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Annu. Rev. Med. 1990. 41:231-38 Copyright © 1990 by Annual Reviews Inc. All rights reserved
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CELLULAR MECHANISM FOR ISCHEMIC VENTRICULAR Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
ARRHYTHMIAS L. H. Opie, M.D., Ph.D.
Medical Research Council/University of Cape Town Ischemic Heart Disease Research Unit, University of Cape Town Medical School, Observatory, Cape Town 7925, South Africa w. T. Clusin, M.D., Ph.D.
Falk Cardiovascular Research Center, Stanford University School of Medi cine , S ta nford , Califor nia 94305, USA KEY WORDS:
potassium, calcium, depolarization, action potential duration, delayed afterdepolarizations.
ABSTRACT
Two of the major ionic abnormalities found early in ischemia are (a) loss of potassium with an increase in the extracellular potassium ion concentration and (b) an increase in free cytosolic calcium. Both of these ionic abnormalities can powerfully predispose to the development of arrhythmias. INTRODUCTION
Ventricular arrhythmias soon after the onset of experimental coronary artery occlusion remain a therapeutic and experimental challenge. Interest in this problem has been promoted by the continuing significance of sudden arrhythmic death as a public health hazard in industrialized countries. Historically, the hypotheses to explain the ionic basis of ventricular arrhythmias related chiefly to the proposed arrhythmogenic role of ischemic 231 0066-4219/90/0401-0231$02.00
232
OPIE & CLUSIN
potassium loss. Next it was the role of sympathetic nerve activity and its messenger cyclic AMP that received attention. Most recently an increase in cytosolic calcium concentration has been recognized as the final common path of several arrhythmogenic mechanisms, including those related to sympathetic nerve activity.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
POTASSIUM IONS
Harris et al in 1954 found that the ischemic myocardium lost potassium concurrently with the onset of early ventricular arrhythmias. They pro posed that the increase of extracellular potassium caused by ischemia was a major excitatory factor in the provocation of ventricular arrhythmias. However, at that time there was no good understanding of the cause of the potassium loss nor of the electrophysiological mechanisms involved. Next came the explanation for the electrophysiological effects-an increased extracellular potassium-promoted depolarization with regional block or slowing of conduction, which are the necessary preconditions for reentry. Potassium-induced depolarization could also promote spon taneous activity of Purkinje fibers, thereby providing the initiating beats. Thus potassium loss could explain both of the commonly accepted e1ectro physiological mechanisms for early ventricular arrhythmias. The estab lished electrophysiological effects of hyperkalemia also include lessening of the overshoot of the action potential and a shortened action potential duration. The intravenous or intra-arterial infusion of potassium salts can rapidly cause ectopic activity and ventricular arrhythmias (I), presumably as a result of current set up between the normally polarized and the depolarized tissue. Mechanisms of Potassium Ion Loss
At least three hypotheses have been put forth to explain potassium loss during ischemia, as outlined below. (SODIUM PUMP) BY LACK OF According to this concept, as cellular ATP falls with the onset of ischemia there is insufficient energy to drive the pump so that intracellular sodium rises, as does extracellular potassium. There are several problems with this hypothesis. First, the extracellular potassium rises very rapidly after the onset of ischemia. In contrast, recent NMR measurements indi cate that the gain of sodium does not start for at least five minutes after the onset of ischemia and requires about 10-15 minutes to be obvious, at least in the rat heart (2). Another difficulty with the proposed role of sodium pump inhibition is that the earliest rise in external potassium INlllBITION OF SODIUM-POTASSIUM ATPASE ENERGY
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233
occurs at a stage when overall cellular ATP has hardly undergone any depletion. Therefore a special role for compartmentalized ATP would be required. COTRANSPORT OF POTASSIUM WITH LACTATE OR PHOSPHATE TO BALANCE
This hypothesis states that, as phosphate and lactate are lost, both ionic groups being negatively charged, potassium is also lost as a cation to "balance" the electrical charges (3). This "cotransport" hypothesis could explain the very early onset of potassium loss because creatine phosphate begins to break down almost immediately after the onset of ischemia so that the formation of inorganic phosphate also occurs very rapidly. The fall in creatine phosphate and rise in inorganic phosphate both stimulate glycolysis to produce lactate, also negatively charged. This hypothesis therefore warrants careful consideration. Although a stoichiometric relation between potassium, lactate, and phosphate has been described by some authors, others have failed to find any consistent stoichiometry.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
IONIC CHARGES
PROPOSED ROLE OF ATP-SENSITIVE POTASSIUM CHANNEL An ATP-sensitive potassium channel has been described (4). At first sight, one would not expect it to play a role in the early ischemic potassium loss, because only a low concentration of ATP is required to "close" the channel, and hence it is unlikely to "open" in the early phases of ischemia. However, the ATP sensitive potassium channel is not governed only by the presence of ATP. Cofactors such as ADP, AMP, and GTP all contribute to the control of this channel. Furthermore, glycolytic ATP produced near the sarcolemma may be more important than mitochondrial ATP in regulating the ATP dependent potassium channel conductance (5). Further evidence favoring the proposed role of the ATP-sensitive potassium channel includes the finding that glibenclamide, a potassium channel "closer," had an anti arrhythmic effect on the early ventricular arrhythmias in the globally ischemic perfused rat heart (6).
