BISC 307L 2nd Edition Lecture 26 Current LectureSympathetic Stimulation Increases Heart RateSympathetic transmitters(epi) raise heart rate, and parasympathetic transmitters(acetylcholine) slow down the heart rate. It works by affecting the nodal tissue. The symp and parasymp innervate the heart as a whole,which is important becausethey affect the strength ofcontractions, but the rate ofbeating is dependent on the SAnode so we are only focusingon the innervation by the S/PSsystems of the SA node. Starts with epi(bottom rightcorner), which is released fromsympathetic nerves, and bindsto a beta adrenergic receptor,which is going to have twoeffects. First is the one goingup and to the left,phosphorylation of norepiallows it to bind to beta adrenergic receptor, activating a kinase A mechanism which phosphorylates the Ca channels, increasing their mean open time, which increases the Ca current (Ica), which lowers the threshold. Why would increasing the open time of Ca channel lower the threshold? Threshold is the voltage at which net inward current exceeds capacity of all outward carrying current channels to compensate. When you saturate the ability of the potassium channels to carry outward current, then you have a net depolarization. If you increase inward Ca current by prolonging the open time of the channels, that’s going to lower the threshold and lower the voltage at which you can get a regenerative response. Second effect is going horizontally left, through a cAMP mediated phosphorylation of the HCN channels (which are responsible for the inward current leak that produces the beginning of the pacemaker potential), increases its mean open time. That increases the inward funny current through the HCN channel, causing a faster depolarization. Both of the channels contribute tothe pacemaker potential, the HCN channels in the more negative ranges, and the Ca channels inthe more positive ranges. Red is normal, blue is with sympathetic stimulation – it crosses threshold sooner, and the slope of the pacemaker potential is steeper. So blue occurs earlier than it would have otherwise. As that repeats, the rate of the heartbeat goes up. Parasympathetic Stimulation Slows Heart RateStarts with ACh release shown in bottom rightcorner. That attaches to a muscarinic AChreceptor, which is metabotropic. That, via a G-protein mechanism, activates a type of potassium channel called a GIRK channel(G-protein activated, inwardly rectifying K+ channel). The activation of GIRK channel causes an increase in the opening of this potassium channel. We are at hyperpolarized levels, so its open. The activation of the open channel reduces the slope of the pacemaker potential. Remember, the pacemaker potential is the balance between inward current carried by HCN channels in the negative ranges, and then Ca channels take over in the more positive ranges, but that’s counteracted by the outward potassium current. Here we are increasing the opening of K channels, letting more K out, so less inward current, and less of a slope. And a more slowly rising pacemaker potential, which reaches threshold(which remains the same in this situation) later, so the heart rate is slowed down. Electrical Conduction in the HeartOn the right is a blown up picture of the right atrium. The SA node is in purple and connected tothem by gap junctions are the contractile cells. SA nodal muscle tissue generates AP but doesn’t contract.To the right, b, c, d, e, and fshow the spread of electricalactivity from the SA node out.The AP spreads is the traditionalmethod: inward current throughone cell causes the flow ofoutward current in another partof cell, and that current flowingout across the membranedepolarizes it, brings it tothreshold, and that AP travels. In (b), the heart is in relaxationphase. Purple dot is where theSA node is, and it representsthat an AP has just beengenerated.(c), the AP has been generatedand is spreading into the rightatrium and the left atrium, because across the interatrial septum, the cells are all coupled by gap junctions. The activity is spreading directly down across the surface of the right atrium, and across and down through the left atrium, so that by (d), we have both atria depolarized with an action potential. In (d), the AP has arrived at another node, the atroventricular node, which it enters. The AV node tissue also has an AP with a slow rate of rise, just like the SA node. So it spreads slowly through the AV node. This is important, because this delay of conduction, allows time for the contraction of the atria to empty whatever blood it has into the ventricles. From the AV node, the AP goes into specialized elongated cardiac muscle cells that don’t contract but do conduct action potentials quickly, and those are the purkinje fibers, and the bundles of fibers that form this conduction path are called the bundles of Hiis. Coming off the AV node there is one bundle called the common bundle(labeled AV bundle in the drawing), and it separates into two main bundles in the interventricullar septum. There’s a left one and a right one. These bundles of purkinje fibers conduct the AP down to the apex (bottom) of the heart. And it spreads up around the sides, and the purkinje fibers end and connect via gap junctions to the contractile fibers down in the apex of the heart. This is fast. About 4m/sec in the purkinje fibers. About 1m/sec in the atria.This arrangement of the Bundle of Hiis, spreading the excitation from the atria down to the ventricles so that the contraction starts at the apex of the heart and spreads up is efficient because the openings from the ventricles through which blood is pumped out are at the top of the ventricles, and having a wave of contractions moving upmilks the blood out of the ventricles more efficiently. So theaction potential does not spread directly into the ventricles,and this is because there is a layer of tissue between theatria and ventricles that are not coupled by gap junctions. The ECG and Electrical Events in the HeartECG = electrocardiogramFigure to the right: The red band is the AP, and it starts atthe apex and spreads up through the ventricles. There areloops of current that go through the tissue but also extendout in the extracellular solution. The loops of current ahead of the AP in the direction that it’s going are flowing the in the opposite direction than the loops of current behind it. So if you put a few electrodes on the body, there will be some