SECTION III THE CARDIOVASCULAR SYSTEM Myocardial Infaretion A 63-year-old mn suddenly felt a crushing pain beneath his stermun.He hecame weak and began to sweat profusely.He called his physician.who advised him to go to the hospital immediately by anbulance.The tests made at the hospital confirmed his physician's helief that the patient had suffered a heart attack":that is,a ma jor coronary artery had suddenly becone occluded. 1.When a coronary artery is occluded,the K+concentration rises in the interstitial fluid of the ischemie region (i.e..the region deprived of its blood supply)of the ventricular mocardiun.What effect does the elevated K+ concentration in the interstitial fluid have on the resting membrane potential of the myocardial cells in the ischemic zone? 2.What effect does the change in resting nembrane potential have on the propagation of the cardiac inpulse？hy？ 3.Why might such a change in impulse propagation lead to reentrant rhythm d1 isturhances？ This patient had cardiac rhytha disturbances within mimutes after he felt the chest pain.He was given an antiarrhythnic drug that inactivated many of the fast Nat channels in the heart. 4.What effect would the antiarrhythmic drug have on the resting meabrane potential of the myocardial cells? 5.What effect would this drug have on the upstroke of the action potemtial and on the propagation velocity of myocardial cells? 6.What effect does this drug have on the action potentials of the automatic cells in the sinoatrial (SA)node and on the action potential of the conduction fibers in the central (N)region of the atrioventricular (AV)node?
SECTION III THE CARDIOVASCULAR SYSTEM Myocardial Infarction A 63-year-old man suddenly felt a crushing pain beneath his sternum. He became weak and began to sweat profusely. He called his physician, who advised him to go to the hospital immediately by ambulance. The tests made at the hospital confirmed his physician's belief that the patient had suffered a "heart attack"; that is, a major coronary artery had suddenly become occluded. 1. When a coronary artery is occluded, the K+ concentration rises in the interstitial fluid of the ischemic region (i.e., the region deprived of its blood supply) of the ventricular myocardium. What effect does the elevated K+ concentration in the interstitial fluid have on the resting membrane potential of the myocardial cells in the ischemic zone? 2. What effect does the change in resting membrane potential have on the propagation of the cardiac impulse? Why? 3. Why might such a change in impulse propagation lead to reentrant rhythm disturbances? This patient had cardiac rhythm disturbances within minutes after he felt the chest pain. He was given an antiarrhythmic drug that inactivated many of the fast Na+ channels in the heart. 4. What effect would the antiarrhythmic drug have on the resting membrane potential of the myocardial cells? 5. What effect would this drug have on the upstroke of the action potential and on the propagation velocity of myocardial cells? 6. What effect does this drug have on the action potentials of the automatic cells in the sinoatrial (SA) node and on the action potential of the conduction fibers in the central (N) region of the atrioventricular (AV) node?
Soon after the patient arrived at the hospital,the activity in the vagus nerve fibers to the heart increased reflexly. 7.What electrophysiologic effects would increased vagal activity have on the automatic cells in the SA node? 8.What electrophysiologic effects would increased vagal activity have on the conduction fibers in the AV node? About I hour after the coronary artery became oceluded,conduc tion in the hundle of His ceased abruptly.The condaction block persisted for several days. 9.At approximtely what rates would the atria and ventricles beat after the His hundles had beea coapletely blocked?Nhere do the impulses originate that initiate the atrial and ventricular contractions in such a patient with complete AV block? Pacing electrodes from an artificial pacemaker were inserted into the patient's right ventricle,and ventricular contractions were induced at a frequency of 75 beats/min. 10.If the artifical pacemker suddenly ceased firing,when would the ventricles begin to coatract spontaneously at their intrinsic rate?Explain ANSVER 1.As the K+concentration rises in the interstitial fluid of the ischemic xone, the ratio of the intracellular K+concentration ([K+]i)to the extracellular K+ concentration ([K+]o)would decrease.The mrocardial cell nenbranes at rest (phase 4)are much more permeable to K+than to any other relevant iom.Bence,the resting membrane potential is very close to that estimated by the Nernst equation for K+, As the [K+]i/K[+]o ratio dininishes.the resting nembrane potential becomes less negative,as predicted by the Nernst equation. 2.The fast Na+channels in the myocardial cell merbranes are voltage sensitive. As the resting nembrane potential of myocardial cells becomes progressively less negative (i.e..partially depolarized),more and more of the fast Nat channels in
