Lecture 1 Notes 2024.docx

BIOC34: LECTURE 1 1. Introduction to the Course This course will cover four major topics: cardiovascular physiology, respiratory physiology, renal physiology, and digestive physiology. 1A. Cardiovascular Physiology We're going to start out with lectures looking at the function of the cardiovascular...

BIOC34: LECTURE 1 1. Introduction to the Course This course will cover four major topics: cardiovascular physiology, respiratory physiology, renal physiology, and digestive physiology. 1A. Cardiovascular Physiology We're going to start out with lectures looking at the function of the cardiovascular system. Today we will begin by looking at electrical activity in the heart: we'll look at how electrical activity is conducted through the heart from the endogenous pacemaker cells through to contractile cells - you've all heard of implantable pacemakers, but there is an endogenous group of cells in the heart that function as the normal pacemaker in normal, non-pathological situations. In the next lecture, we're going to look at the ECG (electrocardiogram), which produces that generally familiar heartbeat pattern, and we'll see what the various deflections, and periods between deflections, represent; as well, we'll see how you can use an ECG to determine whether a heart is functioning normally, or to diagnose disease or abnormal states. We'll then look at what's called the electrical axis of the heart, which is the general, overall direction that electrical activity flows in the heart; again, this is a very useful diagnostic tool that can tell you whether there are various disease states in the heart. The axis can deviate from its normal direction, either to the left or the right, and which direction it goes and the extent to which it deviates can assist you in diagnosing problems. The cardiac cycle, the focus of the next lecture, tells about the various pressure and volume changes, the opening and closing of valves, and the contraction of atria and ventricles that occur during a single beat of the heart (or cardiac cycle). We're then going to look at regulation of cardiac output (cardiac output refers to the amount of blood the heart puts out per unit of time), and regulation of blood flow, and then heart failure and blood pressure. 1B. Respiratory Physiology When we come to respiratory physiology, we'll begin by looking at pulmonary mechanics, i.e., the pressure and volume changes, muscle contraction, and other factors that are associated with a single inspiration and expiration. We'll look at a technique of spirometry, which is used to measure lung volumes and capacities. Again, these are important diagnostic tests, and can be used to diagnose, for instance, whether someone has an obstructive lung disease, a restrictive lung disease, or whether the lung is functioning normally. Alveolar ventilation looks at how the air that we breathe in actually gets into the gas exchange site, the alveoli, and how this can be modified by changing breathing rate and tidal volume and how they are regulated. Blood-gas transport looks at the linkage between oxygen and carbon dioxide transport in the red blood cell; everyone knows that hemoglobin in the red blood cells carries oxygen, but it is also critical for CO2 transport in the blood as well - and you cannot separate oxygen and CO2 transport. Ventilation-perfusion matching looks at how we keep the volume of air that we breathe in, and the volume of blood pumped to our lungs relatively similar and constant in order to allow for optimal gas transfer. Control of breathing looks at mechanisms in the brain that produce breathing: just as there is a pacemaker in the heart to control heart rate, there is what could be called a pacemaker in the brainstem that controls breathing without any conscious thought. And then, we'll look in one lecture at various sleep-related breathing disorders. 1C. Renal Physiology In the renal system, we're going to look at kidney function, the regulation of various ions, the role of different hormones in regulating kidney function, and then at how we have an osmotic gradient going from the outer regions to the inner regions of our kidney, which allows us to form a concentrated urine (without this gradient, we can't produce anything but the most dilute of urine). We'll spend about a lecture and a half looking at acid-base balance, which brings into play the renal, respiratory and cardiovascular systems - so it is a good integrated topic. 1D. Digestive Physiology And then finally, we'll spend the last four lectures looking at the digestive system. We'll look at the functions of the various components of the GI tract, as well as the various accessory organs that provide enzymes and other substances to facilitate gut function. Then we'll look at the digestion and absorption of various nutrients, and the neural and hormonal regulation of the digestive system. 