Pattern of Ischemic Potassium Loss
The time-course of the increase of extracellular potassium and hence of trans sarcolemmal potassium loss is triphasic. The rapid initial rise during the first minutes, called Phase 1 by Harris et al (7), is followed by a second phase in which the potassium is stable or in fact tends to fall. Then there is a third phase, in which a further increase occurs. The explanation for this triphasic pattern is complex and may include the compounding effects of (a) an early phase in which ATP-dependent potassium channels are activated, and also lactate and phosphate are produced; (b) a second phase of enhanced glycolysis, coinciding with catecholamine release from the
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OPIE & CLUSIN
ischemic myocardium, which stimulates the activity of the sodium-potas sium pump to decrease the extent of potassium loss (8); and (c) further depletion of metabolic energy during prolonged ischemia, which eventually inhibits the sodium-potassium pump. However, the explanation of this time-course is still largely conjectural. CALCIUM IONS AND EARLY VENTRICULAR ARRHYTHMIAS
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
Does Internal Calcium Increase in Ischemia?
In view of the importance of theories linking an early increase of cytosolic calcium to electrophysiological abnormalities that could explain early ven tricular arrhythmias (9), it is important to assess whether cytosolic calcium really does rise in ischemia. Although contradictory results have been obtained in hypoxia, the consensus is that in ischemia there is a rapid rise of cytosolic calcium (10-12). Calcium and Early Changes in the Action Potential Two of the basic changes in the action potential dur ing early ischemia are reduction of the resting potential and changes in the action potential duration. Each could be related to the early rise in internal calcium found during ischemia, although the evidence is not decisive. It is of interest that both ischemia and metabolic inhibitors, agents known to increase internal calcium, depolarize cardiac cells, reduce conduction velocity, and facilitate arrhythmia development (9). There are also data suggesting that although ischemic potassium loss may be of most importance in causing ischemic depolarization, a potassium-independent depolarization process occurs in some ischemic conditions. For example, when the heart rate is increased (13), TQ-depression (and hence depolarization) is markedly accelerated. When both rapid pacing and increased external calcium are simultaneously present, then very little of the depolarization is potassium dependent (14). These experimental conditions contrast with those found at slow heart rates and normal calcium where most of the depolarization is due to an extracellular increase in potassium (15). The actual mechanism of the potassium-independent depolarization could involve either an electrogenic sodium-calcium exchange or an opening of nonselective calcium-depen dent cation channels in the sarcolemma. Besides helping to regulate the extent of depolarization, an increase in intracellular calcium may also prolong the action potential duration. The most likely way in which this may occur is that the rise in internal calcium associated with the contraction also triggers a flow of inward current across the cell membrane. The rise in cytosolic calcium can produce an
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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inward current, either by opening calcium channels in the surface mem brane or by activating "electrogenic" sodium-calcium exchange, in which a net ingress of positive charge occurs each time a calcium ion is extruded. When these mechanisms operate, an increase in the peak calcium level of each beat would prolong the plateau. This mechanism was first inferred from studies of arrhythmogenic delayed afterdepolarizations (see below) that occur in digitalis intoxication. More general applicability was shown with the discovery that lO-mM caffeine, which liberates sequestered intra cellular calcium, can elicit a depolarizing current in normal cells (9). Most recently, voltage clamp experiments in single cells have permitted direct demonstration of a calcium-activated inward current at potentials that lie in the plateau range (16). The above mechanism does not explain the predominant effect of ischemia, which is a marked shortening of the plateau. However, two other effects of ischemia on the plateau may be mediated by calcium. First, during the initial minute of both ischemia and metabolic inhibition, there is a temporary increase in the action potential duration. This increase has been attributed to elevation of intracellular calcium, based on concurrent recordings of the calcium transient (11). Second, as discussed below, alter nation of the peak amplitude of the calcium transient is a prominent feature of ischemia, and there is very good evidence that the accompanying alternation in the action potential duration (electrical alternans) might be caused by alternation of thc calcium transients.
