Summary
In acute myocardial ischemia slow conduction and short refractoriness both predispose to cardiac arrhythmias. Moreover, spatial dispersion in these parameters, in part determined by inhomogeneity in extracellular potassium concentration ([K+]0), which develops within minutes, is considered highly arrhythmogenic. The incidence and time distribution of ventricular arrhythmias is determined by these electrophysiological changes and by factors pertinent to the experimental model. In the initial phase of ischemia, glibenclamide, a potent blocker of ATP-sensitive K+ channels (K +ATP channels), reduces the rate of increase in [K+]0 and therfore, presumably, also the inhomogeneity in [K+]0. During this phase of ischemia glibenclamide has an antiarrhythmic effect, which may be based on a reduction in inhomogeneity in [K+]0. In addition, glibenclamide prolongs the action potential of ischemic myocardium. Although under ischemic conditions action potential duration is no longer a reliable parameter of refractoriness, glibenclamide-induced prolongation of refractoriness may play a role in the prevention of arrhythmias. In contrast, openers of KATP/+ channels increase the incidence of ventricular arrhythmias or, in other models, the time course of onset is accelerated. They shorten the duration of the action potential in ischemic tissue. In the globally ischemic rabbit heart, initial changes in [K+]0 are not influenced by cromakalim. It is concluded that activation of the K +ATP channel current during early myocardial ischemia potentially contributes to the development of ventricular arrhythmias. Particularly, the direct electrophysiological effect of increased K+ current is considered arrhythmogenic.
Similar content being viewed by others
References
Cohnheim J, von Schulthess-Rechberg A. Über die Folgen der Kranzarterien-verschliessung für das Herz.Virchow Arch 1881;85:503–537.
Kléber AG. Extracellular potassium accumluation in acute myocardial ischemia.J Mol Cell Cardiol 1984;16:389–394.
Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction.Physiol Rev 1989;69:1049–1169.
Rosen MR, Janse MJ, Myerburg RJ. Arrhythmias induced by coronary artery occlusion: What are the electrophysiological mechanisms? In: Hearse DJ, Manning AS, Janse MJ, eds.Life-Threatening Arrhythmias During Ischemia and Infarction New York: Raven Press, 1987:11–47.
Daughtery A, Frayne KN, Redfern WS, Woodward B. The role of catecholamines in the production of ischemia-induced ventricular arrhythmias in the rat in vivo and in vitro.Br J Pharmacol 1986;87:265–277.
Penny WJ. The deleterious effects of myocardial catecholmines on cellular electrophysiology and arrhythmias during ischemia and reperfusion.Eur Heart J 1984;5:960–973.
Corr PB, Witkowsky FX, Sobel BE. Mechanisms contributing to malignant arrhythmias induced by ischemia in the cat.J Clin Invest 1978;61:109–119.
Coker SJ. Anesthetized rabbit as a model for ischemia- and reperfusion-induced arrhythmias.J Pharmacol Methods 1989;21:263–279.
Pogwizd SM, Corr PB. Reentrant and non-reentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: Results using three dimensional mapping.Circ Res 1987;61:352–371.
Coronel R, Fiolet JWT, Wilms-Schopman FJG, et al. Distribution of extracellular potassium and its relation to electrophysiological changes during acute myocardial ischemia in the isolated perfused porcine heart.Circulation 1988;77:1125–1138.
Fosset M, De Weille JR, Green RD, et al. Antidiabetic sulphonylureas 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.
Gasser RNA, Vaughan Jones RD. Mechanism of potassium efflux and action potential shortening during ischemia in isolated mammalian cardiac muscle.J Physiol 1990;431:713–741.
Nakaya H, Takeda Y, Tohse N, Kanno M. Effects of ATP-sensitive K+ channel blockers on the action potential shortening in hypoxic and ischemic myocardium.Br J Pharmacol 1991;103:1019–1026.
Stern MD, Silverman HS, Houser SR, et al. Anoxic contractile failure in rat heart myocytes is caused by failure of intracellular calcium release due to alteration of the action potential.Proc Natl Acad Sci USA 1988;85:6954–6958.
Sanguinetti MC, Scott AL, Zingaro GJ, Siegl PKS. BRL 34195 (cromakalim) activates ATP-sensitive potassium current in cardiac muscle.Proc Natl Acad Sci USA 1988;85:8360–8364.
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.
Venkatesh N, Lamp ST, Weiss JN. Sulphonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle.Circ Res 1991;69:623–637.
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.
