Welcome back. So, today we want to continue our discussion of muscle. And we're going to consider a second type of involuntary muscle, and this is called the cardiac muscle. And cardiac muscle, as you are aware, makes up the walls of the heart. The cardiac muscle's also found in the vena cava, which is the very large veins which are bringing the blood from the head and also from the body back into the heart. And it is found in the walls of the pulmonary veins, that is, the veins which are coming from the lung back to the heart. So the things we want to consider then today are the structure of the cardiac myocyte and how the contraction of the cardiac myocyte generates force. And so we'll specifically look at how the contraction is going to be regulated. Cardiac myocytes are going to follow the sliding filiment principle which all muscles follows, and that is as that actin and myosin will slide past one another to provide shortening of the cell and also force generation. The other thing we want to talk about is the action potential of these cells. And the third thing, is the mechanism that underlies what's called a refractory period. And this is a period where the cardiac myocyte is not able to have a second action potential initiated. And then its importance to heart function. And then lastly, we want to talk about the absence of tetanus, and that is a Charley horse within the heart itself. Okay, so the first thing then is, what is the cardiac muscle structure? So cardiac muscle cells are blunt-ended cells, and that's what's diagrammed here with this dotted line. They're blunt-ended cells where one cell butts up against a second cell. And at that junction, they will have adhesion plaques. These adhesion plaques are called fascia adherens, and this is for mechanical coupling. These adhesion plaques very heavy in protein, and you can see these as dark lines running across the cells. So there, and the dark lines are called intercalated discs. So the adhesion plaques then allow one cell to contract and to pull against its neighbor. The second thing about the cells is that the cells are fairly large in size. And so they're about 25 micrometers in diameter. And they have a central nucleus. So the cells then are rather large but they're not as big as skeletal muscle which we said could be 75 micrometers in diameter or 100 micrometers in diameter. And they're not as small as the smooth muscle which we saw was only 2 to 20 micrometers in diameter. The other thing to notice about these cells is that they are electrically coupled. And the electrical coupling occurs along the edges of the cell such as here where one cell is interdigitating with a second. And these gap junctions then are electrical coupling which allows one cell to have this, the calcium from one cell then is moving to the second cell, and the cells now will contract in a synchronic manner. These cells are striated. In the light microscope, you can see regular AI banding and the AI banding, of course, are indications of the sarcomeres. And the A band is for the myosin. This is going to be the heavy chain. The light band is the actin and that is the light chain. And so we have a striated muscle. And because we have two types of striated muscle that is skeletal and cardiac then to say that a muscle type is simply striated is insufficient. You have to just distinguish between whether or not it's a skeletal muscle versus a cardiac muscle. Okay so how does this work? So when we talked about the skeletal muscle we said that the electrical activity that was causing a depolarization of the cell would move across the plasma membrane and that it had to enter into the interior of the cell in order to get the entire cell to respond in a synchronous manner. And that was because the cell had such a large diameter. And to do that, we have what are called invaginations of the plasma membrane and these are called T tubules. So the same arrangement is found in cardiac myocytes. So the cardiac myocyte then is thick enough that diffusion is not sufficient to bring calcium into the interior of the cell. And instead, we will bring the electrical activity down the T tubules. And cause a release of intracellularly stored calcium that is stored within the sarcoplasmic reticulum, that organelle that's within the cells. And that that then would dump the calcium into the cytoplasm in sufficient amounts that we can get contraction of the contractal filaments. So this is how it occurs then. The action potential sweeps along the plasma membrane and down the T tubule and that's what diagrammed here. As it comes down the T tubule, it will open a voltage gated calcium channel and this is the dihydropyridine channel. And that's the calcium channel. And a very small amount of calcium enters into the cell. And that small amount of calcium opens the ryanodine channel. The ryanodine channel is a calcium stimulated calcium channel which is located on the sarcoplasmic reticulum. Once that channel opens, and that's what's shown here in number 1, we open then the ryanodine. As we open the ryanodine channel on the SR, calcium leaves the sarcoplasmic reticulum, and bathes all of the myofibrils. And this is what's shown here in step 2. So we now have calcium engaging with the myofibrils, with the myofiliments. And that is actin and myosin. And in cardiac myocytes, just like we saw in skeletal muscle, the regulation will be on the actin, and so the calcium will bind to troponin-tropomyosin complex, cause that complex to unmask the actin's binding sites for myosin. And so this calcium regulation then occurs on actin, or the thin filament. The third event is that we have the calcium taken back up into the sarcoplasmic reticulum and that's by the calcium ATPase. So when we have the calcium is being removed from the contractile elements, then the contractile elements will start to relax. And so the calcium is then stored again within the sarcoplasmic reticulum. So, so far we're paralleling exactly the events