 In this video, I will define stroke volume, heart rate, and cardiac output, describe the intrinsic and extrinsic factors that affect cardiac output, describe the FRONK Starling mechanism, explain how the autonomic nervous system regulates cardiac output, and define enotropic and chronotropic effects. Cardiac output is the amount of blood pumped by each ventricle in one minute. Cardiac output is the product of heart rate and stroke volume. The heart rate is the number of beats per minute, the number of cardiac cycles, in one minute. And the stroke volume is the amount of blood pumped out by a ventricle with each beat. Stroke volume is equal to end diastolic volume minus end systolic volume. The end diastolic volume is the volume of blood in a ventricle at the beginning of ventricular systole, and throughout isovolumetric contraction. And systolic volume is the volume of blood in a ventricle at the beginning of diastole, and throughout isovolumetric relaxation. A number of factors can influence both heart rate and stroke volume, and then lead to an influence on cardiac output. For example, the autonomic nervous system provides extrinsic control over heart rate as well as stroke volume. There are also hormones such as epinephrine that have an influence on cardiac output. Then fitness levels and age also have an influence on our cardiac output as our fitness levels are higher than typically the blood vessels are able to easily stretch and recoil. And the heart is well conditioned to work efficiently, and therefore the heart rate tends to be a little lower at rest than somebody who is very fit because they don't need as much blood pressure in order to maintain blood flow. And then with age our arteries tend to become less elastic, start to become more stiff, and this can lead to an increasing blood pressure that's required to maintain blood flow, and often heart rate will increase in order to help generate that blood pressure. So if the heart is larger, this can lead to a larger stroke volume. Often men have larger hearts than women corresponding to their relatively larger body size and larger amount of muscle mass. The contractility of the heart is a factor that will be influenced by the autonomic nervous system. The sympathetic division of the autonomic nervous system will stimulate an increased calcium concentration inside contractile cells during an action potential, and this will lead to increased stroke volume. So the duration of contraction, how long the systole lasts will also influence stroke volume. A longer duration of contraction can lead to a greater stroke volume, but also the endiastolic volume or preload has a large influence on stroke volume. We'll see that the relationship between preload and stroke volume is known as the Frank Starling Law. So the preload is the amount that the ventricles are stretched by the blood at the endiastolic volume, and as the endiastolic volume increases, the ventricles are stretched more. And this stretching can then lead to an increased force of contraction to increase the stroke volume in proportion to that increased preload. Now in contrast to preload, which is that amount of stretching from the blood filling the ventricles, the afterload is the resistance, or the pressure of the arteries that is making it more difficult for blood to move out of the ventricles during ventricular ejection. And so as the afterload increases, this will lead to a decreasing stroke volume by increasing the end systolic volume. And this is one of the ways that as we age or as we start to develop more stiff blood vessels as our arteries start to be hardened or less elastic with age, the afterload will increase, leading to a proportionally decreased stroke volume. The heart is regulated by the autonomic nervous system. We can see here the sympathetic cardiac nerves are shown in the purple color, and these sympathetic nerves release norepinephrine as the neurotransmitter. So although the preganglionic fibers of the sympathetic nervous system release acetylcholine to excite the postganglionic fibers, the postganglionic sympathetic fibers release norepinephrine in the heart. And this region here is the SA node in the right atrium. And then this region here is the AV node. By releasing norepinephrine in the SA node and AV node, the sympathetic nervous system stimulates an increase in heart rate. So increased heart rate as a result of norepinephrine is a positive chronotropic effect. So any agent that can regulate the heart rate is a chronotropic agent. Norepinephrine is a positive chronotropic agent because it leads to an increased heart rate. In contrast, the parasympathetic division has the opposite effect. The neurotransmitter acetylcholine is released by postganglionic parasympathetic fibers in the heart to produce a decrease in the heart rate. So acetylcholine is considered a negative chronotropic