Welcome back. So, today we want to continue our discussion of muscle. We're going to consider a second type of involuntary muscle. This is called the cardiac muscle. Cardiac muscle, as you are aware, makes up the walls of the heart. The cardiac muscle is also found in the vena cava, very large veins which are bringing the blood from the head and also from the body back into the heart. It is found in the walls of the pulmonary veins. That is, the veins which are coming from the lung back to the heart. The things we want to consider today are the structure of the cardiac myocyte and how contraction of the cardiac myocyte generates force. We'll specifically look at how the contraction is regulated. Cardiac myocytes follow the sliding filiment principle which all muscles follow. That is as that actin and myosin slide past one another to provide shortening of the cell and also force generation. The other thing we want to discuss is the action potential of these cells. The third thing, is the mechanism that underlies what's called a refractory period. This is a period where the cardiac myocyte is not able to have a second action potential initiated. And its importance to heart function. Then lastly, we want to discuss the absence of tetanus, a Charley horse, within the heart itself. Okay, so first, what is the cardiac muscle structure? Cardiac muscle cells are blunt-ended cells. That's what's diagrammed here with this dotted line. They're blunt-ended cells where one cell butts up against a second cell. At that junction, there are adhesion plaques. These adhesion plaques are called fascia adherens. This is for mechanical coupling. These adhesion plaques contain protein. They are seen as dark lines running across the cells. These dark lines are called intercalated discs. The adhesion plaques allow one cell to contract and to pull against its neighbor. The second thing about these cells is that they are fairly large in size. They're about 25 micrometers in diameter. They have a central nucleus. The cells 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. They're not as small as smooth muscle which we is only 2 to 20 micrometers in diameter. The other thing to notice about these cells is that they are electrically coupled. The electrical coupling occurs along the edges of the cell such as here where one cell is interdigitating with a second. These gap junctions enable electrical coupling which allows calcium from one cell to move to the second cell, The cells now will contract in a synchronous manner. NOtice that these cells are striated. In the light microscope, you can see regular AI banding. The AI banding, of course, indicates the sarcomeres. The A band is myosin. This is the heavy chain. The light band is actin. This is the light chain. So we have a striated muscle. Because we have two types of striated muscle, 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? When we talked about skeletal muscle, we said that the electrical activity that caused 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. That was because the cell had such a large diameter. To do that, we have invaginations of the plasma membrane. These are called T tubules. The same arrangement is found in cardiac myocytes. The cardiac myocyte is thick enough that diffusion is not sufficient to bring calcium into the interior of the cell. 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, an organelle within the cells. That depolarization would dump calcium into the cytoplasm in sufficient amounts that we can get contraction of the myofilaments. This is how it occurs then. The action potential sweeps along the plasma membrane and down the T tubule. That's what diagrammed here. It comes down the T tubule, it will open a voltage gated calcium channel, the dihydropyridine channel. That's the calcium channel. A very small amount of calcium enters into the cell. 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 Ca++ channel opens. That's shown here in number 1, we open then the ryanodine channel. 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 now calcium engages with the myofibrils, with the myofiliments. That is actin and myosin. In cardiac myocytes, just like we saw in skeletal muscle, regulation will be on the actin. Calcium will bind to troponin-tropomyosin complex, and cause that complex to unmask the actin's binding sites for myosin. 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. That is done by the calcium ATPase. When calcium is removed from the contractile elements, then the contractile elements will relax. The calcium is then stored again within the sarcoplasmic reticulum. So, far we have paralleled exactly the events that occurred within skeletal muscle. But the cardiac muscle has to remove its calcium very quickly from the cytoplasm in order to be ready for the next beat. In order to that, it has two other ways that it removes the calcium from the myofibrils. And the first of these is it uses a calcium exchanger. The calcium exchanger is a sodium-calcium exchanger. When internal calcium is high, then calcium is extruded to the outside and sodium enters the cell. And the third way is by a second calcium ATPase. That's here. We remove calcium by a calcium ATPase present on the plasma membrane. Under these conditions, then calcium is actively pumped to the outside of the cell. Of these different ways of removing calcium from the cytoplasm, the most important is the sarcoplasmic reticulum calcium ATPase, This is sometimes referred to as SERCA. It's a calcium ATPase which sits on the sarcoplasmic reticulum, or the SR. When we have the presence of calcium, within the cytoplasm then myosin engages actin. We'll get contraction. To remove the calcium from the myofibrils, it is by taken up into the sarcoplasmic reticulum or moved out to the outside of the cell. Then the myofibrils will start to relax and we will have a relaxation event. The cardiac myocyte has a very large action potential if it is a contractile cell that generates force. About 99% of the cells in the heart are these contractile myocytes. These contractile myocytes have what's called the fast action potential. They generate force. We'll talk about the slow action potential, which is the action potential typical of the pacemaker, the next time we come in here. But today we're considering the contractile cells. The contractile cells are the ones that generate force. They are 99% of the heart cells. The fast action potential is what's diagrammed here. At the time of a stimulus, there is a very fast upstroke. This is called phase 0. This rpid depolarization of the cell. This is due to the opening of a voltage-gated sodium channel. Sodium enters the cells. The cells very rapidly depolarize. As the cell reaches a point above threshold, the voltage gated Na channels start to inactivate. Notice that the plasma membrane started at about a minus 85 millivolts. This is a very low resting membrane potential. At 1 or phase 1, we then have the inactivation of the voltage-gated sodium channels. As these channels inactivate, there's an opening of the potassium channels. There is a very slight depolarization which occurs. Then, we reach what is called phase 