okay so we are going to wrap up our talk on cardiac electrophysiology um and we're going to discuss autonomic control in heart rate modulation so it's important here to remember that the heart receives input from both the parasympathetic nervous system and the sympathetic nervous system however the innervation from the parasympathetic nervous system is through the vagus nerve but what i want you to remember is that the vagus nerve supplies the sa node and it also supplies the av node there is some supply to the atria however what's important that you realize is that the vagus nerve almost does not innervate the ventricles so there is no vagal control really over the ventricles this is not the case for the sympathetic nervous system and so you can see here that the sympathetic nervous system really supplies the heart throughout okay so when we're talking about autonomic effects on the heart we have a few terms that i want you to be familiar with when we say there's we have chronotropic effects the chronotropic effect relates to heart rate so if we say an increase in chronotropy that means an increase in heart rate dromotropic effects refers to conduction velocity um in terms of the conduction system of the heart and impulse spread um and also we have inotropic effects and that relates to contractility so when we say there's an increase in ionotropy what we are referring to is an increase in cardiac contractility we um also there's a class of drugs called inotropes and these are drugs that increase inotropy or i.e increased cardiac contractility we should also say that there is um lucitropy which is the ability of the heart to relax ability of the heart to relax and we'll briefly touch upon this um in a little bit um and in this table here this is a good reference for you where here you see different um effects and you see the in the sympathetic nervous system the parasympathetic nervous system what is the specific action what receptor mediates this action and what's the physiological mechanism behind this so for example you can see that the sympathetic nervous system increases heart rate it does this through a beta 1 receptor and the mechanism is through an increase in the funny current and an increase in the calcium current and you can tell that the funny current works in phase four and it's responsible for the automaticity of the sa node and the calcium current is very important for phase zero in the slow response action potential and you can then follow the table for these different effects and you can compare the sympathetic and the parasympathetic effects over and control over heart function let's dive a little bit deeper into how our autonomic nervous system can actually modulate heart rate and there are three main mechanisms for this that we're going to talk about the first one here we're going to talk about the parasympathetic nervous system and then the sympathetic is just going to be the the opposite of that so you can see this in in in the orange here this is your control so you can tell that we have one two and three beats happening in this time period one way in which the parasympathetic nervous system can slow down our heart rate is by reduction of the funny current and the calcium current in addition to an increase in the potassium current so you can see that here actually if you go back here you see there's an increase the sympathetic nervous system does an increase in both of them while the parasympathetic nervous system decreases the funny current decreases the calcium current and increases the potassium current and that's what you would see here and by decreasing the funny current and the calcium current right you can see what that's going to lead to is a slower depolarization so compare this slope compare it with this one right and then you can tell that the slope of the phase 4 slope is is slower in the blue curve compared to the orange and as a result of that instead of getting 1 2 and 3 we are only getting um one and two right only one and two and so that is one mechanism behind our explaining how the autonomic nervous system can control heart rate is by controlling the rate of depolarization rate of d polarization now if you take a a a deeper look here you will see that the effects are a slower depolarization in the sa node and a slower conduction in the av node so why did we say depolarization in the sa node and why did we say conduction in the av node i want you to remember and recall that the function or the effects of acetylcholine on the av node are going to be the same as the effects on the sa node however the difference is from a physiological perspective um the av node is not your main pacemaker right the av node is going to be responsible for conducting the pulse that's receiving that it is receiving from the sa node to conduct that to the ventricles and so that's why we said slower conduction in av node but we said slower depolarization in the sa node that doesn't mean that the effect of acetylcholine is different at the sa node versus the av node it's just that their physiological function is different okay another mechanism um on how we can achieve heart rate modulation is by shifting the maximum diastolic potential remember the maximum diastolic potential is just the name we use for the resting membrane potential but they are really the same thing and by shifting this potential downwards right through hyper polarization you're making it harder and you're going to make it require more time to actually reach threshold so if we compare again here we have one two and three action potentials but if we look at um what's happening in green we only have one and two now the reason behind that is this here let's use the blue this here was the resting membrane potential in the control state but with parasympathetic control the threshold or sorry the resting membrane potential actually dropped down here it is more negative it is hyper polarized and as a result of that it's going to take more time to reach threshold i want you to note and notice that the slopes or the rate of depolarization is the same so there is no change in the rate of depolarization so the rate of depolarization that we saw here is different this is you can tell that these two slopes are not equal but here the slopes are equal the difference is the green slope starts at a lower level therefore takes more time to reach the threshold and this is another mechanism in which we can use in order to decrease heart rate keep in mind that acetylcholine release causes an increase in ik or the potassium current and this is what hyperpolarizes the membrane so if we go back to this slide and you can see what we're talking about right that there's that this increase in the potassium current which will lead to hyper polarization right or an increase in the resting membrane potential okay a third mechanism that we're going to talk about um so we talked about the rate of depolarization we talked about an increase in the rest or a decrease i'm sorry in the resting membrane potential finally we can also have a shift in the threshold and so this is our original threshold in the control state what can happen is that this threshold can actually be increased all the way up here for example what this means is that if you look at how many action potentials one two and three but since this action potential you can see reach threshold here so it can start the action potential come back down and reset and start come back down and repeat the process this one in purple is going to take a little bit more time because it's not going to start here it's