Summary
During acute myocardial ischemia, passage of potassium ions across the sarcolemma to the extracellular space is a well-established phenomenon. A recent hypothesis is that the ATP-dependent potassium channel plays a role in contributing to the potassium loss. As the potassium loss starts while the overall level of ATP is still relatively high, and as the channel is inhibited by rather low concentrations of ATP, the question arises as to how the channel is opened. Among the proposals are that, in addition to the total concentration of ATP, there is modulation of the regulation by its breakdown products, such as ADP and adenosine. Alternatively, or in addition, breakdown products of anaerobic glycolysis, such as lactate and protons, may also play a role. Extracellular acidosis may help to activate the channel, and internal lactate accumulation may have a similar effect. In certain circumstances there is evidence that ATP produced by glycolysis plays a significant role in the control of potassium channel activity. The concept of subsarcolemmal ATP is another explanation for the activation of the channel at relatively high ATP concentrations. Potassium channel closing drugs, such as glibenclamide, may prolong the action potential duration (shortened by ischemia) and thereby decrease the incidence of early ventricular arrhythmias. This same category of drugs may reduce early potassium loss from the ischemic tissue, thereby lessening the potentially protective effect of the external accumulation of potassium on the ischemic zone, the so-called local cardioplegic effect. Conversely, drugs of the potassium channel activating group are likely to have opposite effects on these arrhythmias and on myocardial protection. Channel activators may specifically benefit torsades de pointes. The net overall effects of such drugs are complex and include indirect benefits to the ischemic zone attained by coronary artery vasodilation as well as by local cardioplegia, and a decrease of reperfusion injury. According to the end point examined, it is possible to argue that any of these drugs (potassium channel opening or closing drugs) could be harmful or beneficial in the setting of acute regional ischemia.
Similar content being viewed by others
References
Rahimtoola SH. The hibernating myocardium.Am Heart J 1989;117:211–221.
Camici P, Ferrannini E, Opie LH. Myocardial metabolism in ischemic heart disease: Basic principles and application to imaging by positron emission tomography.Prog Cardiovasc Dis 1989;32:217–238.
Nayler W. Calcium, calcium antagonists, stunning and hibernation. In: Opie LH, ed.Stunning, Hibernation, and Calcium in Myocardial Ischemia and Reperfusion Boston: Kluwer Academic Publishers, 1992;226–234.
Kloner RA, Przyklenk K, Rahimtoola SH, Braunwald E. Myocardial stunning and hibernation: Mechanisms and clinical implication. In: Opie LH, ed.Stunning, Hibernation, and Calcium in Myocardial Ischemia and Reperfusion. Boston: Kluwer Academic Publishers, 1992;251–280.
Opie LH, Owen P, Thomas M, Samson R. Coronary sinus lactate measurements in the assessment of myocardial ischemia. Comparison with changes in the ratios lactate/pyruvate and beta-hydroxybutyrate/acetoacetate and with release of hydrogen, phosphate and potassium ions from the heart.Am J Cardiol 1973;32:295–305.
Harris AS, Bisteni A, Russell RA, et al. Excitatory factors in ventricular tachycardia resulting from myocardial ischemia: Potassium a major excitant.Science 1954;119:200–203.
Opie LH, Coetzee WA, Dennis SC, Thandroyen FT. A potential role of calcium ions in early ischemic and reperfusion arrhythmias.Ann NY Acad Sci 1988;522:464–477.
Kantor PF, Coetzee WA, Carmeliet EE, et al. Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea.Circ Res 1990;66:478–485.
Steenbergen C, DeLeeuw G, Williamson JR. Analysis of control of glycolysis in ischemic hearts having heterogenneous zones of anoxia.J Mol Cell Cardiol 1978;10:617–639.
Noma A. ATP-regulated K+ channels in cardiac muscle.Nature 1983;305:147–148.
Noma A, Shibasaki T. Membrane current through adenosine-triphosphate-regulated potassium channels in guineapig ventricular cells.J Physiol 1985;363:463–480.
Kakei M, Noma A, Shibasaki T. Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells.J Physiol 1985;363:441–462.
Allen DG, Orchard CH. Myocardial contractile function during ischemia and hypoxia.Circ Res 1987;60:153–168.
Furukawa T, Kimura S, Furukawa N, et al. Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia.Circ Res 1991; 68: 1693–1702.