Soon after the patient arrived at the hospital, the activity in the vagus nerve fibers to the heart increased reflexly. 7. What electrophysiologic effects would increased vagal activity have on the automatic cells in the SA node? 8. What electrophysiologic effects would increased vagal activity have on the conduction fibers in the AV node? About 1 hour after the coronary artery became occluded, conduction in the bundle of His ceased abruptly. The conduction block persisted for several days. 9. At approximately what rates would the atria and ventricles beat after the His bundles had been completely blocked? Where do the impulses originate that initiate the atrial and ventricular contractions in such a patient with complete AV block? Pacing electrodes from an artificial pacemaker were inserted into the patient's right ventricle, and ventricular contractions were induced at a frequency of 75 beats/min. 10. If the artifical pacemaker suddenly ceased firing, when would the ventricles begin to contract spontaneously at their intrinsic rate? Explain. ANSWER 1. As the K+ concentration rises in the interstitial fluid of the ischemic zone, the ratio of the intracellular K+ concentration ([K+]i) to the extracellular K+ concentration ([K+]o) would decrease. The myocardial cell membranes at rest (phase 4) are much more permeable to K+ than to any other relevant ion. Hence, the resting membrane potential is very close to that estimated by the Nernst equation for K+, As the [K+]i/K[+]o ratio diminishes, the resting membrane potential becomes less negative, as predicted by the Nernst equation. 2. The fast Na+ channels in the myocardial cell membranes are voltage sensitive. As the resting membrane potential of myocardial cells becomes progressively less negative (i.e., partially depolarized), more and more of the fast Na+ channels in
those cells become inactivated because of their voltage dependency.Hence,when the wave of excitation reaches the partially depolarized cells,a diminished mumher of fast Na+channels are available to be activated.The upstroke of the action potential in myocardial cells is mediated by the influx of Na+through the fast Na+channels. In the myocardial cells in the ischemic zone of the heart.fewer Na+channels are available for activation than in the myocardial cells in the normal regions of the heart.Therefore.in the ischenic cells,the upstroke of the action potential is less steep than normal,and the amplitude of the action potential is diminished. The velocity of impulse propagation varies directly with the amplitude and with the slope of the upstroke of the action potential.Hence.propagation is abmormally slow in the ischeaic zome. 3.Localized regions of slow conduction may lead to unidirectional block,which is one prerequisite for reentry.The unidirectional block is often a teaporal phenomenon:that is,part of a given wave of excitation my approach a given site in the heart froa one direction.If it travels through normal tissue,it may arrive early at the given site,at a time when the site is still refractory from a preceding depolarization.However,if another part of the same vave of excitation arrives at the sane site fron a different direction,but reaches the site later because of a local conduetion delay,the given site nay then have recovered from its refractory period and be excitable.Hence,the inpulse will now he conducted through the given site.but in a different direction.Such"unidirectional block"can lead to prenature depolarizations or paroxysaal tachycardias,by virtue of reentrant conduction. 4.In resting myocardial cells,the cell meabrane is much more permeable to K+ than to any other relevant ion,but it is virtually impermeable to Nat.Hence, inactivation of the fast Nat channels will have no detectable effect on the resting mesbrane potential. 5.As more and more fast Na+channels are inactivated by the antiarrhythmic drug. the action potential upstroke would becone less steep.and the propagation velocity would diminish,as explained in answer 2 above