Role of Internal Calcium Oscillations in Ischemic Arrhythmias Indirect evidence suggests that the oscillatory release and re-uptake of calcium by the sar coplasmi c reticulum may be important in the ventricular arrhythmias of ischemia and reperfusion. Thus, the agents ryanodine and caffeine, known to inhibit or crucially modify such rhythmical uptake of calcium, can prevent both ischemic and reperfusion arrhythmias in the isolated rat heart (17). These arrhythmias are likely to depend on the appearance of delayed afterdepolarizations, which arise from calcium dependent transient inward currents (ItJ Delayed a fterdepo lari zations are electrophysiological manifestations of the oscillations in internal calcium that develop during cytosolic calcium overload. They can be evoked by a variety of conditions, including fast pacing, isoproterenol, dibutyryl cyclic AMP, and intracellular injection of calcium, all of which may cause cal cium overload. Delayed afterdepolarizations are, however, abolished by severe ischemia (18). The most likely explanation is that intracellular energy in the form of ATP (very low or nearly absent in severe ischemia) is required to promote recycling of calcium and is the basis for the delayed afterdepolarizations.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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OPIE & CLUSIN
Evidence for the above hypothesis has been obtained by Coetzee & Opie (18). They show that block of delayed afterdepolarizations by severe metabolic inhibition cannot be due to changes in the A TP-regulated potas sium current nor to changes of internal calcium; rather, ATP depletion by itself blocks IIi so that at least some ATP is needed for this calcium dependent arrhythmia to occur. Therefore they argue (19) that ca1cium dependent delayed afterdepolarizations are more likely to explain the arrhythmias of early reperfusion than those of severe ischemia. None theless, calcium-dependent ventricular arrhythmias may occur during developing ischemia when A TP levels are still relatively high, or in mild ischemia when ATP levels are relatively well maintained (17).
Cytosolic Calcium and Electrical Alternans Alterations in cytoplasmic calcium may also explain the phenomenon of the alternans pattern in the T-wave of the electrocardiogram, preceding the onset of ventricular fibrillation in the dog heart (20). A similar alter nation of the action potential duration occurs in the globally ischemic rabbit heart and is associated with corresponding variations in the ampli tude of the intracellular calcium transient (11). Rapid relocation of the fiber-optic probe that measures intracellular calcium shows variations in the phase relation of the calcium alternans in localized regions of the heart. Local variations in the phase relationship of calcium alternans are presumably the cause of similar heterogeneity in the pattern of action potential alternan!;. Thus abnormalities of cytosolic calcium can contribute to nonuniformity of the action potential duration across the ventricular surface. This process leads to dispersion of refractoriness, which is an essential precondition for ventricular fibrillation.
