Transcription
You know that there are two different types of cardiocytes in your heart: there are specialized cells and contractile cells. Although we are moving into Unit 3, this lecture actually reinforces material we learned in Unit 2. You learned about the second messenger systems that the parasympathetic and sympathetic divisions use. You also learned about drugs that influence parasympathetic or sympathetic function. We're going to review all those again today, so think of it as a review for the Unit 2 exam.
We have a lot to cover, it seems like, from the lecture outline, but trust me when I say it's going to go quickly because most of this stuff you already know from Unit 2. It really is like a review. Your heart muscle is made up of cardiocytes. These are relatively large muscle cells; they are striated like skeletal muscle; they are typically mononucleated; and these fibers—these muscle cells—branch. They are connected to each other by small, wide gap junctions called intercalated discs. This will allow the action potential to go from one cardiocyte to the next, traveling through the cytoplasm. These cells, given their size, have low resistance. Remember, we did a PhysioEx where we learned that the larger axon provided less resistance, so the bigger the muscle cell, the less resistance. These, in turn, intercalated discs, like I said, allow the action potential to travel from one cardiocyte to the next. This allows your heart muscle cells to contract in unison, what we call "sing-sing."
Now, the atria are the two top chambers where blood returns to the heart. The right atrium receives blood from the systemic circuit; the left atrium receives blood from the pulmonary circuit. The atria contract together, so that means atrial systole, followed by the ventricles contracting next—that's ventricular systole. So if I were to model how your heart beats, my top hand being the atria, my bottom hand being the ventricles, this is what it would look like: atria, ventricles; and then the heart relaxes: atria, ventricles, heart relaxes; atria, ventricles, heart relaxes. That's one cardiac cycle: atrial contraction, ventricular contraction, then relaxation. The proper word for contraction is systole; the proper word for relaxation is diastole. So we have atrial systole, atrial diastole, ventricular systole, ventricular diastole; and when all four chambers are relaxed, we call that diastasis. We're going to go through the cardiac cycle step by step, and then the next lecture—won't be today, but in the next lecture, probably on Thursday—that will definitely get you well prepared for your EKG analysis.
There is a skeleton in your heart; it's not made of bone. It is a fibrous skeleton. You see, in order for muscle to contract and do work for you, it has to be anchored into something. The heart muscle is no different. We can actually degrade away the cardiocytes, and all that would be left is this fibrous skeleton made of collagen fibers. The cardiocytes anchor into that, and that's the reason why our heart, when it contracts, has kind of a twisting motion to it. And this helps move blood from one chamber to the next, or out of the heart. And so, in the case, the right ventricle to the pulmonary circuit, or the left ventricle into the systemic circuit. This fibrous skeleton can provide some insulation or resistance to the action potential. There is a fibrous skeleton in between the atria; that's called the atrial septum—that means wall. There's also a fibrous skeleton that divides the ventricles; that's the interventricular septum. There's also a septum separating the atria from the ventricles, and it's this septum that is going to provide part of a delay, delaying the action potential moving from the atria down to the ventricles, and that's a good thing. Blood can only move from high pressure to low; that is the only way that blood will move—high pressure to low. If you want blood to move, you also need valves to be opening or closing, and valves open and close according to pressure changes, too. So we need pressure changes in order to get valves to open and close in order to get blood to move. Blood only moves from high pressure to low. If you do not have a pressure gradient, then there will not be valves opening, for example, and you won't get blood flowing, for example. [Music] [Music] Why? We were both pushing approximately with equal force, but in opposite directions; there was no pressure gradient. The only reason why the door opens when you push on it is because you are pushing on one side, and no one is on the other side pushing back. That's the reason why your door opens, and you flow through it. So from now on, when you leave a classroom and you push on a door, I want you to think, "I'm creating a pressure gradient, and now I can flow through this valve." That's how your blood flows.
