Welcome. So today we have our last lecture on the cardiovascular system. What we want to talk about is how the entire system, that is the heart itself and the vasculature, are regulated in order to maintain the pressures within the body compatible with the needs of the body. We have several objectives that we need to consider. The first is to describe the reflex control of blood pressure. Secondly, we want to explain how baroreceptors, or pressure sensors, control the blood pressure. Third, explain how other sensors, such as the cardiopulmonary receptors, and volume receptors within the kidneys can control blood pressure. And fourth, we want to describe the central control of blood pressure in response to certain perturbations such as exercise whether it's aerobic exercise or anaerobic exercise in states of hypertension. So let's get started then to consider all of these factors. The first thing that we need to remember is that this entire system is governed essentially by factors which are unique to the heart. That is the heart can control stroke volume and heart rate. Cardiac output is controlled by changes in stroke volume and in heart rate. Secondly that we can control the system by changes that are more properties of the vasculature than the heart itself. We can change preload, the filling of the heart, by changing the way venus return is brought back to the heart. That is how much blood is returned to the heart at a given time. In addition to preload,there is post-load, afterload, sorry. It's called afterload. Afterload is simply the amount of pressure that the heart has to generate in order to open the aortic valve or to open the pulmonic valve to allow for distribution to those particular areas, To the circulatory systems which include the systemic and pulmonary system. Pre-load and after-load are governed by multiple factors, as well as by the heart itself. We will consider how all of this is coordinated through a reflex loop. The reflex loop is what's diagrammed here. We have within this system, as all systems, sensors which bring information into the central control site. The central control site, integrator, is where there's a set point. These pressure sensors are present within the cardiovascular ystem itself. They are within the heart and also within the systemic vasculature. The senor can also be present within organs such as the kidney, and in the lung. These pressure sensors send information back to the integrator. The integrator is called the Medullary Cardiovascular Control Center. It is present in the medulla of the brain stem. That's why it's called medullary. This particular control center has a set point. It will compare the information that comes in from the body to the given set point. Whether or not the pressures within the system are higher than the set point or lower than the set point will determine the outflow to the effectors. In the conditions where we have low pressure, if we have low pressure or low volume, then the sympathetic nervous system is activated. The sympathetic nervous system increases norepinephrine discharge at the terminals that is the synapses of this nervous system. It acts on the heart through the beta one adrenergic receptors to increase heart rate and increase stroke volume. In addition, the sympathetic system works on a gland called the adrenal gland. In particular the adrenal medulla. This is a central area of the gland which secretes a catecholamine called epinephrine. Epinephrine also acts on the beta one adrenergic receptors to increase heart rate and stroke volume. So under these conditions then, we can increase stroke volume. The increase in stroke volume will lead to an increase in mean arterial pressure. That feed back correct our low-pressure within the system. Conversely, if we have a high pressure situation, then with the high pressure situation, the parasympathetic system is activated. Activation of the parasympathetic system, releases acetylcholine. Acetylcholine works on the muscarinic receptors of the heart. The muscarinic receptors of the heart will slow the heart rate. So there is a decrease in heart rate. By decreasing heart rate, we decrease cardiac output. Thereby a decrease in mean arterial pressure or the pressures within the system. These are our general reflex loops. Let's consider first some of the sensors that are present in this loop. One of the major sensors within the loop are called baroreceptors. these receptors are stretch receptors. They are sensitive to the transmural changes in tension within the walls of blood vessels. Which are near the heart. They are located within the carotid sinus and the aortic arch. They respond to changes, as I said, in pressure or stretch. These baroreceptors give information on a minute to minute basis to control blood pressure. They send signals to the Medullary Cardiac Control Center. If there is an increase in mean arterial pressure, then this will increase the firing of the baroreceptors. That in turn causes a decrease in the firing of sympathetics and an increase in parasympathetic firing. The baroreceptors are effectively the brakes of the sympathetic nervous system. If we have high pressures within the circulation, they are activated. Notice that they fire in the same direction as the change in blood pressure. So if the blood pressures increase, then baroreceptor firing increases. At the same time, there is a decrease in the sympathetic discharge. An increase in activity of the parasympathetic system decreases pressure within the vasculature. Conversely, if there's a decrease in arterial pressure, then the baroreceptor firing is decreased. Under these conditions, sympathetic discharge increases and we have a decrease in the parasympathetic firing. So, to increase sympathetic tone, there is a decrease in baroreceptor firing. All right, so when does this happen? Well this occurs all the time. Let's say you were lying in bed. As you're lying in bed, blood is distributed throughout the body in an even manner. Now, the telephone rings. You jump out of bed really quickly. As you jump out of bed quickly, all the blood, or a lot of the blood, flows to your feet due to the change