Role of Calcium Antagonists in Early Ischemic Arrhythmias Calcium channel antagonists might act to reduce the depolarization induced automaticity that is associated with the current of injury by several mechanisms (21 ). Calcium antagonists may act hemodynamically to decrease the severity of ischemia and thereby the size of the injury current, with less potassium loss (22). A second and possibly important action of the calcium antagonists, which is usually overlooked, is as follows. Automaticity occurring at depolarized levels of the resting action potential is partially due to a calcium current and is influenced adjacent to the ischemic zone, the occurrence of depolarization-induced automaticity resulting from the flow of injury current may theoretically be inhibited by calcium antagonists. Thirdly, calcium antagonists could decrease the amount of ischemic depolarization, especially at rapid heart
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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rates. Fourthly, during myocardial ischemia the conduction velocity of the propagation of the impulse slows, which may predispose to ischemic arrhythmias. Part of the fall in the conduction velocity is a result of depolarization. However, an increased level of intracellular calcium can also impair conduction by causing electrical uncoupling of contiguous cells. In a model of ischemia (hypoxia, hyperkalemia, and acidosis), the impaired conduction can be improved by calcium antagonists without creating any change in the membrane potential (23). Fifthly, calcium-dependent slow responses can be elicited by cyclic AMP in the presence of substantial degrees of depolarization. These slow responses are specifically dependent on the calcium channel because they are inhibited by l-verapamil but not d-verapamil (24). Although the rate of conduction of ventricular arrhythmias is such that true slow responses are unlikely (25), nevertheless it is difficult to exclude the possibility that slow response action potentials, creating areas of extremely slow conduc tion, could predispose to the formation of reentry circuits, which in turn could have a higher rate of conduction. Finally and importantly, calcium antagonist drugs are able to prevent the inhomogeneity of the action potential duration found in global ischemia (II).
Literature Cited
I. Harris, A. S., Toth, L. A., Hoey, T. E.
2.
3.
4.
5.
6.
1958. Arrhythmic and antiarrhythmic effects of sodium, potassium and cal cium salts and of glucose injected into coronary arteries of infarcted and nor mal hearts. Gre. Res. 6: 570-79 Balschi, J. A., Frazer, J. C, Fetters, J. K., Clarke, K., Springer, S., et aL 1985. Shift reagent and Na-23 nuclear mag netic resonance discriminates hetween extra and intracellular sodium pools in ischemic heart. Cire. Res. 72(SuppL III): III-355 Crake, T., Kirby, M. S., Poole-Wilson, P. 1987. Potassium efflux from the myo cardium during hypoxia: role of lactate ions. Cardiovase. Res. 21: 886--91 Noma, A., Shibasaki, T. 1985. Mem brane current through adenosine-tri phosphate-regulated potassium chan nels in guinea-pig ventricular cells. J. Physiol. 363: 463-80 Weiss, J. N., Lamp, S. T. 1987. Gly colysis preferentially inhibits ATP-sen sitive K + channels in isolated guinea-pig cardiac myocytes. Science 238: 67--69 Kantor, P., Coetzee, W. A., Carmeleit, E., Dennis, S. C, Opie, L. H. 1990. Reduction in ischemic K + loss and
7.
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I I.
arrhythmias: The effect of the sulfonyl urea, glibencIamide. Gre. Res. Tn press Harris, A. S., Bisteni, A., Russell, R. A., Brigham, J. C, Firestone, J. E. 1954. Excitatory factors in ventricular tachy cardia resulting from myocardial isch emia. Science 119: 200--3 Wilde, A. A. M., Peters, R. J. G., Janse, M. J. 1988. Catecholamine release and potassium accumulation in the isolated globally ischemic rabbit heart. J. Mol. Cell. Cardiol. 20: gg7-96 Clusin, W. T. 1989. Role of calcium activated ion currents in the heart. In Physiology and Pathophysiology of the Heart, ed. N. Sperelakis, pp. 95-114. Boston: Kluwer Academic. 2nd ed. Lee, H.-C, Smith, N., Mohabir, R., Clusin, W. T. 1987. Cytosolic calcium transients from the beating mammalian heart. Proc. Natl. A cad. Sci. USA 84: 7793-97 Lee, H.-C, Mohabir, R., Smith, N., Franz, M. R., Clusin, W. T. 1988. Effect of ischemia on calcium-dependent fluo rescence transients in rabbit hearts containing Indo I. Correlation and monophasic action potentials and con traction. Circulation 78: 1047-59
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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12. Allen, D. G., Lee, 1. A., Smith, G. L. 1989. The consequences of simulated ischaemia on intracellular calcium and tension in isolated ferret ventricular muscle. J. Physiol. 410: 297-323 13. Blake, K., Smith, N. A., Clusin, W. T. 1986. Rate dependence of ischaemic myocardial depolarization-evidence for a novel membrane current. Cardiovase. Res. 20: 557--62 14. Blake, K., Clusin, W. T., Franz, M. R., Smith, N. A. 1988. Mechanism of de polarization in the ischaemic dog heart: Discrepancy between T-Q potentials and potassium accumulation. J. Physiol. 397: 307 30 15. Kleber, A. G. 1983. Resting membrane potential, extracellular potassium ac tivity and intracellular sodium activity during acute global ischemia in isolated perfused guinea-pig hearts. eire. Res. 52: 442-50 16. Fedida, D., Noble, Y., Shimoni, Y., Spindler, A. J. 1987. Inward current related to contraction in guinea-pig ven tricular myocytes. J. Physiol. 385: 56589 17. Thandroyen, F. T., McCarthy, J., Burton, K.,Opie, L. H. 1988. Ryanodinc
and caffeine prevent ventricular arrhyth mias during acute myocardial ischemia and reperfusion in rat heart. Cire. Res. 62: 306-14 18. Coetzee, W. A., Opie, L. H. 1987. Effects of components of ischemia and meta bolic inhibition on delayed after depolarizations in guinea-pig papillary muscle. Cire. Res. 61: 157-67 19. Opie, L. R., Coetzee, W. A. 1988. Role of calcium ions in reperfusion arrhyth mias. Relevance to pharmacological
20.