those cells become inactivated because of their voltage dependency. Hence, when the wave of excitation reaches the partially depolarized cells, a diminished number of fast Na+ channels are available to be activated. The upstroke of the action potential in myocardial cells is mediated by the influx of Na+ through the fast Na+ channels. In the myocardial cells in the ischemic zone of the heart, fewer Na+ channels are available for activation than in the myocardial cells in the normal regions of the heart. Therefore, in the ischemic cells, the upstroke of the action potential is less steep than normal, and the amplitude of the action potential is diminished. The velocity of impulse propagation varies directly with the amplitude and with the slope of the upstroke of the action potential. Hence, propagation is abnormally slow in the ischemic zone. 3. Localized regions of slow conduction may lead to unidirectional block, which is one prerequisite for reentry. The unidirectional block is often a temporal phenomenon; that is, part of a given wave of excitation may approach a given site in the heart from one direction. If it travels through normal tissue, it may arrive early at the given site, at a time when the site is still refractory from a preceding depolarization. However, if another part of the same wave of excitation arrives at the same site from a different direction, but reaches the site later because of a local conduction delay, the given site may then have recovered from its refractory period and be excitable. Hence, the impulse will now be conducted through the given site, but in a different direction. Such "unidirectional block" can lead to premature depolarizations or paroxysmal tachycardias, by virtue of reentrant conduction. 4. In resting myocardial cells, the cell membrane is much more permeable to K+ than to any other relevant ion, but it is virtually impermeable to Na+. Hence, inactivation of the fast Na+ channels will have no detectable effect on the resting membrane potential. 5. As more and more fast Na+ channels are inactivated by the antiarrhythmic drug, the action potential upstroke would become less steep, and the propagation velocity would diminish, as explained in answer 2 above
6.A drug that affects only fast Na+channels would have a negligible effect on action potentials of SA node cells or of conduction fibers in the N region of the AV node,because these cardiac cells are "slow response"fibers.The upstrokes of their action potentials depend mainly on influx of Ca++through Ca++channels, rather than on influx of Nat.as in myocardial cells.Also,the slow diastolic depolarization in the SA node cells is mediated by changes in the conductance of K+,Ca++and Nat.Furthermore,the channels that conduct the Na+during the slow diastolic depolarization are the so-called if current channels.not the fast Nat current chaanels. 7.The firing rate of the SA node cells would diminish as a consequence of the increased vagal activity.The acetylcholine (ACh)released fron the vagus nerve endings activates the ACh-regulated K+channels and decreases the conductance of the if channels.The increased K+conductance tends to hyperpolarize the automatic cell peabranes,and therefore the transserbrane potential at the beginning of slow diastolic depolarization is more negative than it is in the absence of vagal activity. This would tend to fncrease the cardiac cycle length (i.e.,decrease heart rate). Also,the vagally induced diminution of the comductance of the if channels would reduce the influx of Na+into the cell,and would thereby decrease the slope of slow diastolic depolarization.This also would tend to decrease heart rate. 8.Increased vagal activity tends to retard AY conduction:that is,the time from the beginming of atrial depolarization to the beginming of vemtricular depolarization may be proloaged.Intense vagal activity ray even prevent the cardiac impulse from being propagated from the atria to the vemtricles.The ACh released fron the vagus merve endings in the AV node activates the ACh-regulated Kt channels and thereby hyperpolarizes the conducting fibers in the AY node.The neurally released ACh also tends to decrease the Cat+current through the Ca*+channels in the cell menbranes of the conducting fibers (which are slow-response fibers).The effects of the ACh on the K+and Ca++currents tend to inpede AV condoction. These direct inhibitory effects of neurally released ACh on AV conduction are moderated by the indireet dromotropic effeet that vagal activity exerts by
6. A drug that affects only fast Na+ channels would have a negligible effect on action potentials of SA node cells or of conduction fibers in the N region of the AV node, because these cardiac cells are "slow response" fibers. The upstrokes of their action potentials depend mainly on influx of Ca++ through Ca++ channels, rather than on influx of Na+, as in myocardial cells. Also, the slow diastolic depolarization in the SA node cells is mediated by changes in the conductance of K+, Ca++ and Na+. Furthermore, the channels that conduct the Na+ during the slow diastolic depolarization are the so-called if current channels, not the fast Na+ current channels. 