Gasser RNA, Vaughan-Jones RD. Mechanism of potassium efflux and action potential shortening during ischaemia in isolated mammalian cardiac muscle.J Physiol 1990;431:713–741.
Wilde AAM, Escande D, Schumacher CA, et al. Potassium accumulation in the globally ischemic mammalian heart. A role for the ATP-sensitive potassium channel.Circ Res 1990;67:835–843.
Ruiz-Petrich E, de Lorenzi F, Chartier D. Role of the inward rectifier IK1 in the myocardial response to hypoxia.Cardiovasc Res 1991;25:17–26.
Jiang C, Crake T, Poole-Wilson PA. Inhibition by barium and glibenclamide of the net loss of86Rb+ from rabbit myocardium during hypoxia.Cardiovasc Res 1991;25:414–420.
Carmeliet E. Use-dependent block of the delayed K+ current in rabbit ventricular myocytes.Cardiovasc Drugs Ther 1993;7(Suppl 3):599–604.
Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system.Am J Physiol 1991;261:H1675-H1688.
Carmeliet E, Storms L, Vereecke J. The ATP-dependent K-channel and metabolic inhibition. In: Zipes DP, Jalife J, eds.Cardiac Electrophysiology. From Cell to Bedside. Philadelphia: WB Saunders, 1990:103–108.
Giesen J, Kammermeier H. Relationship of phosphorylation potential and oxygen consumption in isolated perfused rat hearts.J Mol Cell Cardiol 1980;12:891–907.
Weiss JN, Venkatesh N. Metabolic regulation of cardiac ATP-sensitive K+ channels.Cardiovasc Drugs Ther 1993;7(Suppl 3):499–505.
Nichols CG, Lederer WJ. The regulation of ATP-sensitive K+ channel activity in intact and permeabilized rat ventricular myocytes.J Physiol 1990;423:91–110.
Lederer WJ, Nichols CG. Nucleotide modulation of the activity of rat heart ATP-sensitive K+ channels in isolated membrane patches.J Physiol 1989;419:193–211.
Parent L, Coronado R. Reconstitution of the ATP-sensitive potassium channel of skeletal muscle. Activation by a G-protein-dependent process.J Gen Physiol 1989;94:445–463.
Kirsch GE, Codina J, Birnbaumer L, Brown AM. Coupling of ATP-sensitive K+ channels to A1 receptors by G-proteins in rat ventricular myocytes.Am J Physiol 1990;259:H820-H826.
Coetzee WA. Effects of pyruvate and lactate on current through ATP-sensitive potassium channels in isolated rat and guinea-pig ventricular myocytes: Evidence for a possible extracellular site of action.J Physiol 1991;43S:117.
Coetzee WA. Stimulation of current through K (ATP) channels of guinea pig ventricular myocytes by extracellular pH (abstr).J Mol Cell Cardiol 1992;24(Suppl 1):S109.
Keung EC, Li Q. Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes.J Clin Invest 1991;88:1772–1777.
Opie LH, Mansford KRL. The value of lactate and pyruvate measurements in the assessment of the redox state of free nicotinamide-adenine dinucleotide in the cytoplasm of the perfused rat heart.Eur J Clin Invest 1971;1:295–306.
Cuevas J, Bassett AL, Cameron JS, et al. Effect of H+ on ATP-regulated K+ channels in feline ventricular myocytes.Am J Physiol 1991;261:H755-H761.
Opie LH. Importance of glycolytically produced ATP for the integrity of the threatened myocardial cell. In: Piper HM, ed.Pathophysiology of Severe Ischemic Myocardial Injury. Dordrecht, The Netherlands: Academic Publishers, 1989:41–65.
Owen P, Dennis S, Opie LH. Glucose flux rate regulates onset of ischemic contracture in globally underperfused rat hearts.Circ Res 1990;66:344–354.
Weiss JN, Lamp ST. Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guinea-pig cardiac myocytes.Science 1987;238:67–69.
Weiss JN, Lamp ST. Cardiac ATP-sensitive K+-channels. Evidence for preferential regulation by glycolysis.J Gen Physiol 1989;94:911–935.
Niki I, Ashcroft FM, Ashcroft SJH. The dependence on intracellular ATP concentration of ATP-sensitive K-channels and of Na, K-ATPase in intact HIT-T15 beta-cells.FEBS Let 1989;257:361–364.