21.
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intervention. Cardiovasc. Drugs Ther. 2: 609-22 Kleber, A. G., Janse, M. J., van Capelle, F. J. L., Durrer, D. 1978. Mechanism and time course of S-T and T-Q segment changes during acute regional myo cardial ischemia in the pig heart deter mined by intracellular and extracellular recordings. Cire. Res. 42: 603-13 Opie, L. H., Coetzee, W. A., Dennis, S. c., Thandroyen, F. T. 1988. A potential role of calcium ions in early ischemic and reperfusion arrhythmias. Ann. NY Aead. Sci. 522: 464-77 Coetzee, W. A., Dennis, S. C., Opie, L. H., Muller, C. A. 1987. Calcium channel blockers and early ischemic ventricular arrhythmias: electrophysiological versus anti-ischemic effects. J. Mol. Cell. Car diol. 19(5uppl. II): 77-97 Kimura, S., Nakaya, R., Kanno, M. 1983. Electrophysiological effects of diltiazem, nifedipine and NiH on the subepicardial muscle cells of canine heart under the condition of combined hypoxia, hyperkalemia and acidosis. Naun-Schmiedeberg's Arch. Pharmacol. 324:228-32
24. Thandroyen, F. T., Higginson, L. M.,
Opie, L. H., Yon, E. 1986. The influence of verapamil and its isomers on vulner ability to ventricular fibrillation during acute myocardial ischemia and adren ergic stimulation in isolated rat heart. J. Mol. Cell. Cardiol. 18: 645-49 25. Janse, M. J., Kleber, A. G., Capucci, A., Coronel, R., Wilms-Schopman, F. 1986. Electrophysiological basis for arrhyth mias caused by acute ischemia. Role of the subendocardium. J. Mol. Cell. Car dial. 18: 339-55
Annu. Rev. Med. 1990. 41:231-38 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
CELLULAR MECHANISM FOR ISCHEMIC VENTRICULAR Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
ARRHYTHMIAS L. H. Opie, M.D., Ph.D.
Medical Research Council/University of Cape Town Ischemic Heart Disease Research Unit, University of Cape Town Medical School, Observatory, Cape Town 7925, South Africa w. T. Clusin, M.D., Ph.D.
Falk Cardiovascular Research Center, Stanford University School of Medi cine , S ta nford , Califor nia 94305, USA KEY WORDS:
potassium, calcium, depolarization, action potential duration, delayed afterdepolarizations.