Can I tell you the time when I had a problem opening a door? Yeah. So you know the story about blondes, right, and how they have limited intelligence? I had a problem opening a door—a door like that, a door with a bar. I could not open it. It was when I worked at a biotech firm. See, she can get through that. I could not. I was working in a biotech firm at the time, and we had a fire occur in one of the labs. Fire alarm goes off, and myself and my team of three others—we were in a high-security lab—we were all dressed up in our Tyvek suits and HEPA filters, and we had to evacuate safely. But because of what we were exposed to, we had to use like a different exit strategy. The day before-ish, I saw the two facilities managers, Brian and Tom, and they were unsealing a door that had been cocked shut because we're going to convert another room into another laboratory. So they were opening this sealed door, and as the fire alarm goes off, I turned to my team and I say, "Follow me. I know the quickest exit route because I just saw Brian and Tom the other day open up that door." So they follow me, and I pushed on the door, and it doesn't open. They push on the door again, and it doesn't open. She's finally—Paulette—she goes, "Follow me. This is enough." We were the last group out. The safety officer came up to me and said, "What happened?" And I, of course, went, "Well, I tried to use the exit door that I saw Brian and Tom unseal, and it wasn't open for me, so you might want to go check that out." And Brian and Tom—when they're saying, "Well, don't throw us under the bus. We opened it. It does open"—as to why it's not opening—didn't open. So the next morning, I get there early, and Brian and Tom are working on this door, and they see me, and they start laughing. And I was like, "Did you fix the door? It doesn't—it wasn't opening yesterday, was it?" And he said, "Come here, come here. Show us how you tried to open this door." And I did the same thing again, and it didn't open. And I went, "See?" And they started laughing so hard because—because it was an old-school, you know, the bar, and there was the hitch—parts were outside; there was no—there's no way—anyway. They had to report back to the safety officer. I kid you not, the entire company had to have safety training on how to open a fire door. We had to be trained to use our hands—certain space—depart—to push on the door so that we could figure out which way the door was hinged and open. They all—we all had to be trained for that. Then the safety officer didn't think that was enough; they put yellow tape with arrows, you know, in the sign saying "Push here" on all the doors. And you better believe that I came to work one day, and on my desk was a whole bunch of dumb blonde jokes—a whole bunch of them—was awesome, how I failed to open a door. And one of my favorite ones was, "How does a blonde turn on the light after sex? She opens the car door." Yeah, I'm fairly certain these days that would be sexual harassment in the workplace, but yeah, I thought it was funny.
So the big idea you can see here in yellow—those are special cardiocytes called specialized cells—and you can see that the action potential is spreading first through the atria. There's a momentary delay going through the fibrous skeleton before we see the action potential get to the ventricles. And you're seeing, as a result of this action potential, movement of blood. Again, blood will only move from high pressure to low. If the atria and ventricles contracted at the same time, they would have equal and opposite force on the blood inside—that's a lot like me trying to get out the door with someone else pushing on the other—we're not going to go anywhere. So we need the atrial sing-sing—zhmm—followed by a ventricular systole. This contraction is going to occur in the ventricles, starting from the apex, and we'll pull up from the IV septum, pull up, and then this is the lateral wall—squeeze in the blood inside. That's going to be important as opposed to contracting from the base down to the apex. If it contracted from the base down, we push blood further into the ventricles, not up, out the outlet from the ventricles. Remember, are the semilunar valves, and they're in the ceiling of the ventricle. So we need the ventricles to pull up the apex and then squeeze on the blood inside to eject it out of the semilunar valves. There is a delay going from the atria to the ventricles because of that fibrous skeleton. We're going to see that there are two places where this delay occurs. There's going to be the AV nodal delay; there's also going to be a delay in the bundle of His. I'll explain why just a moment. So the specialized fibers—those were shown in yellow—specialized fibers are also called leader cells when you're talking about heart cells. They start the action potential; they are not nerves; they are not nerves; they are merely cardiac cells that have automaticity—that means they can depolarize on their own, reach threshold, and once the action potential is started, it spreads through all of the other cells. And most of the cells of the heart are called contractile cells, also called follower cells. They would stay at a resting membrane potential forever if it weren't for the specialized cells starting the action potential that can then travel through those intercalated discs and spread from one cell to the next. So again, those gap junctions—very important.
Now, sometimes I've heard some professors call the specialized cells the "Barbra Streisand cells." Do you all remember who Barbra Streisand is? She was—she was the Lady Gaga of my day. Okay, same big nose, too. Um, and I find it amazing that "A Star Is Born," right, this kind of a throwback to Barbra Streisand in this story. We call the leader cells "Barbra Streisand cells" because when Barbra Streisand first started out, she was an understudy in a play; she was not the lead actress. And one day, the lead actress—that's it—and Barbra Streisand said, "Give me a chance. Let me start the show. Let me be the lead today." And the audience loved her so much that she became the lead actress for that play from then on out. Now, you have some Barbra Streisand cells in you, and that they—they take the lead; they're the leader. But the weird thing about these Barbra Streisand cells—these leader cells—is the following: Have you ever noticed, if you've ever ordered carpet or flooring of any type, someone always has to come out and measure for you? And when they take their measurements, they always order more carpet, more flooring than what you actually need. Why do they do that? Just in case they mess up, or just in case there's a weird cut that they need to do to the carpet, whatever. Well, when your heart was being modeled, when it was growing, you had extra Barbra Streisand cells, and just like Barbra Streisand, these cells didn't make the cut; they're not the ones starting the action potential; they're still lingering in your heart. And today, if they could talk, they would say, "Just give me a chance. Just give me a chance. Put me in. Put me in." And given the opportunity, they will start an action potential, but they won't follow the sing-sing; they won't follow the typical movement