure is still lower than aortic pressure so aortic valve is closed. When ventricular pressures rises from 10 to 80 mmHg and equals aortic pressure, isovolumetric contraction is complete. •3. Rapid ejection. (33% of ventricular systole) Begins with opening of aortic valve and ends when ventricular and aortic pressures peak, their pressure waves are almost identical. Ventricular contraction will exceed 80 mmhg in aorta which causes aortic valve to open, aorta to distend and accept volume of blood from ventricle, and the aortic BF to increase dramatically from 0 to over 5 L/min. Middle ST segment. •4. Reduced ejection. Begins when ventricular and aortic pressures begin to drop and ends when aortic valve closes. Although ventricle IS contracting and blood IS flowing through aorta, its a slower rate. T wave. •5. Isovolumetric relaxation. Begins with closure of aortic valve which signals start of ventricular diastole, and ends with opening of mitral valve. Ventricular pressure drops with no change in ventricular volume. When ventricular pressure falls below aortic pressure, blood flows back toward ventricle which causes the aortic valve to snap shut and causes the dicrotic notch in the aortic pressure curve. Thus both valves are closed and volume doesn't change. Segment right after the T wave. •6. Rapid filling. Begins with opening of mitral valve once ventricular pressure drops below atrial pressure, and ends when filling is leveled off. Atrial and ventricular pressure decline slightly and there's no aortic flow. •7. Reduced ventricular filling. Begins around 1/3 of the way through diastole and ends with start of atrial systole. Atrial and ventricular pressure, and aortic flow do not change but there is a steady decline in aortic pressure due to aorta recoiling and propelling blood through the systemic circuit thus losing pressure.