ABSTRACT
Two of the major ionic abnormalities found early in ischemia are (a) loss of potassium with an increase in the extracellular potassium ion concentration and (b) an increase in free cytosolic calcium. Both of these ionic abnormalities can powerfully predispose to the development of arrhythmias. INTRODUCTION
Ventricular arrhythmias soon after the onset of experimental coronary artery occlusion remain a therapeutic and experimental challenge. Interest in this problem has been promoted by the continuing significance of sudden arrhythmic death as a public health hazard in industrialized countries. Historically, the hypotheses to explain the ionic basis of ventricular arrhythmias related chiefly to the proposed arrhythmogenic role of ischemic 231 0066-4219/90/0401-0231$02.00
232
OPIE & CLUSIN
potassium loss. Next it was the role of sympathetic nerve activity and its messenger cyclic AMP that received attention. Most recently an increase in cytosolic calcium concentration has been recognized as the final common path of several arrhythmogenic mechanisms, including those related to sympathetic nerve activity.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
POTASSIUM IONS
Harris et al in 1954 found that the ischemic myocardium lost potassium concurrently with the onset of early ventricular arrhythmias. They pro posed that the increase of extracellular potassium caused by ischemia was a major excitatory factor in the provocation of ventricular arrhythmias. However, at that time there was no good understanding of the cause of the potassium loss nor of the electrophysiological mechanisms involved. Next came the explanation for the electrophysiological effects-an increased extracellular potassium-promoted depolarization with regional block or slowing of conduction, which are the necessary preconditions for reentry. Potassium-induced depolarization could also promote spon taneous activity of Purkinje fibers, thereby providing the initiating beats. Thus potassium loss could explain both of the commonly accepted e1ectro physiological mechanisms for early ventricular arrhythmias. The estab lished electrophysiological effects of hyperkalemia also include lessening of the overshoot of the action potential and a shortened action potential duration. The intravenous or intra-arterial infusion of potassium salts can rapidly cause ectopic activity and ventricular arrhythmias (I), presumably as a result of current set up between the normally polarized and the depolarized tissue. Mechanisms of Potassium Ion Loss
At least three hypotheses have been put forth to explain potassium loss during ischemia, as outlined below. (SODIUM PUMP) BY LACK OF According to this concept, as cellular ATP falls with the onset of ischemia there is insufficient energy to drive the pump so that intracellular sodium rises, as does extracellular potassium. There are several problems with this hypothesis. First, the extracellular potassium rises very rapidly after the onset of ischemia. In contrast, recent NMR measurements indi cate that the gain of sodium does not start for at least five minutes after the onset of ischemia and requires about 10-15 minutes to be obvious, at least in the rat heart (2). Another difficulty with the proposed role of sodium pump inhibition is that the earliest rise in external potassium INlllBITION OF SODIUM-POTASSIUM ATPASE ENERGY
ISCHEMIC VENTRICULAR ARRHYTHMIAS
233
occurs at a stage when overall cellular ATP has hardly undergone any depletion. Therefore a special role for compartmentalized ATP would be required. COTRANSPORT OF POTASSIUM WITH LACTATE OR PHOSPHATE TO BALANCE
This hypothesis states that, as phosphate and lactate are lost, both ionic groups being negatively charged, potassium is also lost as a cation to "balance" the electrical charges (3). This "cotransport" hypothesis could explain the very early onset of potassium loss because creatine phosphate begins to break down almost immediately after the onset of ischemia so that the formation of inorganic phosphate also occurs very rapidly. The fall in creatine phosphate and rise in inorganic phosphate both stimulate glycolysis to produce lactate, also negatively charged. This hypothesis therefore warrants careful consideration. Although a stoichiometric relation between potassium, lactate, and phosphate has been described by some authors, others have failed to find any consistent stoichiometry.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
IONIC CHARGES
PROPOSED ROLE OF ATP-SENSITIVE POTASSIUM CHANNEL An ATP-sensitive potassium channel has been described (4). At first sight, one would not expect it to play a role in the early ischemic potassium loss, because only a low concentration of ATP is required to "close" the channel, and hence it is unlikely to "open" in the early phases of ischemia. However, the ATP sensitive potassium channel is not governed only by the presence of ATP. Cofactors such as ADP, AMP, and GTP all contribute to the control of this channel. Furthermore, glycolytic ATP produced near the sarcolemma may be more important than mitochondrial ATP in regulating the ATP dependent potassium channel conductance (5). Further evidence favoring the proposed role of the ATP-sensitive potassium channel includes the finding that glibenclamide, a potassium channel "closer," had an anti arrhythmic effect on the early ventricular arrhythmias in the globally ischemic perfused rat heart (6).
Pattern of Ischemic Potassium Loss
The time-course of the increase of extracellular potassium and hence of trans sarcolemmal potassium loss is triphasic. The rapid initial rise during the first minutes, called Phase 1 by Harris et al (7), is followed by a second phase in which the potassium is stable or in fact tends to fall. Then there is a third phase, in which a further increase occurs. The explanation for this triphasic pattern is complex and may include the compounding effects of (a) an early phase in which ATP-dependent potassium channels are activated, and also lactate and phosphate are produced; (b) a second phase of enhanced glycolysis, coinciding with catecholamine release from the
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OPIE & CLUSIN
ischemic myocardium, which stimulates the activity of the sodium-potas sium pump to decrease the extent of potassium loss (8); and (c) further depletion of metabolic energy during prolonged ischemia, which eventually inhibits the sodium-potassium pump. However, the explanation of this time-course is still largely conjectural. CALCIUM IONS AND EARLY VENTRICULAR ARRHYTHMIAS
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
Does Internal Calcium Increase in Ischemia?