that are occurring within skeletal muscle. But the cardiac muscle has to move its calcium very quickly from the cytoplasm in order to be ready for the next beat. And in order to that, it has two other ways that it removes the calcium from the myofibrils. And the first of these is that it uses a calcium exchanger. So the calcium exchanger is a sodium calcium exchanger. And when calcium is high, then the calcium is extruded to the outside and sodium enters the cell. And the fourth way is that there is also a calcium ATPase. And the fifth way, that's here, the fifth way that we remove calcium is that we have a calcium ATPase which is present on the plasma membrane. And under these conditions, then calcium Is actively pumped to the outside of the cell. Of these different ways of moving calcium out of the cytoplasm, the most important of these is the sarcoplasmic reticulum calcium ATPase, and this is sometimes referred to as SERCA. So it's a calcium ATPase which sits on the sarcoplasmic reticulum, or the SR. So when we have the presence of calcium, then within the cytoplasm we will have myosin engaging with actin and we'll get contraction. And then we remove the calcium from the myofibrils by taking it back up into the sarcoplasmic reticulum or moving it back out to the outside of the cell and then the myofibrils will start to relax and we will have a relaxation event. Now, the cardiac myocytes has a very large action potential for the cells which are the contractile cells. About 99% of the cells in the heart are contractile myocytes. And these contractile myocytes have what's called the fast action potential. They're the ones that are going to generate force. We'll talk about the slow action potential, which is the action potential which is typical of the pacemaker the next time we come in here. But today we're only going to talk about the contractile cells and the contractile cells are the ones that generate the force. And they are 99% of the heart cells. The fast action potential is what's diagrammed here. And so at the time of a stimulus, we will have a very fast upstroke, which is called phase 0, which is the depolarization of the cells. And this is the opening of a voltage-gated sodium channel. As the sodium enters the cells, the cells very rapidly depolarize and then reach a point where they are now above threshold, they're in a positive position and now that the voltage gated channels start to close. The plasma membrane starts at about a minus 85 millivolts. So we have a very low resting plasma membrane. At 1 or phase 1, we then have the closing, it is the inactivation of the voltage-gated sodium channels. And as these channels inactivate, there's an opening of the potassium channels. And so, there is a very slight depolarization which occurs. Then, we reach what is called phase 2 and phase 2 is the plateau phase. And under this condition, we have calcium, which is entering into the cells. We're opening the voltage-gated calcium channels and we still have open the voltage-gated potassium channels, which are causing the cells to repolarize. And it's the balance between the calcium channel, where calcium's entering the cell and potassium channel, where potassium is leaving the cell which causes an isoelectric or plateau phase to the action potential. And then, in phase 3, the calcium channel, the voltage-gated calcium channel, is closed. And we now have only open the voltage-gated potassium channels. We have efflux of potassium from the cell, which causes a repolarization of the cells. And the cells go back down to the resting membrane potential at a minus 85 millivolts. And then in phase 4, we have a re-establishment of the sodium and potassium amounts that are distributed across the plasma membranes. Yeah, so there's a few things to notice about this action potential. One is, is that this plateau phase is rather long and it is unique to cardiac myocytes. If you recall, when we were dealing with nerve and with skeletal muscle that the action potentials were very fast up and down. The second thing that you should notice is that the time of the action potential is quite large and so that takes 200 milliseconds for the duration of this action potential. And that's in contrast to nerve, where nerve had an action potential of 1 millisecond, and in contrast to skeletal muscle, where skeletal muscle had an action potential of about 2 milliseconds. So the cardiac myocyte then has a very long lasting action potential. That is the contractile cells of the heart. And we'll come back to the importance of that in just a second. All right, so now we want to consider the refractory period. The refractory period is what's shown here. So the first thing to notice is that we have our fast action potential, and that's what's diagrammed here. So the fast action potential has a very rapid upstroke or depolarization. Then we have the phase 1, where we have a slight repolarization. And then phase 2, where we have a very long sort of plateau phase. And then phase 3, where the cell repolarizes. And then we have phase 4, which is again, our resting membrane potential. Now during this period, we had in phase 0 then we had a very fast opening of these voltage-gated sodium channels and the sodium channels then inactivated in phase 1. And as they're inactivating in phase 1, if you recall, these are the same channels that we saw within nerve, and that is if you try to stimulate them while they're inactivated, they cannot reopen. But they have to go into a closed phase before they can be reopened. And the closed phase does not occur until we repolarize the cells. So during from about time 0, that is at the point of stimulation, to about 180 milliseconds, we have a period of time where those voltage-gated sodium channels cannot be reopened. They are in an inactive state and that's called the refractory period. So this is a fast action potential, absolute refractory period, which is occurring between 0 and 180 milliseconds. No matter how hard we