agent that decreases heart rate. The last thing I'd like to point out on this slide is that the sympathetic fibers illustrated in the purple color, in addition to branching into the SA node and AV node where they can regulate the auto-rhythmic cells to control heart rate, these sympathetic fibers also branch into the ventricular myocardium. And the function of these sympathetic fibers in the ventricular myocardium is to stimulate an increased stroke volume. And so an enotropic agent, in contrast to a chronotropic agent, will lead to a change in stroke volume. And a major positive enotropic agents include norepinephrine, the neurotransmitter released by postganglionic sympathetic fibers, and also epinephrine, the hormone that's released by the adrenal medulla in response to increased activity of the sympathetic nervous system. And so sympathetic activity will lead to increased heart rate, a positive chronotropic effect, and increased stroke volume, a positive enotropic effect. In contrast, acetylcholine, the neurotransmitter released by the parasympathetic fibers only affects the heart rate. And so it's a negative chronotropic agent, but it's not an enotropic agent. So here we can see the mechanism for signaling from the beta-adrenergic receptor that leads to an increased heart rate. So the sympathetic postganglionic fibers release norepinephrine in the SA node and AV node, and norepinephrine will bind to beta-adrenergic receptors on the surface of auto-rhythmic cells. The beta-adrenergic receptor is a G-protein-linked receptor that, when it's activated by norepinephrine or epinephrine, will then stimulate an increased activity of the enzyme adenylyl cyclase that synthesizes the second messenger cyclic AMP. Cyclic AMP then binds to a site on the HCN channel. The hyperpolarization activated cyclic nucleotide gated channel, HCN channel, is the channel that produces the pacemaker potential. The spontaneous depolarization at the beginning of the pacemaker potential to generate an action potential. As more HCN channels are open in response to sympathetic stimulation, the slope of the pacemaker potential increases as depolarization occurs more rapidly. This causes the auto-rhythmic cells to reach threshold for the action potential more rapidly and leads to an increased heart rate. So here we can see a comparison of the normal or resting auto-rhythmic cell action potential. And with sympathetic stimulation, we see here the auto-rhythmic cell action potential has changed to have a faster rate of depolarization. So that means that the slope of the pacemaker potential has increased. So increased slope of pacemaker potential. I'll go ahead and just highlight that with the purple color here. So we increase the slope of the pacemaker potential. This is the effect of the sympathetic division of the autonomic nervous system. Nor epinephrine and epinephrine both lead to this faster rate of depolarization or increased slope of the pacemaker potential. And this leads to increased heart rate. Now we'll look at the mechanism that leads to a decrease in heart rate in response to parasympathetic stimulation. So post-ganglionic parasympathetic fibers release the neurotransmitter acetylcholine into the SA node and AV node. Acetylcholine binds to the muscarinic acetylcholine receptor, which is another G-protein linked receptor. The beta-gamma subunits of the muscarinic acetylcholine receptor are activated to then stimulate a potassium channel in auto-rhythmic cells. And so stimulating the opening of a potassium channel will lead to a slower rate of depolarization. As potassium moves out of the cell, this has the effect of decreasing the value of the membrane potential. And so open potassium channels will have the opposite effect of open HCN channels because sodium enters through the HCN channel. Represent that here. Sodium is moving the other direction through the HCN channel, causing spontaneous depolarization. But having an increased number of potassium channels that are open and potassium is moving out of the cell will slow down this spontaneous depolarization, leading to a decreased slope of the pacemaker potential and a decreased heart rate. So another mechanism that leads to the decreased heart rate following parasympathetic stimulation involves the alpha subunit of the muscarinic acetylcholine receptor. The alpha subunit of the muscarinic acetylcholine receptor inhibits the enzyme adenolyl cyclase. So inhibition of adenolyl cyclase leads to a decreased concentration of cyclic AMP. Cyclic AMP has the effect in auto-rhythmic cells of stimulating the HCN channels. With a decreased concentration of cyclic AMP, we're going to have a reduced amount of sodium entering the cell. So the rate of spontaneous depolarization will decrease, leading to a decreased slope of the pacemaker potential and decreased heart rate. And so here we see the auto-rhythmic