In view of the importance of theories linking an early increase of cytosolic calcium to electrophysiological abnormalities that could explain early ven tricular arrhythmias (9), it is important to assess whether cytosolic calcium really does rise in ischemia. Although contradictory results have been obtained in hypoxia, the consensus is that in ischemia there is a rapid rise of cytosolic calcium (10-12). Calcium and Early Changes in the Action Potential Two of the basic changes in the action potential dur ing early ischemia are reduction of the resting potential and changes in the action potential duration. Each could be related to the early rise in internal calcium found during ischemia, although the evidence is not decisive. It is of interest that both ischemia and metabolic inhibitors, agents known to increase internal calcium, depolarize cardiac cells, reduce conduction velocity, and facilitate arrhythmia development (9). There are also data suggesting that although ischemic potassium loss may be of most importance in causing ischemic depolarization, a potassium-independent depolarization process occurs in some ischemic conditions. For example, when the heart rate is increased (13), TQ-depression (and hence depolarization) is markedly accelerated. When both rapid pacing and increased external calcium are simultaneously present, then very little of the depolarization is potassium dependent (14). These experimental conditions contrast with those found at slow heart rates and normal calcium where most of the depolarization is due to an extracellular increase in potassium (15). The actual mechanism of the potassium-independent depolarization could involve either an electrogenic sodium-calcium exchange or an opening of nonselective calcium-depen dent cation channels in the sarcolemma. Besides helping to regulate the extent of depolarization, an increase in intracellular calcium may also prolong the action potential duration. The most likely way in which this may occur is that the rise in internal calcium associated with the contraction also triggers a flow of inward current across the cell membrane. The rise in cytosolic calcium can produce an
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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235
inward current, either by opening calcium channels in the surface mem brane or by activating "electrogenic" sodium-calcium exchange, in which a net ingress of positive charge occurs each time a calcium ion is extruded. When these mechanisms operate, an increase in the peak calcium level of each beat would prolong the plateau. This mechanism was first inferred from studies of arrhythmogenic delayed afterdepolarizations (see below) that occur in digitalis intoxication. More general applicability was shown with the discovery that lO-mM caffeine, which liberates sequestered intra cellular calcium, can elicit a depolarizing current in normal cells (9). Most recently, voltage clamp experiments in single cells have permitted direct demonstration of a calcium-activated inward current at potentials that lie in the plateau range (16). The above mechanism does not explain the predominant effect of ischemia, which is a marked shortening of the plateau. However, two other effects of ischemia on the plateau may be mediated by calcium. First, during the initial minute of both ischemia and metabolic inhibition, there is a temporary increase in the action potential duration. This increase has been attributed to elevation of intracellular calcium, based on concurrent recordings of the calcium transient (11). Second, as discussed below, alter nation of the peak amplitude of the calcium transient is a prominent feature of ischemia, and there is very good evidence that the accompanying alternation in the action potential duration (electrical alternans) might be caused by alternation of thc calcium transients.
Role of Internal Calcium Oscillations in Ischemic Arrhythmias Indirect evidence suggests that the oscillatory release and re-uptake of calcium by the sar coplasmi c reticulum may be important in the ventricular arrhythmias of ischemia and reperfusion. Thus, the agents ryanodine and caffeine, known to inhibit or crucially modify such rhythmical uptake of calcium, can prevent both ischemic and reperfusion arrhythmias in the isolated rat heart (17). These arrhythmias are likely to depend on the appearance of delayed afterdepolarizations, which arise from calcium dependent transient inward currents (ItJ Delayed a fterdepo lari zations are electrophysiological manifestations of the oscillations in internal calcium that develop during cytosolic calcium overload. They can be evoked by a variety of conditions, including fast pacing, isoproterenol, dibutyryl cyclic AMP, and intracellular injection of calcium, all of which may cause cal cium overload. Delayed afterdepolarizations are, however, abolished by severe ischemia (18). The most likely explanation is that intracellular energy in the form of ATP (very low or nearly absent in severe ischemia) is required to promote recycling of calcium and is the basis for the delayed afterdepolarizations.