2. Phase 2 is the plateau phase. At phase 2, calcium enters into the cells. We have opened the voltage-gated calcium channels. We still have open voltage-gated potassium channels, which are causing the cells to repolarize. There is balance between the calcium channel, where calcium enters the cell and the potassium channel, where potassium leaves the cell. This causes an isoelectric or plateau phase to the action potential. Then, in phase 3, the calcium channel, the voltage-gated calcium channel closes. Now only the voltage-gated potassium channels are opne. There is efflux of potassium from the cell, which causes repolarization of the cells. The cells return to the resting membrane potential at a minus 85 millivolts. In phase 4, we have a re-establishment of the sodium and potassium that are distributed across the plasma membranes. So there's a few things to notice about this action potential. One is that this plateau phase is rather long. It is unique to cardiac myocytes. If you recall, when we were dealing with nerve and with skeletal muscle, 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. It takes 200 milliseconds for the duration of this action potential. 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 2-10 milliseconds. So the cardiac myocyte then has a very long lasting action potential. That is true for the contractile cells of the heart. 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. The first thing to notice is that we have our fast action potential. That's what's diagrammed here. The fast action potential has a very rapid upstroke or depolarization, phase 0. Then we have phase 1, where there is a slight repolarization. Then phase 2, where we have a very long plateau phase. Then phase 3, where the cell repolarizes. Then we have phase 4, which is again, our resting membrane potential. Now during this period, in phase 0, we had a very fast opening of voltage-gated sodium channels. These sodium channels then inactivated in phase 1. They inactivated in phase 1. If you recall, these are the same channels that we encountered in nerve. That is if you try to stimulate them while they're inactivated, they cannot reopen. They have to go into a closed phase before they can be reopened. The closed phase does not occur until we repolarize the cells. So during the period from about time 0, that is 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. That's called the refractory period. This is a fast action potential, absolute refractory period. It, occurs between 0 and 180 milliseconds. No matter how hard we stimulate this cardiac myocyte in that time frame, the cardiac myocyte cannot initiate a second action potential. 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. They've moved from an inactive state to a closed state. 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 I've superimposed the time of the twitch. That is a single contraction from a single action potential. That is shown here in green. This is tension. This single twitch or contractile period, is also diagrammed on the same time scale. Notice that the twitch is very long. It covers about 250 milliseconds. Most of the time that the twitch is occurring, then the cell is in an absolute refractory period. We cannot stimulate the cell and get a second twitch to occur. That means there is no summation of contractile events. We can't summate the contractions as we could in skeletal muscle. Now, why is that important? If you think about it. The heart, can never sum twitches to reach to tetanus. You can't stimulate the heart so rapidly that you will get a Charlie Horse within the heart or a cramp. 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. 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 would lose its pumping action. That would be lethal, that would be death. This is a very important concept. The fast action potential of the contractile myocyte has almost the same time duration as the contractile event itself. One other thing to consider when we're talking about the heart. That is tension. In skeletal muscle, we were able to recruit more fibers to get stronger and stronger, and stronger contractions. This cannot occur within the heart. When the heart is simulated to contract, all of the fibers contract in synchrony. That's due to the presence of the gap junctions. In order to develop more tension within the heart, the heart has to do other things that will allow it to get a greater tension or a greater strength of contraction. That's what's diagrammed here. Tension is on the y-axis and the sarcomere length which is our actin-myosin overlap shown on the x-axis. The cardiac myocyte in the resting condition is sitting here. This is the resting state. And as you see, that it is at a place where we are not developing optimal tension. That is the overlap then is not optimal. But as we fill the heart, we 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. The heart uses filling to cause a better contraction. As you stretch the fibers, the myofibers, the alignment of actin and myosin changes such that there is a stronger contraction. This means that as you fill the heart, if you fill the heart more, then you will get a stronger contraction. This is called the Frank Starling Law of cardiac myocytes or of the heart. This is in contrast to skeletal muscle. Skeletal muscle tends to sit in its optimal overlap length. That is because skeletal muscles attach to the skeleton. They are attached to bone. The bone keeps it in its optimal length for the generation of power. Okay, so what are our key concepts? The first is that cardiac muscle is an involuntary, striated type of muscle. Second, 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. This process involves cross bridge formation between the actin and the myosin, and it's driven by the myosin ATPase. The myosin ATPase in the heart is a slow myosin ATPase. It has slow kinetics. The enzymatic reaction is slow. Third, the coupling between the membrane action potential and contraction is mediated by calcium ions. In cardiac muscle, calcium regulates the thin filament. Again, unmasking of actin enables cross bridge formation. Calcium affects the troponin-tropomyosin complex, which is blocking actin. This complex moves out of the grove. Myosin can now engage actin. Fourth, the autonomic nervous system regulates cardiac muscle. 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. Sodium enters through voltage-gated sodium channels. These channels move to an inactive state and then have to be moved from an inactive state to close before they are available for reopening. Then sixth, the cardiac muscle contracts in unison. This is due to the gap junctions which electrically couple all of the cells. The cardiac myocytes cannot develop fused tetanus. This is due to the length of the contraction itself. Its length is 250 milliseconds. This is almost the same length as the duration of the action potential of the cardiac myocyte, 200 to 220 milliseconds. Okay, so the next time we come in here, we're going to consider the cardiac myocytes. But we're going to talk about them now in the heart. How they're used to govern the activity of the heart. Okay, so see you then.