of the action potential. And when that happens, we say you have an ectopic pacemaker; you have some of these leader cells saying, "We want to be the lead," and now you get erratic heart contractions, and you don't get proper blood flow. Okay, so let's go through the pathway of this conduction—the way it's supposed to go. Everything shown here in red are your specialized cells—your leader cells—the ones that can depolarize and reach threshold on their own. Again, they are not nerves. The SA node is called the pacemaker in the heart, why? Because it depolarizes first; it reaches threshold first. But all of the cells shown here in red can depolarize on their own; they're just—they're just going to take longer. The SA node, because it depolarizes the most quickly, starts the action potential, and then it spreads through all the intercalated discs—that's why it's called the pacemaker—but it can fail. And if it fails, the next specialized cell in line is the AV node. Your heart rate would be reduced because they are going to take longer to reach threshold. There is a delay of the action potential in the AV node—why? The cells are small here; that creates more resistance, and there are fewer intercalated discs. There's also a delay as the action potential goes through the bundle of His because that's specialized cells that are going through that fibrous insulator. In both places we find this delay, and it allows the atria to have their contraction and finish before the ventricles get their turn at contraction and then relaxation. We want the atria to contract first, then the ventricles, in order to get proper blood flow. Then we see that the bundle of His is going to branch into a right and left bundle branch. Then this arcs around the apex of the heart to the ventricular walls, and those are called Purkinje fibers. Those Purkinje fibers are very large cells—very little resistance—and this means the action potential is going to pick up speed as it's traveling along the ventricular walls. Again, the SA node is called the pacemaker of the heart because it reaches threshold first. Once the action potential is started, it spreads through the intercalated discs from cell to cell. We're going to talk about the different kinds of channels that these specialized cells have. We're going to learn that calcium is actually part of the action potential—not an aftereffect; calcium is part of the action potential. That's new. Calcium—never—never in Unit 2, when we looked at the action potential profile—the upstroke, the downstroke, the hyperpolarization—never in there do we label calcium channels opening, did we? Never. In skeletal muscle contraction, the action potential comes and spreads through the skeletal muscle cell, and as an aftereffect, calcium channels are open, and then calcium binds to troponin, and we get tropomyosin changing conformation, and then we get contraction. In these cells, calcium is part of the action potential profile; it's also going to be a part of the follower cells as well; it's part of the action potential, and that's a game-changer for cardiocytes. It will mean that you cannot reach tetanus—not physiologically—and you don't want your heart to reach tetanus. If the heart is in tetanus, you don't get blood flow. So the calcium channels being part of the action potential—it's going to be a huge, huge changer when we talk or compare cardiocyte physiology to skeletal muscle. When the action potentials start in the SA node, it will spread not just down, but across the interatrial septum to the left atrium. So that's what we call internodal pathways. When it hits the AV node, again, there's going to be a delay there because the cells are small and they don't have a lot of intercalated discs. There's also a secondary delay in the AV bundle, also known as the bundle of His. Both of those delays allow enough time for the atrial systole and atrial diastole before the ventricles are going to have their turn for ventricular systole. This allows valves to open and close appropriately and blood to flow from the atrium to the ventricle and then from the ventricle out of the heart. The AV bundle is also known as the bundle of His—H-I-S. So again, the bundle is going to branch into bundle branches; there's a right bundle branch and a left bundle branch going through the IV septum. The right bundle branch actually has a strange anatomical bend to it. So if I—if I have my right arm here and my left arm here, the left bundle branch is more of a straight shot towards the apex; the right bundle branch has kind of this—where it goes up and then it goes down. The picture does not show that here, but it turns out that little detour is going to be an important finding for some of you in your EKG analysis. Now, all of you will have this finding, but some of you will, and when we find them, we'll say, "See, your right bundle branch is really taking a detour." It's not bad; that's just a normal anatomical finding that we've seen in a lot of people. That don't display more of that. So you can get a regular heartbeat for a myriad of reasons. To drink coffee today—coffee can give you irregular heartbeats. You can have too much of a delay in your AV node and the bundle—bundle of His. We'll talk about first-degree, second-degree, and third-degree AV nodal delay and what finding you would find on the heart and your EKG. There are a myriad of reasons why you could have an ectopic pacemaker that is causing changes in your cardiac conduction, so it—there's not just one easy answer for that question, but it's a good question. And then the Purkinje system—again, large cells—and we're going to see that the action potential speed really picks up here. And if I were to put a timeframe on this in seconds—here's our starting point—the action potential will reach the AV node; there, it's going to be a delay; it's going to be another delay through the bundle of His; then I'm going to see the action potential spreading down the right, left bundle branch and then around the ventricular wall back up towards the base. The base of the heart, remember, is the widest part—way up here—the left ventricle. These cells way up here—you notice they're waiting the longest for the action potential to arrive. If you look at the right ventricular wall, it doesn't wait as long. That might not seem significant to you, but do you think the left ventricular wall—those cells on the very top of the myocardium—have to wait the longest? Which side of the ventricles is thicker? The left. Why is it thicker? The muscle has hypertrophy. Why does muscle hypertrophy? Why do you go to the gym and hypertrophy your muscles? Now you have to say that—I'm going to go to the gym to hypertrophy my muscles. What does that mean? You're using your—increasing the workload to increase your muscle mass. Well, the left ventricle has to push the blood into the systemic circuit—that's a big circuit; that's a large workload; that's why it's hypertrophied compared to the right side. And all of those cells, because there's a thicker distance, the action potential has to travel through those cells just underneath it—the pericardium, the epicardium—they're going to wait the longest for the action potential to arrive.