Ashcroft FM, Kakei M. ATP-sensitive K+ channels in rat pancreatic beta-cells: Modulation by ATP and Mg2+ ions.J Physiol 1989;416:349–367.
Bokvist K, Ammala C, Ashcroft FM, et al. Separate processes mediate nucleotide-induced inhibition and stimulation of the ATP-regulated K+-channels in mouse pancreatic beta-cells.Proc R Soc Lond 1991;243:139–144.
Deutsch N, Klitzner TS, Lamp ST, Weiss JN. Activation of cardiac ATP-sensitive K+ current during hypoxia: Correlation with tissue ATP levels.Am J Physiol 1991;261:H671-H676.
Fosset M, De Weille JR, Green RD, et al. Antidiabetic sulfonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels.J Biol Chem 1988;263:7933–7936.
Venkatesh N, Lamp ST, Weiss JN. Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle.Circ Res 1991;69:623–637.
Mitani A, Kinoshita K, Fukamachi K, et al. Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in isolated perfused rat hearts.Am J Physiol 1991;261:H1864-H1871.
Aversano T, Ouyang P, Silverman H. Blockade of the ATP-sensitive potassium channel modulates reactive hyperemia in the canine coronary circulation.Circ Res 1991;69:618–622.
Belloni FL, Hintze TH. Glibenclamide attenuates adenosine-induced bradycardia and coronary vasodilation.Am J Physiol 1991;261:H720-H727.
Cacciapuoti F, Spiezia R, Bianchi U, et al. Effectiveness of glibenclamide on myocardial ischemic ventricular arrhythmias in non-insulin-dependent diabetes mellitus.Am J Cardiol 1991;67:843–847.
Daut J, Maier-Rudolph W, Von Beckerath N, et al. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels.Science 1990;247:1341–1344.
Grover GJ, Selph PG, Dzwonczyk S. Pharmacologic profile of cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs.J Cardiovasc Pharmacol 1990;16:853–864.
Grover GJ, McCullough JR, Henry DE, et al. Anti-ischemic effects of the potassium channel activators pinacidil and cromakalim and the reversal of these effects with the potassium channel blocker glyburide.J Pharmacol Exp Ther 1989;251:98–104.
Galinanes M, Shattock MJ, Hearse DJ. Influence of potassium channel modulation on the ischemic tolerance of the isolated rat heart: Does potassium loss during ischemia exert a cardioplegia-like effect?J Mol Cell Cardiol 1992;24:S275.
Kammermeier H, Reffelmann T. Effects of K ATP+ -channel modulation on electrical and mechanical function of hypoxic isolated rat hearts (abstr).J Mol Cell Cardiol 1992;24(Suppl 1):S276.
Chi L, Uprichard ACG, Lucchesi BR. Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.J Cardiovasc Pharmacol 1990;15:452–464.
Kerr MJ, Wilson R, Shanks RG. Suppression of ventricular arrhythmias after coronary artery ligation by pinacidil, a vasodilator drug.J Cardiovasc Pharmacol 1985;7:875–883.
Spinelli W, Sorota S, Siegal M, Hoffman BF. Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil.Circ Res 1991;68:1127–1137.
Fish FA, Prakash C, Roden DM. Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators.Circ Res 1990;82:1362–1369.
Takahashi N, Ito M, Saikawa T, Arita M. Nicorandil suppresses early after depolarisation and ventricular arrhythmias induced by caesium chloride in rabbits in vivo.Cardiovasc Res 1991;25:445–452.
Carlsson L, Abrahamsson C, Drews L, Duker G. Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization.Circulation 1992;85:1491–1500.
Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.Circ Res 1991;69:571–581.
Hicks MN, Cobbe SM. Effect of glibenclamide on extracellular potassium accumulation and the electrophysiological changes during myocardial ischaemia in the arterially perfused interventricular septum of rabbit.Cardiovasc Res 1991;25:407–413.
Wilde AAM. Role of ATP-sensitive K+-channel current in ischemic arrhythmias.Cardiovasc Drugs Ther 1993;7(Suppl 3):521–526.
Author information
Authors and Affiliations
Additional information
This article was assessed by Dr. M. Hiraoka with the aid of two anonymous referees before acceptance in revised form.
Rights and permissions
About this article
Cite this article
Opie, L.H. Modulation of ischemia by regulation of the ATP-sensitive potassium channel. Cardiovasc Drug Ther 7 (Suppl 3), 507–513 (1993). https://doi.org/10.1007/BF00877615
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00877615