cell action potential at rest. In contrast, here we see the effect of parasympathetic stimulation. So parasympathetic stimulation led to a slower rate of spontaneous depolarization by stimulating an increased number of potassium channels that are open and a decreased number of HCN channels that are open. There's a decreased slope of the pacemaker potential. So this region of the graph, the pacemaker potential, has a decreased slope, meaning it takes longer for the auto-rhythmic cells to spontaneously depolarize enough to reach threshold, and therefore the heart rate decreases. The Frank Starling mechanism, also known as the Frank Starling Law of the Heart, is a major intrinsic regulation mechanism that's controlling stroke volume. This graph here shows us the relationship between stroke volume and endiastolic volume. The volume of blood found inside of the ventricles at the beginning of ventricular systole during the isovolumetric contraction phase. If there's a larger endiastolic volume, that means that the heart muscle is being stretched out more. This is the preload, increased stretching of the contractile fibers in the myocardium. Now the length-tension relationship is that an increased length of the contractile fibers in the heart will lead to an increased muscle tension, leading to increased stroke volume. So an increase in endiastolic volume will produce an increased stroke volume under normal circumstances at the typical endiastolic volume and contractile fiber lengths that the heart is usually functioning with it. The Frank Starling mechanism is an intrinsic property of the heart. Stretching of the myocardium increases the number of crossbridges formed between actin and myosin, leading to increased contraction force, increased muscle tension, and this increased contraction will then cause that increase in stroke volume. And it's a proportional increase in stroke volume, so essentially the heart can pump the amount of blood that it's receiving. The endiastolic volume is influenced by the rate of venous return. If blood flows more rapidly from the veins into the heart, the endiastolic volume will increase. Whereas if there's a decrease in venous return, this leads to decreased endiastolic volume and a proportional decrease in stroke volume. So while cardiac muscle normally functions below the optimal length, enabling this Frank Starling mechanism, it is possible for the cardiac muscle to be stretched past its optimal length. And once the endiastolic volume produces stretching greater than the optimal length, there's a proportional decrease in stroke volume with further increases in endiastolic volume. So this is not a very healthy situation. This occurs during congestive heart failure as the venous return continues to increase. The volume of blood inside of the heart is increasing, but the force of contraction is decreasing and the amount of blood that can be forced out into the arteries decreases, which impairs the function of the heart eventually leading to heart failure. So the regulation of contractility by the autonomic nervous system is primarily the sympathetic division where the sympathetic cardiac nerves release norepinephrine and the adrenal glands release epinephrine. Both norepinephrine and epinephrine are positive inotropic agents. So an inotropic agent influences contractility influencing stroke volume by regulating the concentration of calcium inside of contractile cells during inaction potential because norepinephrine and epinephrine are positive inotropic agents. They stimulate an increased concentration of calcium inside of the contractile cells with each action potential. As a higher level of calcium concentration is achieved, there's a greater contractility producing a larger stroke volume. The mechanism of the positive inotropic effect of norepinephrine and epinephrine involve the activation of the beta-adrenergic receptor on contractile cells in the myocardium. The G protein of the beta-adrenergic receptor stimulates the enzyme adenolil cyclase to produce the second messenger cyclic AMP. Cyclic AMP then binds to the enzyme protein kinase A, activating it, and protein kinase A will phosphorylate L-type calcium channels. This phosphorylation of L-type calcium channels by protein kinase A stimulates the L-type calcium channels so that more L-type calcium channels open allowing a greater influx of calcium to stimulate increased contractility. There's also activation of the ryanodine receptors on the membrane of the sarcoplasmic reticulum. So the protein kinase A also phosphorylates the ryanodine receptor and this activates the ryanodine receptors, stimulating an increased flow of calcium from the sarcoplasmic reticulum into the cytosol. So this increased cytosol calcium concentration inside of the contractile cells stimulates increased contractility leading to an increase in stroke volume.