Now, how can these specialized cells actually reach threshold on their own? Membrane transport is the reason why. They are going to be more leaky to sodium and less leaky to potassium. They also are going to allow some calcium to diffuse in. So if I'm allowing more sodium in, more calcium in, and less potassium going out, we can appreciate that the inside of the cells are getting more and more positive. And as soon as they reach threshold, sodium voltage-gated channels, and you're going to see calcium voltage-gated channels, are going to open. So again, they are becoming more permeable to sodium and less leaky to potassium, and that means as the cells get more and more positive, they're going to start migrating towards threshold. These cells never have a resting membrane potential; they are never at a stable resting membrane potential. They have what's called a prepotential; they're constantly migrating up towards threshold and then spiking an action potential. So as more positive charges come in, the prepotential starts climbing, and we reach threshold, and then there's an action potential. The specialized fibers in this picture are all shown in this more purple color. Again, all of those cells—the SA node, the AV node, the internodal pathways, bundle of His, right and left bundle branches, Purkinje fibers—they all can reach threshold on their own—all on their own. The pacemaker is given the title—or the SA node is given the title—pacemaker because it reaches threshold the fastest, which means it's the most leaky to sodium, least leaky to potassium; it is accumulating positive charges faster than all of the other specialized cells. If you could actually dissect them away from each other and put them in a dish, you would see them all spike an action potential and contract as a result. It's just that the SA node would be faster than the ones in the Purkinje fibers.
When I was a graduate student, I did some pretty cool—gross, morbid, but cool—experiments. I had to harvest—I had to take mice—fetal mice—from a pregnant mouse, and I took these tiny little prenatal, you know, mice fetuses, and I cut them open and dissected out their tiny, tiny little hearts. And I minced up all of these hearts, and I created a cell slurry, and I plated these cells in a petri dish. And what I noticed was, as these cells plated, some of them just kind of sat there living; they were alive in the dish, and some—I would watch them—shown here in my green picture—they would just ball up on their own and then flatten back down, and ball up on their own and flatten back down. And the ones that were living but not contracting—those were the contractile cells, the follower cells. The ones that were contracting on their own were the leader cells. I actually was able to detect them away from each other. I had to take fetal mice because the heart cells were still mitotic, and as those cells replicated and divided, eventually they all touched each other. We say the dish was confluent, and once they all touched each other, they created the gap junctions, and the entire layer of cells in the petri dish would contract up and then flatten back down—contract up and flatten back down. Yeah, it was really cool. Wow. More of it, but cool. Yeah, yeah, morbid, but cool. So these specialized cells—all of them on their own—can reach threshold, but the one that reaches it first will start the action potential, and it spreads through the gap junctions. So let's look at the action potential of a specialized cell—the leader cells. Again, their action potential profile is very different than what you've learned for Unit 2. In green, you're seeing the action potential. Now I'm going to go through it bit by bit. We see the prepotential. What's happening here? The membrane is becoming more permeable to sodium, less permeable to potassium, and we're reaching threshold. The upstroke is called—caused by—calcium voltage-gated channels. Calcium is part of the action potential. The downstroke—our good old friend—potassium voltage-gated channels are opening, and the cell becomes negative again, but it never reaches rest—not resting membrane potential—that prepotential starts over again. Now, what would that look like compared to a contractile cell? So this is the action potential of a contractile cell, and it has five different phases, numbered 0 through 4. You can see that it is a very negative cell inside, and it has a stable resting membrane potential. Not until the specialized cells spike the action potential will the contractile cell also, in turn, now have one. I'm going to go through all five phases and just evolve it. My question to you, though, is what would the action potential look like for the specialized cells if you could detect them out and put them in individual petri dishes? What would the slope of their prepotential look like? Because it would be different for every single one. They all can reach threshold on their own. SA node reaches threshold the fastest, so what does that tell you about the slope of the prepotential? If it reaches threshold first, it's steeper, right? If the Purkinje cells can reach threshold on their own, but they are slow to do that, their slope would not be as steep; it'd be more gradual. So we could actually draw that out if you wanted to—look something like this for the SA node, but for the Purkinje fibers, that prepotential isn't as steep, and they take longer to reach threshold. Can you tell me what would happen to your heart rate?
