Skip to main content
Log in

ATP-sensitive potassium channels and myocardial ischemia: Why do they open?

  • Editorial
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

There is evidence that the “ATP-sensitive” potassium channel opens, at least during the early stages of myocardial ischemia, despite relatively high ATP levels. Thus, channel opening may partially contribute to potassium efflux and accumulation of extracellular potassium, but probably much more profoundly to electrical abnormalities associated with ischemia, including the development of lethal arrhythmias. Several factors are discussed that may promote a significant open-channel probability of the channel, in spite of relatively high levels of ATP. It is argued that, even with a very low open probability, the magnitude of total membrane current carried by these channels may be substantial (comparable to other potassium currents) because of the high density and conductance of the ATP-sensitive potassium channel. Finally, it is shown how the ATP-sensitive potassium channel may play a role in various tissue types, ranging from the physiological to the pathophysiological. This potassium channel is therefore increasingly targeted for drug development and research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  • Allen SL, Boyle JP, Cortijo J, et al. Electrical and mechanical effects of BRL 34915 in guinea pig isolated trachealis. Br J Pharmacol 1986;89:395–405.

    Google Scholar 

  • Arena JP, Kass RS. Enhancement of potassium-sensitive current in heart cells by pinacidil-Evidence for modulation of the ATP-sensitive potassium channel. Circ Res 1989;65:436–445.

    Google Scholar 

  • Arena JP, Kass RS. Activation of ATP-sensitive K channels in heart cells by pinacidil: Dependence on ATP. Am J Physiol 1989;257:H2092-H2096.

    Google Scholar 

  • Asheroft FM, Kakei M, Kelly PR, Sutton R. ATP-sensitive K+ channels in human isolated paneratic β-cells. FEBS Lett 1987;215:9–12.

    Google Scholar 

  • Ashford MLJ, Boden PR, Treherne JM. Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflügers Archiv 1990;415:479–483.

    Google Scholar 

  • Ashford MLJ, Sturgess NC, Trout NJ, et al. Adenosine-5′-triphosphate-sensitive ion channels in neonatal rat cultured central neurones. Pflügers Arch 1988;412:297–304.

    Google Scholar 

  • Cameron JS, Kimura S, Jackson-Burns DA, et al. ATP-sensitive K+ channels are altered in hypertrophied myocytes. Am J Physiol 1988;255:H1254-H1258.

    Google Scholar 

  • 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.

    Google Scholar 

  • Coetzee WA, Hearse DJ, ATP-sensitive potassium current in guinea pig ventricular myocytes is inhibited by extracellular pyruvate-Is there a role for intracellular pyruvate? J Mol Cell Cardiol 1991; 23(Suppl V):abstract S.7.

  • Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischaemia/reperfusion damage. Circ Res 1991;69:571–581.

    Google Scholar 

  • Cook DL, Hales CN. Intracellular ATP directly blocks K+ channels in pancreatic β-cells. Nature 1984;311:271–273.

    Google Scholar 

  • Cook NS, Quast U, Hof RP, et al. Similarities in the mechanism of action of two new vasodilator drugs: Pinacidil and BRL 34915. J Cadiovasc Pharmacol 1988;11:90–99.

    Google Scholar 

  • Crake T, Kirby MS, Poole-Wilson PA. Potassium efflux from the myocardium during hypoxia: Role of lactate ions. Cardiovasc Res 1987;21:886–891.

    Google Scholar 

  • De Weille JR, Fosset M, Mourre C, et al. Pharmacology and regulation of ATP-sensitive K+ channels. Pflügers Arch 1989;414(Suppl I):S80-S87.

    Google Scholar 

  • Dunne MJ, Peterson OH. Phorbol ester and cell-permeable diacylglycerol evoke closure of ATP-sensitive K+ channels in a cultured insulin-secreting cell-line. J Physiol 1987;390:73P.

    Google Scholar 

  • Edwards G, Weston AH. Structure-activity relationships of K+ channel openers. TIPS 1990;11:417–422.

    Google Scholar 

  • Elliot AC, Smith GL, Allen DG. Simultaneous measurements of action potential duration and intracellular ATP in isolated ferret hearts exposed to cyanide. Circ Res 1989;64:583–591.

    Google Scholar 

  • Escande D. The pharmacology of ATP-sensitive K+ channels in the heart. Pflügers Arch 1989;414(Suppl 1):S93-S98.

    Google Scholar 

  • Escande D, Thuringer D, Leguern S, Cavero I. The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes. Biochem Biophys Res Commun 1988;154:620–625.