stimulate this cardiac myocite in that time frame, the cardiac myocite cannot initiate a second action potential. So this is the absolute refractory period. There is between 180 and 200 milliseconds a period where some of those voltage-gated sodium channels have now closed. So they've moved from an inactive state to a closed state. And under these conditions they can be re-opened if there is a stimulus at this point. And so under the relative refractory period, which occurs between 180 and 200 milliseconds, a stimulus then could cause a second action potential. Now the thing to notice about this diagram is that we've superimposed the time of the twitch, that is a single contraction from a single action potential and that's what's shown here in green. So this tension, that is our single twitch or contractile period, is also diagrammed on the same time scale. And if you notice that the twitch is very long and so it covers about 250 milliseconds. And so most of the time that the twitch is occurring, then we are in a absolute refractory period so that we can not stimulate the cell and get a second twitch to occur, and that means that there is no summation of contractile events. So, we can't summate The contractions as we could, we'll scale it to muscle. Now, why is that important? If you think about it for the heart, that means that you could never sum it to tetanus within the heart. So, you can't stimulate the heart so rapidly that you will get a Charlie Horse within the heart or a cramp. And that's really important because if you think about it, every beat the heart has to fill with blood in order to expel the blood to the body. And so for each beat, we have to relax and then fill during relaxation, and then contract to expel the blood. If the heart is constantly contracted, it would not be able to fill the heart and so it would lose the pumping action from the heart. And so that would be lethal, that would be death. So, this is a very important concept then that the fast action potential of the contractile myocyte is almost the same time period as the contractile event itself. One other thing to consider when we're talking about the heart, and that is a set. When we have skeletal muscle, we were able to recruit more fibers and get stronger and stronger, and stronger contraction. This cannot occur within the heart. So when the heart is simulated to contract, all of the fibers will contract in synchrony, and that's due to the presence of the gap junctions. In order then to develop tension within the heart, the heart has to do other things that will allow it to get a greater contraction or a greater strength of contraction. And so that's what's diagrammed here. So we have tension which is on the y-axis and the sarcomere length which is again our actin-myosin overlap on the x-axis. The cardiac myocyte in the resting condition is sitting here. So this is the resting state. And as you see, that it is then at a place where we are not developing optimal tension. So that, that is the overlap, then is not optimal. But as we fill the heart, we then reach the optimal position for the overlap of the sarcomere, of the myosin and actin. And under these conditions then we get a very strong contraction. So the heart uses filling in order to cause a better contraction. So as you stretch the fibers, the myofibers, the alignment of the actin and myosin is such that it becomes a better contraction. So the cardiac myocyte then is that as you fill the heart. If you fill the heart more, then you will get a stronger contraction. And this is called the Frank Starling law of cardiac myocytes or of the heart. This is in contrast to skeletal muscle, where skeletal muscle tends to sit in its optimal overlap length, and that is because skeletal muscles attach to the skeleton. That is it's attached to bone, and the bone keeps it, then in its optimal length for generation of power. Okay, so what are our key concepts? So the first is, is that cardiac muscle is an involuntary, striated type of muscle. Secondly, that the cardiac muscle contains overlapping protein myofilaments, which are actin and myosin. And that the relative sliding of the actin and the myosin produces shortening and generates force. And that this process involves cross bridge formation between the actin and the myosin, and it's driven by the myosin ATPase. So that myosin ATPase in the heart is again, a slow myosin ATPase. It's a slow kinetics to the enzymatic reaction. Third, that the coupling between the membrane action potential and contraction is mediated by calcium ions. And in cardiac muscle, calcium regulates these thin filament. Again, the thick, the actin enabling the cross bridge formation. And that is affecting then the troponin-tropomyosin complex, which is blocking the actin, moving it out of the grove and myosin can now engage the actin. Fourth, the autonomic nervous system regulates the cardiac muscle. And we didn't really discuss that in any great length in this particular lecture, but we'll talk about that in great length in the next lecture. And five, the action potentials are initiated by an influx of extracellular sodium, and they're coming in through those voltage-gated sodium channels. Which move to an inactive state and then have to be moved from an inactive state to close and become then available for reopening. And then sixth, the cardiac muscle contracts in unison, and this is due to the gap junctions which are electrically coupling all of the cells. And that the cardiac myocytes cannot develop fused tetanus. And this is due to the length of the contraction itself. It's almost the same length, 250 milliseconds. Is almost the same length as the length of the action potential of the cardiac myocyte, which is 200 to 220 milliseconds. Okay, so the next time we come in here then, we're going to consider the cardiac myocytes. But we're going to talk about them now in the heart and how they're used then to govern the activity of the heart. Okay, so see you then.