Smallwood JK, Ertel PJ, Steinberg MI. Modification by glibenclamide of the electrophysiological consequences of myocardial ischemia in dogs and rabbits.Naunyn-Schmiedebergs Arch Pharmacol 1990;342:214–220.
Cole WC, McPherson CD, Sontag D. ATP regulated K+ channels protect the myocardium against ischemia/reperfusion damage.Circ Res 1991;69:571–581.
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.
Kantor PF, Coetzee WA, Carmeliet EE, et al. Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulphonylurea.Circ Res 1990;66:478–485.
Bekheit S, Restivo M, Boutjdir M, et al. Effects of glyburide on ischemia-induced changes in extracellular potassium and local myocardial activation: A potential new approach to the management of ischemia-induced malignant ventricular arrhythmias.Am Heart J 1990;119:1025–1033.
Mitani A, Kinoshita K, Fukamachi K, et al. Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion.Am J Physiol 1991;261:H1864-H1871.
Homburg H, Knopf H, Friedrich M,. Hirche H. Does K+-channel blockade influence K+ release and the development of arrhythmias during hypoxic perfusion in isolated rat hearts (abstr).Pflügers Arch 1991;418(Suppl 1):R90.
Reiß N, Knopf H, Friedrich M, Hirche H. The effects of glibenclamide (GC) on extracellular ion concentrations and arrhythmias during myocardial ischemia in isolated guinea pig heart (abstr).J Mol Cell Cardiol 1989;21(Suppl 4):FC62.
Stuart JS, Alexander, L, Lamp ST, et al. Effects of cromakalim on K+ loss and cardiac function during acute myocardial ischemia (abstr).Circulation 1991;84(Suppl II):II617.
Aksnes G. Why do ischemic and hypoxic myocardium lose potassium?J Mol Cell Cardiol 1992;24:323–331.
Ballagi-Pordány G, Kószeghy-Gesztesi A, Koltai MZ, Pogátsa G. Effect of tolbutamide, gliclazide and glipizide on the ventricular ectopic beats and ventricular fibrillation caused by coronary occlusion in rats (abstr).Diabetologica 1987;30:496a.
Wolleben CD, Sanguinetti MC, Siegel PKS. Influence of ATP-sensitive potassium modulators on ischemia-induced fibrillation in isolated rat hearts.J Mol Cell Cardiol 1989;21:783–788.
Billman GE, Avendano CE, Halliwill JR, Burroughs JM. Effect of the potassium channel antagonist, glybenclamide, on sudden death: Protection from ventricular fibrillation (abstr).J Am Coll Cardiol 1991;17:165A.
Niho T, Notsu T, Ishikawa H, et al. Study of mechanisms and effects of sodium 5-hydroxydecanoate on experimental ischemic ventricular arrhythmia.Folia Pharmacol Jpn 1987;89:155–167.
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;875–883.
Imanishi S, Arita M, Aomine M, Kiyosue T. Antiarrhythmic effects of nicorandil on canine cardiac Purkinje fibers.J Cardiovasc Pharmacol 1984;6:772–779.
Liu B, Golyan F, McCullough JR, Vassalle M. Electrophysiological and anti-arrhythmic effects of the K-channel opener, BRL 34915, in cardiac Purkinje fibers.Drug Dev Res 1988;14:123–139.
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.
Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP).Diabetes 1972;21:976–979.
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.
Ohneda A, Maruhama Y, Itabashi H, et al. Vascular complications and long-term administration of oral hypoglycemic agents in patients with diabetes mellitus.Tohoku J Exp Med 1978;124:205–222.
Grover GJ, Newburger J, Sleph PG, et al. Cardioprotective effects of the potassium channel opener cromakalim: Stereo-selectivity and effects on myocardial adenine nucleotides.J Pharmacol Exp Ther 1991;257:156–162.
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 blocker glyburide.J Pharmacol Exp Ther 1989;251:98–104.
Gross G. Pieper G, Farber NE, et al. Effects of nicorandil on coronary circulation and myocardial ischemia.Am J Cardiol 1989;63:11J-17J.
Auchampach JA, Maruyama M, Cavero I, Gross GJ. The new K+ channel opener aprikalim (RP 52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes.J Pharmacol Exp Ther 1991;259:961–967.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wilde, A.A.M. Role of ATP-sensitive K+ channel current in ischemic arrhythmias. Cardiovasc Drug Ther 7 (Suppl 3), 521–526 (1993). https://doi.org/10.1007/BF00877617
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00877617