    Google Scholar 

  • Fan Z., Nakayama K., Hiraoka M. Multiple actions of pinacidil on adenosine triphosphate-sensitive potassium channels in guinea-pig ventricular myocytes. J Physiol 1990a;430:273–295.

    Google Scholar 

  • Fan Z., Nakayama K., Hiraoka M. Pinacidil activates the ATP-sensitive K+ channel in inside-out and cell-attached patch membranes of guinea-pig ventricular myocytes. Pflügers Arch 1990b;415:387–394.

    Google Scholar 

  • Findlay I. ATP4- and ATP.Mg inhibit the ATP-sensitive K+ channel of rat ventricular myocytes. Pflügers Arch 1988; 412:37–41.

    Google Scholar 

  • Fiolet JWT, Baartscheer A, Schumacher CA, et al. Transmural inhomogeneity of energy metabolism during acute global ischaemia in the isolated rat heart: Dependence on environmental conditions. J Mol Cell Cardiol 1985;17:87–92.

    Google Scholar 

  • Fish FA, Prakash C, Roden DM. Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation 1990;82:1362–1369.

    Google Scholar 

  • Kozlowski RZ, Ashford MLJ. ATP-sensitive K+ channel rundown is Mg2+ dependent. Proc R Soc Lond (B) 1990;240: 397–410.

    Google Scholar 

  • Kurachi Y. Voltage-dependent activation of the inward-rectifier potassium channel in the ventricular cell membrane of guinea-pig heart. J Physiol 1985;366:365–385.

    Google Scholar 

  • Lederer WJ, Niggli E, Hadley RW. Sodium-calcium exchange in excitable cells: Fuzzy space. Science 1990;248:283.

    Google Scholar 

  • Lederer WJ, Nichols CG. Nucleotide modulation of the activity of rat ATP-sensitive K+ channels in isolated membrane patches. J Physiol 1989;419:193–211.

    Google Scholar 

  • Liu B, Golyan F, McCullough JR, Vassalle M. Electrophysiological and antiarrhythmic effects of the K-channel opener, BRL 34915, in cardiac Purkinje fibres. Drug Dev Res 1988;14: 123–139.

    Google Scholar 

  • McDonald TF, MacLeod DP. Anoxia-recovery cycle in ventricular muscle: Action potential duration, contractility and ATP content. Pflügers Arch 1971;325:305–322.

    Google Scholar 

  • McDonald TF, MacLeod DP. The effect of 2–4-dinitrophenol on electrical and mechanical activity, metabolism and ion movements in guinea pig ventricular muscle. Br J Pharmacol 1972;44:711–722.

    Google Scholar 

  • Nakayama K, Fan Z, Marumo F, Hiraoka M. Interrelation between pinacidil and ATP concentrations on activation of the ATP-sensitive K+ current in guinea pig ventricular myocytes. Circ Res 1990;67:1124–1133.

    Google Scholar 

  • Nakayama K, Fan Z, Marumo F, et al. Action of nicorandil on ATP-sensitive K+ channel in guinea-pig ventricular myocytes. Br J Pharmacol 1991;103:1641–1648.

    Google Scholar 

  • Neumcke B, Weik R. Blockers and inhibitors of ATP-sensitive K+ channels in adult mouse skeletal muscle. Pflügers Arch 1989;414(Suppl 1):S181-S182.

    Google Scholar 

  • 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.

    Google Scholar 

  • Nichols CG, Rippol C, Lederer WJ. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ Res 1990;68:280–287.

    Google Scholar 

  • Noma A, Shibasaki T. Membrane current through adenosinetriphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol 1985;363:463–484.

    Google Scholar 

  • Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983;305:147–148.

    Google Scholar 

  • Noma A. Chemical-receptor-dependent potassium channels in cardiac muscle. In: Noble D, Powell T, eds. Electrophysiology of single cardiac cells. London: Academic Press, 1987; 223–246.

    Google Scholar 

  • Opie LH, Substrate and energy metabolism of the heart. In: Sperelakis N, eds. Physiology and pathophysiology of the heart. 2nd ed, Boston: Kluwer Academic Publishers, 1989: 327–359.

    Google Scholar 

  • Pilsudski R, Rougier O, Tourneur Y Activation of an ATP-sensitive K+ current is promoted by internal GDP in frog atrial myocytes. Pflügers Arch 1989;414(Suppl 1):S177.

    Google Scholar 

  • Podzuweit T, Lubbe WF, Opie LH 1976. Cyclic adenosine monophosphate, ventricular fibrillation, and antiarrhythmic drugs. Lancet 1976:341–342.

    Google Scholar 

  • Ribalet B, Eddlestone GT, Ciani S. Metabolic regulation of the K(ATP) and a maxi-K(V) channel in the insulin-secreting RINm5F cell. J Gen Physiol 1988;92:219–237.