If your SA node failed, if your AV node failed, if your bundle branches failed, Purkinje fibers were the only specialized cells left; your heart rate would be roughly in the teens, low 20s beats per minute. That is not compatible with life, so it's bad enough when the SA node fails; we don't want the AV node really to be in charge next. That's the reason why some people get an artificial pacemaker inserted in their tissue.
So these specialized cells are not nerves, but they are modified by the autonomic nervous system. Yeah, Unit 2, and we know that the sympathetic division is going to release epinephrine, for example, on beta-1 receptors of the heart, and this increases heart rate and force of contraction. Heart rate is called chronotropy, right? So we would have an increased chronotropy, and we would have an increased inotropy, which is the word we used for force of contraction.
We know that the parasympathetic division releases acetylcholine on muscarinic receptors, and when that happens, chronotropy is decreased. Well, there's a molecular reason why heart rate can either go up or down. For the sympathetic, that epinephrine and norepinephrine is going to allow more sodium and calcium entry, less leakiness to potassium, and you're going to reach those positive charges even faster. With the acetylcholine released onto muscarinic acetylcholine receptors, it leads to increased potassium permeability; that's a loss of positive charge. It's going to take longer for the cells to reach threshold, and heart rate will drop. So we get a faster rate of polarization and faster heart rate for the sympathetic response; slower rate of depolarization and slower heart rate as a result of parasympathetic influence.
Now, the sympathetic division—you heard me say—increases heart rate, but also force of contraction, and here's the reason why. The sympathetic division not only targets the SA node and AV node, but it also innervates ventricles, and it leads to more calcium. Just like in skeletal muscle, the more calcium that's available, the greater the force of contraction because actin and myosin can interact longer. The parasympathetic division does not innervate the ventricles; it only innervates the SA node and AV node, which is why the sympathetic division has little to no influence on inotropy. That's a good thing. That's a good thing because what happens to your heart rate when you fall asleep at night? It goes down, of course it does, typically, unless you're having a nightmare and you're running for your life in your nightmare. But if the parasympathetic division is gaining more control when you're sleeping, if it also reduced inotropy, then the force of contraction could conceivably drop to the point where you can't get blood ejected out of the ventricles. Then you want to get enough blood going to your brain, and if you don't get enough blood flow to the brain, that's ischemia; it's going to lead to hypoxia, anoxia, and then an infarct—right, death. You would not want that to happen. Little to no influence on inotropy by the parasympathetic division.
If I actually looked at the prepotential and the pacemaker cells of the SA node and I showed you how the prepotential slope compared to normal under sympathetic stimulation versus parasympathetic, you can see how the prepotential becomes more steep when the sympathetic division has more control, and the prepotential is less steep when the parasympathetic division has more control. How does this occur? How does the steepness of the prepotential get altered? Membrane permeability changes. The sympathetic division will allow more sodium and calcium entry and less potassium leakiness, trapping positive charges, leading to threshold faster. The parasympathetic division leads to more potassium leakiness, less permeability to sodium, and it turns out most papers say that it's the changes in potassium that is the number one influence on that prepotential slope—number one. That's why I have it highlighted here in blue.
So we can go back to that one video I showed, and we can see the action potential spreading across the internal pathways, see the delay in the AV node, and then another delay in the bundle of His before the ventricles get the action potential transmitted to them, and then they can have their contraction. Again, chronotropy—heart rate; inotropy—force of contraction. Chronotropy is always listed first if you ever see this nomenclature; inotropy second. So the sympathetic division would have a positive chronotropy and a positive inotropy. The parasympathetic division would have a negative chronotropy but no influence on inotropy; that's why that second position is blank. And we know on a molecular level the second messenger systems that are used by the sympathetic and parasympathetic division. Have we memorized the steps yet? These second messenger systems: sympathetic—adrenaline. Sympathetic is all about the A's, right? Adrenaline binds to an adrenergic receptor, and it's going to activate a G-protein, right? But then is adenyl cyclase, which is going to activate or make cyclic AMP, which will then activate PKA. It's all about the A's. And then the parasympathetic division sounds like a really bad rap song. We got acetylcholine binding to the muscarinic acetylcholine receptor, activating a G-protein; then we got the PLC deactivating or making IP3 and the DAG, and that's calcium from the ER, and we get the PKC. Right, just sounds like a bad, bad rap song: PLC, and the IP3, and the DAG, and calcium from the ER. It's horrible. It's horrible. So we know all about that molecular change down inside the cell.