in gravity. You went from a prone position to a vertical position. With this change, gravity increases transiently the blood flow towards the feet. That means the baroreceptors, which are located in the carotid arches, up here in your neck and at the aortic arch, which close to the heart, those sensors then detect less stretch. There's less volume in the system locally. The volume is moving towards your feet. There's less stretch, and with less stretch, the baroreceptors decrease their firing. When they decrease their firing, sympathetic discharge occurs. The sympathetics cause constriction of the vessels by activating the alpha one adrenergic receptors. These are present on smooth muscle of blood vessels. By doing so, they increase resistance within the system. By increasing resistance within the system, then we correct for the transient low cardiac output and low pressures. That's an example of orthostatic hypotension. Another example is when, and I'm sure all of you've seen this, when one of the guards outside of the royal castle in London, suddenly just topples over. What's happening is that as he's standing at attention. He's standing at attention and he's standing at attention, then eventually gravity pull is such that it causes the blood, to pool in his feet. He eventually he becomes light-headed. He has an insufficient amount of blood being delivered to the brain. He gets dizzy and he collapses. Once he collapses, he's in a prone position. Now the blood distribution to the brain is increased. He wakes up and he's perfectly fine. This is called orthostatic hypotension. In addition to the baroreceptors, which are very fast in firing and are the ones who regulate minute-to-minute control, we also have other receptors. You'll hear more about some of these when we consider the respiratory system. There are also chemoreceptors. These chemoreceptors can detect CO2 levels, the level of free protons, and the level of oxygen within the system. These receptors send information not only to the Cardiovascular Control Center system, but also to the Respiratory Control Center, which is also located within the medulla. For instance, if there's a rise in CO2 in the blood, then these receptors cause an increase in sympathetic tone. This will increase the rate of breathing. The skeletal muscles of the chest and diaphragm contract faster. When you breathe at a faster rate, then you blow off the CO2. There are other receptors which are present within the hypothalamus itself. These receptors control temperature. As you all know that if you're out on a hot day then vasodilation occurs which opens the capillaries beneath the skin. Some of the heat is then radiated into the environment. This removes heat from the body. Under those conditions, your skin may become reddish in color. Or as you run, you can generate a lot of heat from the working skeletal muscle. Again, there will be dilation of capillary beds beneath the surface of the skin to lose heat through radiation. Conversely, if you're cold, then those capillary beds are not perfused. The blood stays within the core of the body, into the central portion of the body. So the distribution of blood into these capillary beds changes pressures. When blood is moved into the capillary beds, there is a lowering of pressure. When blood is directed towards the central core, then an increase central pressure. This governed by the hypothalamus. THat regionn of the brain that governs body temperature. We also have a sensor in the kidney. The kidney controls fluid volume in body. The kidney is sensitive to hormone control. We'll talk about this at the end of the course. But the kidney, itself can controlled whether to either pee out more volume if there's an excess of volume or high pressure, or to retain volume, that is to make very concentrated urine, and to move the fluids (water) back into the blood space. Under condition where we have an excess of volume, or high pressure within the system, then more volume is delivered to the atria of the heart. This stretches the atria of the heart. The cardiac myocytes within the atria of the heart, when they're stretched, secrete a hormone. This hormone is called atrial, for atria, natriuretic factor. This factor acts in the kidney to cause an increase in the loss of fluid into urine. It increases fluid output into urine. Conversely, when we have a situation when we have dehydration or a loss in volume, then the hypothalamus of the brain secretes a hormone called anti-diuretic hormone or vasopressin. This hormone acts on the kidney. In this condition, it causes water to move from the kidney tubules back into the blood circulation. we concentrate urine. All right, so lets consider a few examples. One is hypotension, hypotension, as occurs in hemorrhage. In hemorrhage, there is a loss of volume. With hemorrhage, the loss of volume could be let's say a liter of blood. We had an accident. We cut our leg. We've lost a liter of blood. That decrease in volume means that the baroreceptors decrease their firing. By decreasing their firing, then there is an increase in sympathetic drive within the body. By increasing the sympathetic drive, we increase resistance. Activation of the alpha 1 adrenergic receptors that are present on the blood vessels will cause vasoconstriction. We'll have contraction of the smooth muscle. This will constrict vessels to move blood back to the heart.This is to try to maintain cardiac output. In addition, we will activate on the heart the beta one adrenergic receptors. Activation of the beta one adrenergics on the heart increases heart rate. Activation of the alpha one adrenergics on the blood vessels increase resistance. In addition to that, the kidney will sense this lower blood pressure or this loss in volume. The kidney has specific cells, called juxtaglomerular cells or JG cells. These are actually smooth muscles cells of arterioles within the kidney. They secrete a chemical called renin. Renin activates a series of reactions, which will lead to an increase in vasoconstrictors within the vasculature. Two major vasoconstrictors are angiotensin II, and again, ADH, or a vasopressin, which comes from