    Google Scholar 

  • Ribalet B, Ciani S, Eddlestone GT. ATP mediates both activation and inhibition of K(ATP) channel activity via cAMP-dependent protein kinase in insulin-secreting cell lines. J Gen Physiol 1989;94:693–717.

    Google Scholar 

  • Rorsman P, Berggren P-O, Bokvist K, Efendic S. ATP-regulated K+ channels and diabetes mellitus. NIPS 1990;5: 143–147.

    Google Scholar 

  • Sakmann B, Trube G. Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol 1984a;347:641–657.

    Google Scholar 

  • Sakmann B, Trube G. Voltage-dependent inactivation of inward-rectifying single-channel currents in the guinea pig heart cell membrane. J Physiol 1984b;347:659–683.

    Google Scholar 

  • Sanguinetti MC, Scott AL, Zingaro GJ, Siegl PKS. BRL 34915 (cromakalim) activates ATP-sensitive K+ current in cardiac muscle. Proc Natl Acad Sci USA 1988;85:8360–8364.

    Google Scholar 

  • Shibasaki T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol 1987;387:227–250.

    Google Scholar 

  • Spinelli W, Follmer C, Parsons R, Colatsky T. Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs. Eur J Pharmacol 1990; 179:243–252.

    Google Scholar 

  • 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.

    Google Scholar 

  • Spruce AE, Standen NB, Stanfield PR. Studies of the unitary properties of adenosine-5′-triphosphate-regulated potassium channels of frog skeletal muscle. J Physiol 1987;382:213–236.

    Google Scholar 

  • Standen NB, Quayle JM, Davies NW, et al. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 1989;245:177–180.

    Google Scholar 

  • Steinberg MI, Ertel P, Smallwood JK, et al. The relation between relaxant and cardiac electrophysiological effects of pinacidil. J Cardiovasc Pharmacol 1988;12(Suppl 2):S30-S40.

    Google Scholar 

  • Taniguchi J, Noma A, Irisawa H. Modification of the cardiac action potential by intracellular injection of adenosine triphosphate and related substances in guinea pig single ventricular cells. Circ Res 1983;53:131–139.

    Google Scholar 

  • Trube G, Rorsman P, Ohno-Shosaku T. Opposite effect of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic β-cells. Pflügers Arch 1986;407:493–499.

    Google Scholar 

  • Tseng G-N, Hoffman BF. Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP. Pflügers Arch 1990;415:414–424.

    Google Scholar 

  • Venkatesh N, Lamp ST, Weiss JN. Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischaemia, and metabolic inhibition in mammalian ventricle. Circ Res 1991;69:623–637.

    Google Scholar 

  • Vleugels A, Vereecke J, Carmeliet E. Ionic currents during hypoxia in voltage clamped cat ventricular muscle. Circ Res 1980;47:501–508.

    Google Scholar 

  • Weir SW, Weston AH. The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels. Br J Pharmacol 1986;88:121–128.

    Google Scholar 

  • Weiss JN, Lamp ST. Cardiac ATP-sensitive K+ channels. Evidence for preferential regulation by glycolysis. J Gen Physiol 1989;94:911–935.

    Google Scholar 

  • Weston AH, Abbott A. New class of antihypertensive acts by opening K+ channels. TIPS 1987;8:283–284.

    Google Scholar 

  • Wilde AAM, Escande D, Schumacher CA, et al. Glibenclamide inhibition of ATP-sensitive K+ channels and ischaemia-induced K+ accumulation in the mammalian heart. Pflügers Arch 1989;414(Suppl I):S176.

    Google Scholar 

  • Wilde AAM, Escande D, Schumacher CA, et al. Potassium accumulation in the globally ischaemic mammalian heart. A role for the ATP-sensitive potassium channel. Circ Res 1990;67:835–843.

    Google Scholar 

  • Wolleben CD, Sanguinetti MC, Siegl PKS. Influence of ATP-sensitive potassium channel modulators on ischaemia-induced fibrillation in isolated rat hearts. J Mol Cell Cardiol 1989; 21:783–788.

    Google Scholar 

  • Wollheim CB, Dunne MJ, Peter-Riesch R, et al. Activators of protein kinase C depolarize insulin-secreting cells by closing K+ channels. EMBO J 1988;7:2443–2449.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coetzee, W.A. ATP-sensitive potassium channels and myocardial ischemia: Why do they open?. Cardiovasc Drug Ther 6, 201–208 (1992). https://doi.org/10.1007/BF00051140

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00051140

Key Words

Navigation