2. The Cardiovascular System I've already alluded to the various topics that we're going to cover; and throughout our study of the cardiovascular system, we're always going to come back to some basic principles and equations that can really help in your understanding of cardiovascular control. The amount of blood pumped out of the heart per unit of time is called cardiac output, and it is a function of heart rate, and stroke volume. Stroke volume is the volume of blood pumped per beat. Thus, cardiac output is produced by the equation CO = HR x SV. All of the cardiovascular regulatory systems we're going to look at have, at their core, one basic, critical function: and that is to prevent blood pressure from falling too low. High blood pressure will kill, but it will take years; low blood pressure will kill in minutes. So every adjustment we see in the heart and blood vessels throughout cardiovascular function ultimately boils down to keeping blood pressure up so blood flow can occur to organs that are critically sensitive to low oxygen levels. We can calculate blood pressure by multiplying cardiac output by what is called peripheral resistance. This refers to the resistance to blood flow within the circulatory system. We'll see that this resistance occurs primarily in small vessels, particularly small arteries called arterioles. So, cardiovascular regulatory mechanisms are going to impinge primarily on these three factors: heart rate, stroke volume, and peripheral resistance. Whether it’s a nervous mechanism or a hormonal mechanism, all adjustments that occur in the cardiovascular system are usually going to affect one or more of these three variables with the ultimate goal of keeping blood pressure levels up. Blood volume is a fourth variable that can affect blood pressure. If volume goes up (i.e., a person is retaining fluid) then blood pressure will increase; if fluid levels go down then blood volume and pressure will decrease. Think of diuretics being used to treat high blood pressure. 2A. Heart Anatomy Before we start looking at electrical activity, I want to cover some basic heart anatomy to place everything into perspective, and then look at some basic patterns of blood flow. The human heart, like the hearts of other mammals, is a four-chambered heart. There is a left side and a right side; with both an atria and ventricle on either side. Blood comes back from circulation via the vena cava, with the inferior vena cava coming from the lower body and a superior vena cava coming from the upper body: they empty into the right atria, and then blood flows through an atrioventricular valve, in this case the tricuspid valve to the right ventricle. When the right ventricle contracts, it pumps blood through the pulmonary arteries to the lungs. Oxygenated blood returns to the heart via the pulmonary veins and enters the left atria. It moves from there to the left ventricle, and then up to the aorta, into systemic circulation. The atria and the ventricles are separated by several septa - there is an interatrial septum that separates the atria, and an interventricular septum that separates the two ventricles. The left ventricle is the ventricle that pumps blood to the systemic circulation, which has rather high resistance; thus the left ventricle's muscle is substantially greater than those of the right. When we look at blood flow, we'll see how the pulmonary circuit (which is supplied by the right ventricle) has substantially less pressure in it: and so the right ventricle doesn't need to pump with such force, as it faces far less resistance. To reiterate the pattern of blood flow, then, we have deoxygenated blood from the systemic circulation coming into the right side of the heart, and then being pumped through the pulmonary arteries to the lungs. The blood is oxygenated, returns to the heart via the pulmonary veins, goes into the left ventricle and then is pumped via the aorta back to the systemic circulation. The pulmonary circuit is the only place where we see an artery carrying deoxygenated blood and a vein carrying oxygenated blood; the opposite is true throughout the rest of the body. This is because the designation of artery/vein has nothing to do with oxygenation, but rather whether it is carrying blood towards (vein) or away from (artery) the heart. Red and blue colours are generally used to designate oxygenated and deoxygenated blood, respectively. 2B. The Conduction System of the Heart So next, let's look at the electrical conduction system of the heart. The electrical activity that will eventually cause the heart muscle to depolarize and contract is generated in a little region in the right atria called the sinoatrial (SA) node. It consists of a group of cells that have no resting membrane potential, and will spontaneously depolarise, thereby sending a wave of electrical activity through this conduction system (described below); where it will go to the contractile muscle cells, and cause the heart to contract. Everything, then, begins in the sinoatrial node. We have action potentials fired in the sinoatrial node cells, in the pacemaker cells, and this electrical activity spreads throughout the atria, through what are termed internodal pathways. The pathways travel out from the SA node throughout the atria, carrying waves of depolarisation. These waves of depolarisation cause the heart to contract. They travel through the atria, to the ventricle, through a single pathway, the AV (atrioventricular) node. The septa, between the atria and the ventricles, prevent any electrical activity from simply going anywhere in the heart - instead, all electrical activity must, at some point, go through the AV node. So we have these waves of depolarisation, going from the SA node, through the atria, to the AV node, where they pass on to the ventricles. From there, these waves of depolarisation travel through the AV bundle, also called the Bundle of His, and then through two branch bundles, a left and a right, which go through the interventricular septum. From there, the activity goes through what are known as Purkinje fibres, which originate at the bottom (apex) of the heart and move upward into the contractile muscle. This pattern of activity has the effect of causing the heart to contract starting at the bottom, resulting in the flow of blood up into the aorta (left side) or the pulmonary artery (right side). The cells in this conduction pathway system are modified muscle cells. They do not contract. They