7. The firing rate of the SA node cells would diminish as a consequence of the increased vagal activity. The acetylcholine (ACh) released from the vagus nerve endings activates the ACh-regulated K+ channels and decreases the conductance of the if channels. The increased K+ conductance tends to hyperpolarize the automatic cell membranes, and therefore the transmembrane potential at the beginning of slow diastolic depolarization is more negative than it is in the absence of vagal activity. This would tend to increase the cardiac cycle length (i.e., decrease heart rate). Also, the vagally induced diminution of the conductance of the if channels would reduce the influx of Na+ into the cell, and would thereby decrease the slope of slow diastolic depolarization. This also would tend to decrease heart rate. 8. Increased vagal activity tends to retard AV conduction; that is, the time from the beginning of atrial depolarization to the beginning of ventricular depolarization may be prolonged. Intense vagal activity may even prevent the cardiac impulse from being propagated from the atria to the ventricles. The ACh released from the vagus nerve endings in the AV node activates the ACh-regulated K+ channels and thereby hyperpolarizes the conducting fibers in the AV node. The neurally released ACh also tends to decrease the Ca++ current through the Ca++ channels in the cell membranes of the conducting fibers (which are slow-response fibers). The effects of the ACh on the K+ and Ca++ currents tend to impede AV conduction. These direct inhibitory effects of neurally released ACh on AV conduction are moderated by the indirect dromotropic effect that vagal activity exerts by
decreasing heart rate.AV conduction tends to vary inversely with heart rate:that is,the greater the frequency at which the atrial imulses reach the AV node,the slower will those impulses be conducted through the AV junction,and vice versa. Increased vagal activity will dininish the heart rate.This reduced heart rate will tend to facilitate AV conduction,and will thereby attemuate the inhibitory effect that neurally released ACh will exert directly on the AV node coeducting fiber. 9.When conduction in the AV node or bundle of His is blocked,the atrial and ventricular rhythns are 'dissociated.The atrial rhythm will be set by the SA node, and the atrial rate vill usually be betveen 60 and 90 beats/nin.The ventricular rhythn will he set by specialized conduction (Purkinje)fibers.which would discharge at rates of about 30 to 45 beats/min. 10.When autoratic cells,such as Purkinje fibers,are driven at a rate greater than their normal firing frequency.excessive amounts of Nat enter the cells during each depolarization.Hence,the pump (Na+,K+-ATPase)operates at an accelerated rate to extrude the excess intracellular Nat.The Nat pump is an electrogenic purp.in that it ejects 3 Nat for every 2K+that it pulls in.This disparity in cation exchange tends to hyperpolarize the cell.When the overdrive ceases (i.e..when the artificial pacemaker stops firing),the activity of the Na*punp returns gradually toward normal, and hence the hyperpolarization is dissipated rather slowly.This retards the rate at which the Purkinje fibers in the ventricles regain their normal firing frequency. This delay in the return to normal activity by a period of high-frequency stimulation is called owverdrfve suppression
decreasing heart rate. AV conduction tends to vary inversely with heart rate; that is, the greater the frequency at which the atrial impulses reach the AV node, the slower will those impulses be conducted through the AV junction, and vice versa. Increased vagal activity will diminish the heart rate. This reduced heart rate will tend to facilitate AV conduction, and will thereby attenuate the inhibitory effect that neurally released ACh will exert directly on the AV node conducting fiber. 9. When conduction in the AV node or bundle of His is blocked, the atrial and ventricular rhythms are "dissociated." The atrial rhythm will be set by the SA node, and the atrial rate will usually be between 60 and 90 beats/min. The ventricular rhythm will be set by specialized conduction (Purkinje) fibers, which would discharge at rates of about 30 to 45 beats/min. 10. When automatic cells, such as Purkinje fibers, are driven at a rate greater than their normal firing frequency, excessive amounts of Na+ enter the cells during each depolarization. Hence, the pump (Na+,K+-ATPase) operates at an accelerated rate to extrude the excess intracellular Na+. The Na+ pump is an electrogenic pump, in that it ejects 3 Na+ for every 2 K+ that it pulls in. This disparity in cation exchange tends to hyperpolarize the cell. When the overdrive ceases (i.e., when the artificial pacemaker stops firing), the activity of the Na+ pump returns gradually toward normal, and hence the hyperpolarization is dissipated rather slowly. This retards the rate at which the Purkinje fibers in the ventricles regain their normal firing frequency. This delay in the return to normal activity by a period of high-frequency stimulation is called overdrive suppression