the brain. These vasoconstrictors augment the increase in resistance within the vasculature. This further increases resistance. This helps increase venous return. It helps to move the blood back to the heart. There's a third hormone that will be released under these conditions.d This hormone is called aldosterone. It is secreted by the adrenal glands. Aldosterone works on the kidney tubule to move sodium and the water back into the body. Under these conditions, we can increase volume within the vasculature. By increasing volume within the vasculature, it offsets our loss in volume. This volume is added back from the presumptive urine. By increasing the resistance and by increasing volume in the vasculature. then, we will increase stroke volume. That is due to increased preload to the heart. If you increase preload, then you increase stroke volume. And we know that we have increased heart rate. We have a sympathetic drive which, again, augments contractility and stroke volume. These responses help to offset the loss in the cardiac output. They are activated to try to bring cardiac output back its starting state. All right. What happens when we're going to exercise? Let's say that you've decided to go running. You're running in a marathon. This is a strenuous aerobic exercise. At your pre-exercise level, the cardiac output is about five liters per minute. But as you're exercising, you have to increase the cardiac output. This can go as high 20 to 30 liters per minute. Obviously at rest your blood pressure is 70 beats per minute, but your blood pressure will rise to 150 to even 200 beats per minute as you're exercising. So you increase cardiac output and you increase heart rate. And as you know, running activates a sympathetic drive. The sympathetic drive also increases stroke volume. All right, so let's think about what's happening to the body in general. At the beginning, the basal flow to the muscles, the skeletal muscles, is only about 20% of cardiac output. This is your basal resting state. But as you exercise, then the muscles can receive as much as 80% of the cardiac output. So there is increased flow to the skeletal muscle because they're exercising. They need more oxygen to maintain their new state of activity. To increase the flow within the skeletal muscle then you had to dilate the arterioles. When you dilate the arterioles, then you decrease the the resistance within the system. That means your total peripheral resistance actually will decrease. So from your basal state to the your active state, TPR or total peripheral resistance within the body is decreased. This occurs because the size (volume) of the capillary beds within the skeletal muscles is extensive. There is a lot of profusion within that regions. There is a decrease in total resistance within the muscles. What does that actually do to the mean arterial pressures within the system? There is increased cardiac output but decreased total peripheral resistance. So the increase in mean arterial pressure is only slight. So the increase of mean arterial pressure is slight. It is offset by the decrease in the total peripheral resistance. That's what occurs when we perform aerobic, strenuous aerobic exercise. What happens if you're doing something like anaerobic exercise? Let's say anaerobic exercise in which you are lifting weights. When you lift weights, it is anaerobic exercise. Under these conditions, as the muscle contracts, it actually causes a reactive hyperemia within these working muscles. We're getting an ischemic event during contraction. Then when we relax the muscle, hyperemia occurs. This washes out the metabolites that accumulated during the contraction, during the ischemia. This is called reactive hyperemia. What's happening to total peripheral resistance? We increase cardiac output because we are lifting a heavy load. We need to have higher cardiac output so more oxygen is delivered to the tissues. But we are also increasing total peripheral resistance. Under these conditions, the mean arterial pressure has to increase. What is happening with the barrel receptors? Why are the barrel receptors not fighting us as we are exercising? It turns out that the baro-receptors are able to reset. Just before we run our marathon, we increase cardiac output. As you're sitting there about to take off in the race, the baro-receptors reset to a higher level. They allow the system to work at a higher mean arterial pressure. The same reset occurs with anaerobic exercise. Then when you're finished with the exercise, the baroreceptors reset again. So the set point then is changed to a lower, basal state. The baro-receptors can reset to constant chronic input. If that occurs, then we have hypertension. Hypertension is a state where the heart may be weak. Because the heart is weak, then it adjusts some of the other parameters within the vasculature to try to increase stroke volume and to increase cardiac output. Under these conditions, we can develop hypertension. The hypertension is tolerated because the baroreceptors reset to a higher level. Hypertension can be anywhere greater than 139 millimeters of mercury for systolic pressure and greater than 89 millimeters of mercury for diastolic pressure. Let's see how this is actually develops. We have a case where we have hypertension. The hypertension has occurred because we have weak cardiac muscle. The weak cardiac muscle means that there was a lower ejection volume, and a lower stroke volume. Because we have a lower stroke volume, then to adjust cardiac output, we had to increase heart-rate. Okay so by increasing heart-rate, Then we can augment the loss in cardiac output. In addition to changing the pressures within the heart itself, the stroke volume, or heart rate There is also a change in the vasculature. The kidney will detect low cardiac output. Because the kidney senses low cardiac output, it will hold water within the system. So here, is diagrammed injection volume, that is, stroke volume on the Y axis, The left ventricular end diastolic volume is on the X axis. The normal heart sits here at 100 mls for the left ventricular end diastolic volume. It has a stroke volume that's about 