are not neurons. Their job of these cells is to pass waves of depolarisation onto the contractile cells, thereby triggering their contraction and the contraction of the heart as a whole in a smooth coordinated nammer. Cells within the heart are electrically coupled via gap junctions. From the SA node, strands of cardiac muscle cells allow passage of electrical activity through them - and this rapid transfer of current is due to the gap junction connection between the cells. There is no need to wait for neurotransmitters to be released, and for the pre- and post-synaptic events involved in neurotransmission: instead, current is directly transferred over the gap junctions. The cells are held together by protein fibers called desmosomes, which help to resist stretching in the heart. When the heart is filled with blood, it obviously must stretch to some degree to accommodate the filling: and this stretching can be important in increasing stroke volume. However, in general, heart stretching is bad - and if a heart is stretched too far, over a long period of time, it can begin to grow larger, a condition called cardiac hypertrophy. Any stretching, or any excess work (for example, due to high blood pressure) will cause the heart to grow, and this is undesirable is it can make it difficult for the heart to contract properly. So continual stretching, leading to heart growth, can lead ultimately to heart failure. If we were to look closer at the cycle of electrical activity in the heart, we would begin in the SA node. Remember, these cells have no resting membrane potential. So these cells depolarise, and the wave of depolarisation passes through the atria through internodal pathways. This conduction is very rapid, because these cells are very large- thus, there is little resistance to current flow. This continues until the wave of depolarisation reaches the AV node; at this point, the flow of current slows. The resistance increases, because the AV node's cells are rather small. This slowing-down of the wave is important, because it means that the atria will finish contracting before the ventricles begin to contract. If this did not occur, it would mean the atria would be contracting and pushing blood into the ventricles, whilst the ventricles were contracting and pushing blood into the aorta/pulmonary artery. It is the slight increase in resistance caused by the AV node that prevents this from happening. In reality, however, the atria don't actually need to contract for blood to fill the ventricles: 90% of ventricular filling is passive (see cardiac cycle lectures). The blood filling the heart comes from either the vena cava on the right, or the pulmonary veins on the left, flows right through the atria, past the bicuspid and tricuspid valves and into the ventricles. The contraction of the atria only accounts for about 10% of blood flow under resting conditions, and it is only under exercise that this percentage increases. The SA node is our endogenous pacemaker; it has no resting potential. But this is true of all cells in this conduction system (i.e., internodal pathways, AV node, Bundle of HIS, branch bundles and Purkinjie fibres). Note that the contractile muscle cells DO have a resting membrane potential. The SA node is our heart’s pacemaker simply because it depolarises faster than the other region. The AV node is the second fastest - so, if for some reason the SA node fails, the AV node takes over as pacemaker. If the AV node were to fail, different areas can take over. For example, when we look at ECG traces, we'll see traces indicative of a heart in which the pacemaker is actually located somewhere in the ventricles. Any area functioning as a pacemaker that is not 'normal' (i.e., not the SA node) is called an ectopic pacemaker. If the AV node does become the pacemaker, it can't spread electrical activity upwards because those muscles are in a refractory period (having been stimulated by a slower-than-normal depolarising SA node). Thus, even though SA and AV nodes can both spontaneously depolarise, they can't be in competition with each other, and sending competing signals. So the waves of depolarization pass through the Bundle of His and the branch bundles, quite rapidly, and once all of the ventricles depolarise the heart contracts, from the bottom to the top - and then, we return to resting conditions. Everyone has heard of implantable pacemakers: if the SA node is not working properly, an artificial one can be installed. Early ones were hooked up to wall electricity, and stimulated the heart at set rates. A more modern pacemaker is implanted in the chest, and has two leads going into the heart through the vena cava; one to the right atria, and another to the apex of the ventricles. The former lead attempts to stimulate the SA node; the latter stimulates the large muscle mass in the ventricles, so that the normal bottom-to-top method of contraction can proceed. Modern pacemakers are computerized, and can sense heart rate and stimulate the heart as needed. 