going to have to continue all the way to this new threshold level and this is going to cost time and if it's costing it more time then the absolute number of action potentials that we can get in a set time period is going to be reduced and you can think about it from the the effects of the physiological effects is that acetylcholine causes a decrease in the calcium current right and remember that this calcium current is very important for phase 0 in the slow response action potential and because of the reduction in the calcium current this is going to make it harder or require more time in order to actually generate an action potential so the three mechanisms again there's a change in the rate of depolarization there is a reduction in the resting membrane potential or ie becomes more negative the maximum diastolic potential which is the same as the resting membrane potential becomes more negative and finally a positive shift in threshold requires more time to reach that threshold and can therefore also contribute to a reduction in heart rate so these are three mechanisms in which we can modulate heart rate so the parasympathetic nervous system is going to slow it down while the sympathetic nervous system is going to speed it up um when we're looking at dromotropic effects dromotropy relates to conduction velocity and this correlates with the size of the inward current of the ap upstroke which is again phase zero right but this also the rate of the rise is also very important as we have seen in the previous slide oh sorry not the previous slide but we were talking about the rate of depolarization the dromotropic effects are actually very important at the av node because it's the gatekeeper between the atria and the ventricles with sympathetic stimulation we get an increase in conduction velocity and with parasympathetic stimulation we get the opposite we get a decrease in conduction velocity the calcium current is very important for this because not just that the calcium current will affect the rate of the rise of the upstroke but also there's going to be shortening of the effective refractory period and this leads to faster conduction and recall that in the slow response action potential the refractory period was extended it's it's longer than in in a fast response action potential and so slowing down or reducing the effective refractory period is going to be significant and will allow for faster conduction with parasympathetic stimulation the opposite is going to happen but we also have a potassium current that is going to contribute to slowing things down and if there is a very strong parasympathetic stimulation what can happen is a heart block in which the impulse coming from the sa node that normally should pass through the av node to the ventricles does not pass because of the reduction in the speed of conduction at the av node and this can lead to clinical problems and should be treated right away which is usually the case um inotropic effects um or again remember ionotropy refers to contractility remember that the heart is different from the skeletal muscle in many ways in skeletal muscle we were increasing force production by increasing motor unit recruitment but the heart doesn't act that way remember it's a functional syncytium um and so that's not how we can increase cardiac contractility so what's an alternative mechanism cardiac contractility to a great extent is really controlled um by the amount of intracellular calcium the more calcium we have the stronger the contraction is going to be and vice versa and the amount of intracellular calcium right or the concentration of calcium inside is going to depend upon the amount of calcium that's released from the sarcoplasmic reticulum well okay the more the calcium release the greater that's we can understand that but well what controls that well there's two things that you should recall here the amount of calcium coming in from the ecf right this is going to be number one which is calcium coming in from the ecf the more calcium coming in from the ecf or in other words the size of the inward calcium current the greater that is the greater the calcium that's going to be released from the sarcoplasmic reticulum but also the amount of calcium that is previously stored in the sarcoplasmic reticulum is going to play a factor so if we have high levels of calcium stored in the sr once the sr opens and allows calcium to exit the more calcium we have stored the more calcium is going to come out and so that kind of makes sense so these are two very important factors to remember we've seen this um this figure before it's not the first time and this shows the effect of calcium channel blockers and you can see that when we increase the concentration of the calcium channel blockers you see the change in the action potential but you also see the reduction in the amount of force generation and also remember that these calcium channel blockers they really inhibit um the inward calcium current right the side the the calcium that's coming in from the ecf so this is what we are inhibiting and you can see the importance of that calcium coming in when you see how significant the reduction in force can be this slide here shows um there's a little bit more detail on the different molecular mechanisms of how the sympathetic stimulation can actually increase cardiac contractility and so what you see here is epinephrine or norepinephrine can bind to a beta receptor that beta receptor is going to utilize the gs signaling pathway you're going to get cyclic amp and then eventually you're going to get protein kinase a which is a very important secondary messenger protein kinase a is then going to travel into cell and it's just going to have a bunch of different effects this is going to include phosphorylate phosphorylation of the calcium channels on the cell membrane but also the reacting channels on the sr when they're phosphorylated this will allow for greater calcium to be released the greater the calcium that's released from the sr and from or coming in from the ecf is going to lead to an increase in peak tension like we see here and an increase in the rate of development but also protein kinase a is going to phosphorylate this protein that's present on the sarcoplasmic reticulum called phospholamine b or plb um what phospholamine b is going to do is that it's going to enhance the activity of circa well what does circa do if you remember circa actually pulls calcium into the sr so well why is that a good thing because when we're enhancing the ability to pull calcium into the sarcoplasmic reticulum that means we get faster relaxation and that's actually very important for the heart we want strong contractility but we want the ability to relax faster so we can contract again right that's one mechanism of increasing heart rate the faster that we can relax and accept more blood right not just the more the faster the heart rate is going to be but the greater the cardiac output because the heart can now relax and accept more blood so ventricular filling also increases but there's another point to this the more calcium you're able to put in the sarcoplasmic reticulum the more calcium you can send out again and so this is one another mechanism by how enhancing circa activity can actually lead to inotropic effects by increasing or by increasing the calcium stores you're also increasing the amount of calcium that you can release with every subsequent [Music] contraction and this would really wrap up our discussion on the autonomic control of the cardiovascular system thank you so much for listening