70 ml. With the weak heart, the cardiac output drops. Now at the same end diastolic volume, there is a stroke volume of only 35 milliliters. The kidney holds water to compensate. BY holding water, the end diastolic volume increases to B. B is now 200 millilitres. The heart is stretched. There is a lot of volume in the ventricles. The heart myocytes are stretched. By stretching them, look what happens to stroke volume. The stroke volume increases. Now the stroke volume is close to 50 ml. So, we've improved the stroke volume of the system by holding water in the system. The stroke volume increased. The problem is that by increasing the fluid retention, or fluid within the system, there is increased pressure within the system. That means an increase in the afterload. Although we augmented the preload, that is the filling of the heart, to improve stroke volume, there is also increased stretch of the heart. There is also increased afterload. The afterload on the weak heart is difficult. That's the problem. In trying to improve the performance of the heart by adjusting stroke volume and heart rate, we have increased mean arterial pressure within the system. This pressure increased due to the amount of increased volume within the system. Now because there is higher pressures within the system, we have hypertension. what happens to these individuals? Let's say they have hypertension. There is more blood in the left ventricle of the heart. What happens to the capillaries? In the capillaries, there is higher hydrostatic pressure. The hydrostatic pressure is increased across the entire length of the capillary. It's greater than the oncotic pressure. So we have filtration across the capillaries. In the feet where we have gravity pull, we can now accumulate fluid within the ankles or within the feet themselves. This results in edema in those locations. Okay, so what's our general concepts? The first is that cardiac output is matched with tissue blood flow by maintaining mean arterial blood pressure relatively constant. Cardiac output is equal to mean arterial pressure divided by total peripheral resistance. If we want to maintain the mean arterial pressure as constant, relatively constant, and cardiac output has dropped, then total peripheral resistance must increase. The increase occurs in order to keep a constant mean arterial pressure. Secondly, the baroreceptors act as short term regulators of arterial blood pressure. They provide sensory information to the cardiovascular center which is located within the medulla of the brain stem. The autonomic nervous system is an outflow from this center to maintain the blood pressure constant. If there is a drop in pressure, then there is decreased firing of the baroreceptors and an increase in sympathetic drive and an in increase in resistance within the system. This increases preload but will also increase afterload. If the pressure is too high, then we have the converse response. That is the parasympathetic system will decrease heart rate and cardiac output and decrease mean arterial pressure. Third, changes in total blood volume can change end diastolic volume of the ventricles. Increased filling can thereby change stroke volume. Recall that cardiac output is equal to stroke volume times heart rate. Then fourth, a hemorrhage can reduce the end diastolic volume leading to hypotension. This is due to a loss in the volume within the system. In hypotension due to hemorrhage, the compensatory response is smooth muscle constriction of the arteries and the arterioles. The capacitance veins then will receive more blood. They will then deliver more blood to the heart, trying to fill the heart better. Preload will then increase. There is also an increase in heart rate and in contractility by the sympathetic drive. Five, hypotension can result in either a sudden postural change, that is if we were lying down in bed and we jump out of bed to answer the door bell or answer the phone. This change from a prone position to a vertical position can cause a loss in pressure within the head. It's just a momentary thing, because the baro-receptors will decrease firing, resulting in an increase in sympathetic drive. That will correct the pressures in the upper body. Six, in aerobic exercise, we can increase cardiac output up to 30 liters per minute. But aerobic exercise reduces total peripheral resistance. This is due to vasodilation. There is a reduction in resistance. This fills the capillaries and arterioles of the skeletal muscle. The mean arterial pressure does not increase as much as it would if we didn't have this offset due to the vasodilation within the muscles. In weightlifting, that doesn't occur. Here there is an increase in cardiac output. Also there is an increase in total peripheral resistance. And there is an increase in mean arterial pressure. Seven, failure of the heart to maintain normal cardiac output, can lead to increased resistance within the system because the system is trying to augment delivery of blood to the tissues. It's trying to maintain mean arterial pressure. recall that cardiac output times total peripheral resistance equals mean arterial pressure. If the cardiac output drops, the body will try to increase total peripheral resistance in order to keep mean arterial pressure constant. An eight, we have compensation for decreased cardiac output. Because there is a weak heart, other organs may try to compensate. We will increase heart rate, total peripheral resistance, and increase vasoconstriction of the veins to increase preload. Also retention of water by the kidneys to increase volume within the system. But by doing so, these responses will cause hypertension. It's sort of a balance then between these different factors. In the one case, the body's trying to maintain cardiac output so provide adequate profusion of the tissues, but on the other side of the equation, the weak heart must work against higher pressures. That actually is negative resolution for a weak heart. It makes the weaker heart Work even harder to maintain mean arterial pressures. Okay, so the next time we meet we will discuss the respiratory system. Okay, see you then, bye-bye.