2C. The Pacemaker Potential We're now going to look at two action potentials in the heart; action potentials that happen in the pacemaker cells (and conduction pathway), and ones in the contractile muscle. First, let's look at action potentials in a neuron, for comparison. In a neuron, starting with a resting membrane potential of -70mV, a slower (but still fairly quick) depolarisation occurs, hitting a threshold level of -55mV before quickly reaching a high of +30mV. A repolarisation then happens, with an undershoot where membrane potential levels actually fall below the resting level, and then a gradual increase back up to the resting membrane potential of -70 mV. The depolarisation in a neuron is a result of enhanced sodium permeability, with an opening of voltage-gated sodium channels. The repolarisation is a result of decreased sodium permeability, and enhanced potassium permeability (due to the opening of voltage-gated potassium channels). It is the interplay of sodium and potassium levels inside the cell that lead to changes in membrane potential, during an action potential, in a neuron. In the heart, both in the pacemaker and cardiac contractile muscle cells, there are more players involved: calcium ions and a different form of potassium channel are involved. For pacemaker cells, there is no flat resting potential; it is either depolarising or repolarising. It is never at rest. In the pacemaker cells, the first, slow phase of depolarisation, before the threshold level is reached, is the pacemaker potential. In the extracellular fluid, we have high sodium, low potassium and high calcium levels, and the reverse is true inside a cell. The equilibrium potential for each ion is the potential to which the ion will move in an attempt to make the membrane potential equal to the equilibrium potential. In the pacemaker cells, the equilibrium potential for sodium is +60 mV, for potassium -94 mV, and for calcium +123 mV: so potassium ions will move in order to get the average membrane potential to be -94 mV. There are four phases to the pacemaker potential/action potential. In the first phase (1), the potassium channels close, keeping positively charged K+ ions in the cell. Then, what are termed 'funny' channels, which are actually cation channels allowing both sodium and potassium through, will open. Sodium flows in, potassium out - but the balance of the two is overwhelming towards sodium coming in, and thus, what we see in the first phase is a reduction of potassium permeability, and an increase in sodium permeability: and it is this that drives the depolarisation. In the second phase (2), the funny channels begin to close. They close just short of the threshold level, so in order to get enough depolarisation to trigger an action potential, T-type calcium channels begin to open. So, it is calcium entry that continues the depolarisation. Unlike neurons, which rely only on Na and K to trigger action potentials, in cardiac pacemaker cells, changes in calcium permeability are what drives the rest of the depolarisation. At the end of the pacemaker potential, threshold has been reached, so the action potential phase begins (3). In the third phase, a second type of calcium channel opens - this time, an L-type calcium channel. These channels allow a massive amount of calcium through, and it is these channels that cause the large upswing in the depolarisation we see on the figure. In the fourth phase (4), repolarisation occurs, as the voltage-dependent potassium channels reopen and the calcium channels close. Calcium entry ceases, potassium is no longer “trapped” in the cell, and the cell’s membrane potential returns to the first phase of the pacemaker potential. The speed of this whole process within the SA node is what makes those particular cells the pacemaker cells of the heart. They “pace” the heart. Later, we'll look at how changes in permeability and conductance (particularly of Ca and K) can be caused by sympathetic and parasympathetic innervation of the heart, and how various components of the pacemaker potential are affected by nervous activity. 2D. The Cardiac Action Potential So now let us look at the cardiac action potential, within the contractile muscle cells. It is a very long action potential that looks very different from those in neurons and cardiac pacemaker cells. It ranges from 250 to 300 milliseconds in length, and does not simply go up and then down like a wave of depolarization/repolarisation does: instead, there is a plateau of relatively high membrane potential for about 100 milliseconds. We once again have an important role for calcium, unlike in neurons. However, unlike pacemaker cells, we also have a stable resting potential at -90mV. These contractile muscle cells must be stimulated by a signal in order for their action potential to commence; this signal is the wave of depolarisation originating from the pacemaker cells. We can divide the cardiac action potential into several phases, just as we did with the pacemaker potential. The large upswing, the large depolarisation (which here we'll call phase 0) is once again caused by the opening of voltage-gated sodium channels, and a large increase in sodium permeability. After this initial depolarisation, the role of sodium is finished; the rest of the process will be continued by other ions. When we get into phase 1, it is the beginning of a repolarisation, but it is not a steep decline: in fact it is the first part of a plateau. The sodium channels close, but this is opposed by changes in calcium and potassium permeability. What are called inward-rectifying potassium channels (different from what you see in nerves) close, trapping positively-charged potassium in the cell, and keep the membrane potential at an elevated level. L-type calcium channels open as well. These changes continue into the second phase, the plateau (phase 2). The membrane potential remains high, though there continues to be a slight decline. In phase 3, we see the opening of standard delayed-rectifying potassium channels, as well as the inward-rectifying ones that closed in phase 1. The calcium channels close, and so we see an increase in potassium permeability, a decrease in calcium permeability, and this leads to the large repolarisation. Finally, we return to resting membrane potential, phase 4, as the cell awaits stimulation once more.