I asked you a question last week about our sympathetic versus parasympathetic influences and tone, and I gave you the water faucet analogy. How could you get—if you turned your bathroom faucets on halfway equally—your water would be lukewarm, right? How could you get it to be warmer? You have two choices: you could increase the outflow from the hot water, and you could also decrease the outflow of cold water. We can do the same thing if we want to speed up heart rate. We can give more control directly to the sympathetic division, and we can block muscarinic acetylcholine receptors with a drug, blocking the parasympathetic indirectly gives more control to the sympathetic, and we use both of those to increase a person's heart rate. Get the atropine, get the epinephrine; you're using both mechanisms to speed up heart rate. Okay.
When we are talking about contractile cells, they are the majority of the heart. Only a few cells of the heart are actually the leader cells. And when we look at the action potential of a contractile cell, we see this profile, and it has five different phases, numbered 0 through 4. So here is the action potential in your contractile cell of your heart, and here is the force of contraction that is generated. If I compare that to skeletal muscle, we see how short, or in short duration, the action potential is than the skeletal muscle, and here we're seeing the force of contraction. What you can't see very well with this projection unit is there's a band of blue; you see that thin band in blue, and then we see a band in yellow right next to it. The blue represents absolute refractory period; the yellow represents relative refractory period. And if you look at skeletal muscle, the muscle starts its force of contraction after relative refractory period, after which means the twitches can summate, and we did a PhysioEx where we rapidly pushed on our mouse to keep stimulating the skeletal muscle cell to try and reach tetany—twitches summing, but they can't in heart muscle—why? Long-lasting action potential. See how long the absolute refractory period is. Relative refractory period shown here in yellow; force of contraction; the heart muscle starts during the action potential, during, not after, like skeletal muscle does—during. And the reason is calcium is part of the action potential, not a result of the action potential; it's part. And in your PhysioEx, you learned that muscle can reach tetany if it's stimulated enough such that it never is given a chance to relax. Do you remember us talking about that? If you never give it a chance to relax, then it can reach tetany. This action potential is repolarizing during the absolute refractory period; there's just a little bit of it, but it counts. The electrical event of repolarization will lead to a mechanical event that we call relaxation. This contractile cell is relaxing during absolute refractory period, and that means it can't reach tetany. In order to reach tetany, you can't let muscle relax at all in between stimuli. This is a safety mechanism, an intrinsic safety mechanism to ensure your heart does not reach tetany under normal physiological conditions. If the heart reaches tetany, if it's holding a contracted state, then how is it going to fill? How will blood return to the atrium and into the ventricles if it's contracted? It can't. When the heart is relaxed, that's when we get blood returning to the heart, going to the atria and pouring, continuing into the ventricles. We don't want our heart to reach tetany. So people who have myasthenia gravis, their heart doesn't stop because of the myasthenia. Myasthenia gravis is an autoimmune disorder that is destroying preferentially nicotinic acetylcholine receptors, so it's not going to affect the heart because that has muscarinic, yeah, and beta-1. Good. Okay. And again and again, those receptors are for the autonomic nervous system to influence the natural activity of the heart.
A person can have a heart transplant. We cut the autonomic nerve fibers to do that transplant; we cut them, take out the heart, put in somebody else's heart into their thoracic cavity. There is no way for us to sew back together the cut nerve endings. There is no way; that's like trying to sew two paintbrushes together with the bristles. How do you do that? And yet, when I put a new heart into your thoracic cavity, it will continue to beat. Why? The cells, the leader cells, are autorhythmic; they don't require innervation. The innervation merely augments their natural action. Now, that person with a heart transplant, they're going to have a faster heart rate at rest than a person who doesn't have a heart transplant. You know why? The SA node likes to reach threshold faster, but it's the parasympathetic division that slows it down. So if you are cutting the nerves to give the person a new heart, that SA node is like, "Oh, I get to do what I want now," with no parasympathetic influence. But if they get into an alarm state, their heart rate is going to go really high, real quickly, because we forget that the sympathetic division has a hormonal component to it: epinephrine released by the adrenal medulla, and that epinephrine is going to stimulate beta-1 receptors on that transplanted heart. It's going to take them longer to get their heart rate to come back down. Why? There's no parasympathetic hormone equivalent; there isn't. So it's going to take them longer to get their heart rate to come down because we need to wait for the epinephrine to be degraded. Adjusting it is the sympathetic. Yes. Okay.