Annu. Rev. Med. 1990.41:231-238. Downloaded from www.annualreviews.org Access provided by University of York on 01/27/15. For personal use only.
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Evidence for the above hypothesis has been obtained by Coetzee & Opie (18). They show that block of delayed afterdepolarizations by severe metabolic inhibition cannot be due to changes in the A TP-regulated potas sium current nor to changes of internal calcium; rather, ATP depletion by itself blocks IIi so that at least some ATP is needed for this calcium dependent arrhythmia to occur. Therefore they argue (19) that ca1cium dependent delayed afterdepolarizations are more likely to explain the arrhythmias of early reperfusion than those of severe ischemia. None theless, calcium-dependent ventricular arrhythmias may occur during developing ischemia when A TP levels are still relatively high, or in mild ischemia when ATP levels are relatively well maintained (17).
Cytosolic Calcium and Electrical Alternans Alterations in cytoplasmic calcium may also explain the phenomenon of the alternans pattern in the T-wave of the electrocardiogram, preceding the onset of ventricular fibrillation in the dog heart (20). A similar alter nation of the action potential duration occurs in the globally ischemic rabbit heart and is associated with corresponding variations in the ampli tude of the intracellular calcium transient (11). Rapid relocation of the fiber-optic probe that measures intracellular calcium shows variations in the phase relation of the calcium alternans in localized regions of the heart. Local variations in the phase relationship of calcium alternans are presumably the cause of similar heterogeneity in the pattern of action potential alternan!;. Thus abnormalities of cytosolic calcium can contribute to nonuniformity of the action potential duration across the ventricular surface. This process leads to dispersion of refractoriness, which is an essential precondition for ventricular fibrillation.
Role of Calcium Antagonists in Early Ischemic Arrhythmias Calcium channel antagonists might act to reduce the depolarization induced automaticity that is associated with the current of injury by several mechanisms (21 ). Calcium antagonists may act hemodynamically to decrease the severity of ischemia and thereby the size of the injury current, with less potassium loss (22). A second and possibly important action of the calcium antagonists, which is usually overlooked, is as follows. Automaticity occurring at depolarized levels of the resting action potential is partially due to a calcium current and is influenced adjacent to the ischemic zone, the occurrence of depolarization-induced automaticity resulting from the flow of injury current may theoretically be inhibited by calcium antagonists. Thirdly, calcium antagonists could decrease the amount of ischemic depolarization, especially at rapid heart
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rates. Fourthly, during myocardial ischemia the conduction velocity of the propagation of the impulse slows, which may predispose to ischemic arrhythmias. Part of the fall in the conduction velocity is a result of depolarization. However, an increased level of intracellular calcium can also impair conduction by causing electrical uncoupling of contiguous cells. In a model of ischemia (hypoxia, hyperkalemia, and acidosis), the impaired conduction can be improved by calcium antagonists without creating any change in the membrane potential (23). Fifthly, calcium-dependent slow responses can be elicited by cyclic AMP in the presence of substantial degrees of depolarization. These slow responses are specifically dependent on the calcium channel because they are inhibited by l-verapamil but not d-verapamil (24). Although the rate of conduction of ventricular arrhythmias is such that true slow responses are unlikely (25), nevertheless it is difficult to exclude the possibility that slow response action potentials, creating areas of extremely slow conduc tion, could predispose to the formation of reentry circuits, which in turn could have a higher rate of conduction. Finally and importantly, calcium antagonist drugs are able to prevent the inhomogeneity of the action potential duration found in global ischemia (II).
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and caffeine prevent ventricular arrhyth mias during acute myocardial ischemia and reperfusion in rat heart. Cire. Res. 62: 306-14 18. Coetzee, W. A., Opie, L. H. 1987. Effects of components of ischemia and meta bolic inhibition on delayed after depolarizations in guinea-pig papillary muscle. Cire. Res. 61: 157-67 19. Opie, L. R., Coetzee, W. A. 1988. Role of calcium ions in reperfusion arrhyth mias. Relevance to pharmacological
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