So excitation-contraction coupling happens in skeletal muscle, and it also happens in the heart, but in a different way. We have got to link the action potential to contraction, and the link behind that is the mobilization of calcium. In skeletal muscle, the action potential comes down the T-tubules, and as a result of that action potential, voltage-gated channels inside the cell on the sarcoplasmic reticulum open and release calcium. It takes time for that calcium to bind to troponin, time for calcium to change the conformation of tropomyosin and expose actin; that takes time, about approximately 11 milliseconds, and that's the reason why the skeletal muscle cell will be completely out of absolute and relative refractory period before you even see a twitch, and those twitches can summate. At the end, we need the calcium ATPase to re-sequester the calcium back into the sarcoplasmic reticulum in order to get relaxation. But the T-tubules and cardiocytes are much bigger, much wider, and they have an extracellular source of calcium, not just intracellular—extracellular. What created that extracellular source of calcium? A calcium-sodium exchanger. You know secondary active transport; sodium is allowed to diffuse in, and calcium is pushed out into the T-tubules. The action potential comes down the T-tubules, and as it comes down the T-tubules, it opens calcium voltage-gated channels. Some of that calcium that comes in is going to bind to a receptor on the sarcoplasmic reticulum and release even more calcium, but some of the calcium that came in from the T-tubule can go to troponin, remove tropomyosin inhibition, and expose actin. During the action potential, we start to see contraction. The excitation-contraction coupling time is much more reduced compared to skeletal muscle, and again, we need the calcium ATPase to re-sequester calcium, and we need this calcium-sodium exchanger to keep pushing the calcium back out if we want to have relaxation.
Going through the five phases of a contractile cell, we have this upstroke phase; that's phase zero, and that's when sodium voltage-gated channels are opening. Then we see the peak on the action potential profile start to drop a little bit; that's phase one; that's from sodium voltage-gated channels closing, and the cell starts to repolarize, but then we see this plateau phase; that's phase two, where we get calcium entering the picture—calcium voltage-gated channels opening—and it's during that phase we're going to see the peak force of contraction. Then phase three is the potassium voltage-gated channels opening, and we repolarize. And phase four is your stable resting membrane potential. So those are your contractile cells. Now, believe it or not, I just nailed about two pages worth of homework packet three, which I know you're not even thinking about, but I did. Having you diagram the action potentials of the specialized cells and contractile cells is towards the back of the homework packet. So important things to consider: cardiac muscle starts to contract during the action potential—why? Calcium is part of the action potential. There still is excitation-contraction coupling, but this is much shorter in time than the skeletal muscle. We also see that the muscle of the cardiocytes starts to contract during the action potential; the peak phase is during that plateau phase. We see that it starts to repolarize during absolute refractory period, and that means the cardiac tissue starts to relax, and that means we cannot summate the twitches; you cannot reach tetany under normal physiologic conditions. So what does the heart do when it's relaxed? It's resting; it's taking a break, but it's also filling. The heart has to relax in order for blood to flow back to the atrium and into the ventricles. Blood will only flow from high pressure to low. There's something else that the heart is doing when it's relaxing: that is the only time it gets perfused. You see, I think there is a slight anatomical problem with the openings of the coronary arteries. Do you know where they are? The coronary arteries are the first branches off of the ascending aorta; they are the first. Where are the openings? Anatomy was a prereq. Does anybody want to be a YouTube star in my video? No? Anyone here who wants doesn't mind me video recording you? Who is wearing a jacket with a hoodie? It'll be okay; I just need your pity. There we go. Yeah, right. Good. Okay. So this is considered one of the cusps of the semilunar valves, the aortic semilunar valve; there would be three. And when the heart contracts, these cusps are pushed against the aorta, and blood is ejected out of the heart. But when the heart relaxes, blood momentarily, just briefly, regurgitates—that means backwards flow—and then it fills those cusps, and it shuts the semilunar valves. Inside the cusps is the opening for the coronary arteries; inside that means there is no blood flowing through the coronary arteries when the heart is contracting because the cusps are flattened up against it; it's only when the heart relaxes that the blood fills those cusps and now can flow through the coronary arteries. Think about that: when your heart rate goes up, when your heart rate goes up, arguably your heart should get more blood flow; it's working harder, shouldn't it? And yet there's less time for it relaxing in between beats; it's getting less. A working muscle, working tissue bed should get more blood flow. This is a huge—no one is seeing the threat of this—arguably another reason why not to work out. I've given you more reasons not to. Too good. No, it is actually better for your heart for you to work out. Here's why it pays off when you're done working out. You see, when you do cardiovascular exercises like running, your heart muscle hypertrophies in a healthy way, and that means at rest your heart is stronger and ejects more blood, and then that means you get more opportunity for it to rest, and you're going to learn why the brain is going to send a signal down to the heart saying, "You are so good as a pump that you can take more time to relax in between beats." So your heart actually becomes more efficient at rest as a result of exercising. That's going to take more time for me to explain. This is just day one of Unit 3.
Let's review what we've learned. The SA node reaches threshold first; it's going to spread through the intercalated discs—those are modified gap junctions—it's going to reach the AV node where there is a delay, and another delay in the bundle of His. The atria are having their systole; they are contracting, pushing more blood down to the ventricles. Then finally, the action potential goes down the bundle branches, around the ventricular walls. The apex is pulled up, and then the ventricular walls contract. When the apex is pulled up, this pushes the blood up securely closer to the semilunar valves, and when the—the walls, lateral walls—contract, this is going to spurt the blood out of the semilunar valves, and then we're going to see relaxation. Next week you're going to do EKGs. Everyone in this room is going to be hooked up to the EKG machine, and you're going to get a tracing—every single one of you. You paid five dollars for material fees; this is worth the price of registration of this class alone. Do you know how much you'd have to pay to get an EKG done in a doctor's office just for kicks? It's expensive compared to what you paid for the materials fees. You're going to want to be hooked up, and you're going to want to take a picture of your EKG and keep it in your phone, and if you can keep your EKG tracing in your wallet—heaven forbid—if you ever have a heart condition develop in the future, having a baseline read before you had that problem can cut down the diagnostic time involved in depth in figuring out what's wrong with your heart. So if they have a baseline read of what your heart looked like, your conduction profile looked like before you had issues, it will save you hours in the emergency room, I promise you. So everyone is going to have this picture. Now, do you know the difference between the electrocardiogram and an electrocardiograph? What is the machine, and one is the actual picture or tracing? That's what most people think because graph, we think of graphing paper, and the EKG paper looks like graphing paper, but the electrocardiograph is the machine; the electrocardiogram is the picture. Yeah, just like a telegraph is the machine to send a telegram. No, was that too old of an analogy? Now, this is meant—I did not want you to print this out; that's why there were two different files—this is meant to be shown to you as a video, like a series of slides, when we do our EKGs next week. Where do the electrodes go? Do you know? And what do they look like? They look like little circles with metal squares or squares; we've got both kinds. Where do they go? That didn't—look, look, look. There is no naked Tuesday and Thursdays, so we're not disrobing each other, Brett Kavanaugh; we're not doing that. I'm putting that on YouTube. There's no naked time. We're going to put them in the old placements of the Victorian time; it was improper to ask a woman to show a lot of her skin, so I'm going to put them on the wrists and on the ankles. Make sure you shave your legs if you are going to be weird about that. The people are hooking you up; the electrodes are on the outside of your skin. That was totally different than the Hodgkin and Huxley experiments. Hodgkin and Huxley experiments—where did they put the electrodes? Into the squid axon, right? They pierced. There will be no piercing of the—putting electrodes through our chest wall to get to our heart. The electrodes are on the outside, not inside. That means we have to switch our perspective. In Unit 2, you learned why the inside of the cell was negative at rest; you learned that during the upstroke of the action potential, the inside of the cell got positive; during the downstroke, the cell became negative again. Well, that was because the electrodes were in the cell. Next week our electrodes are outside of us, and that means we need to entertain the charge of the outside of the cell during the action potential. I know. So if the cell is becoming positive during the upstroke inside, then what is it doing on the outside? Becoming negative. If the inside of the cell at rest is negative, then what's the outside of the cell? Positive. If the inside of the cell is getting negative during the downstroke, then what's the outside doing? It's getting positive. Rest and repol—rest and repol—rest and repol. The outside of the cell is positive during depolarization; the outside of the cell is negative. And you have to remember that when you are looking at an EKG, the electrodes are on the outside of the person. Think of that as outside of the cell. So that means that the inside of the cell is reaching threshold and spiking an action potential, then the outside is becoming negative, and when the cell repolarizes and becomes negative inside again, the outside is becoming positive. Rest and repol—the outside of the cell is positive. The atria—how do they depolarize? Top-down, like this, from the SA node to the AV node. Which direction is that? Where is the SA node found? Where? Okay, I know it's in the right atrium, but where? It's in the top, top right. Where's the AV node? In the floor of the atrium towards the left. Okay. So if that current is spreading from the SA node to the AV node, point on your person what that current would look like; wouldn't it be spreading down into the left? Do you agree? Down and to the left. Then the current is going to get into the IV septum; it's going to have a straight shot down the left bundle branch, but the current is going to have to go up and then down for the right bundle branch. Then the current is going to go around the apex and along the ventricular walls through the Purkinje fibers. We can give direction to that: AV node from the SA node to the AV node, down to the left, then down into the left through the bundle branches. Correct? Is your heart sitting slightly at an oblique angle? Not only that, the apex is kind of coming out at you, out of your chest like this; it's resting on the back. Then it gets to the apex; it's going to go this way around the right ventricle and then this way around the left, but which cells have to wait the longest? The left, right? So do this on your person: I'm going to go down into the left, then down to the left even more, then around the right side, but it all seems to the left, and because you have more muscle mass on the left, we point more that way. What direction is that? Up and to the left. Okay. So let's look at how the ventricles are going to depolarize. So let's look at atrial repolarization again. It depolarized top-down; it's going to repolarize top-down. That makes sense, right? What about the ventricles? Down the IV septum and around to the left—top-down, and then back up again. But how will it repolarize? Reverse. Okay, so push your seats back; we're going to ask something out. I