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Electrophysiologic effects of potassium channel openers

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Summary

Potassium-channel openers or activators have been introduced as a new class of antihypertensive and antianginal agents that act by increasing membrane conductance to potassium, mainly through augmentation of the ATP-sensitive potassium current. Recent in vitro studies have shown that K+-channel openers exert concentration-dependent effects on cardiac electrophysiology. A shortening of the cardiac action potential by acceleration of repolarization has been reported in multicellular preparations as well as in isolated myocytes. However, drug concentrations that affect the action potential duration of myocardial cells are considerably higher (10- to 100-fold) than those needed for effects on vascular smooth muscle cells. Studies in which mostly high concentrations of K+-channel openers were used have demonstrated that these drugs may accelerate automaticity and may promote reentrant activity. Particular interest has focused on the question whether opening of potassium channels may be potentially arrhythmogenic in the setting of acute myocardial ischemia. On the other hand, recent studies have shown that K+-channel openers are effective in suppressing polymorphic ventricular tachyarrhythmias induced by early afterdepolarizations and triggered activity in vivo. The clinical relevance of these experimental studies to the clinical situation is still unclear. Some K+-channel openers have been shown to produce electrocardiographic T-wave changes in patients in whom their effectiveness as antihypertensives was tested. However, this effect was not associated with adverse effects and has not been demonstrated for all compounds. So far the worsening of existing arrhythmias or the induction of new arrhythmias by K+-channel openers in humans has not been reported.

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References

  1. Anderson KE. Clinical pharmacology of potassium channel openers.Pharmacol Toxicol 1992;70:244–254.

    PubMed  Google Scholar 

  2. Escande D, Henry P. Potassium channels as pharmacological targets in cardiovascular medicine.Eur Heart J 1993;14(Suppl B):2–9.

    Google Scholar 

  3. Robertson DW, Steinberg MI. Potassium channel modulators: Scientific applications and therapeutic promise.J Med Chem 1990;33:1529–1541.

    PubMed  Google Scholar 

  4. Kinoshita M, Sakai K. Pharmacology and therapeutic effects of nicorandil.Cardiovasc Drugs Ther 1990;4:1075–1088.

    PubMed  Google Scholar 

  5. Frampton J, Buckley MM, Fitton A. Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris.Drugs 1992;44:625–655.

    PubMed  Google Scholar 

  6. Goldberg MR. Clinical pharmacology of pinacidil. A prototype for drugs that affect potassium channels.J Cardiovasc Pharmacol 1988;12(Suppl 2):S41-S47.

    Google Scholar 

  7. Ahnfelt-Ronne I. Pinacidil: History, basic pharmacology, and therapeutic implications.J Cardiovasc Pharmacol 1988;12(Suppl 2):S1-S4.

    Google Scholar 

  8. Friedel HA, Brogden RN. Pinacidil: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of hypertension.Drugs 1990;39:929–967.

    PubMed  Google Scholar 

  9. Thomas PMS, Dixon SJ, Winterton SJ, Sheridan DJ. Acute haemodynamic effects of cromakalim in patients with angina pectoris.Br J Clin Pharmacol 1990;29:325–331.

    PubMed  Google Scholar 

  10. Gotanda K, Satoh K, Taira N. Is the cardiovascular profile of BRL 34915 characteristic of potassium channel activators?J Cardiovasc Pharmacol 1988;12:239–246.

    PubMed  Google Scholar 

  11. Damiano BP, Stump GL, Cheung WM, Slata JJ. In vivo cardiac electrophysiologic effects of RWJ 29009, a new potassium-channel activator, in comparison to cromakalim and nicardipine.J Cardiovasc Pharmacol 1993;22:143–152.

    PubMed  Google Scholar 

  12. Auchampach JA, Gross GJ. Anti-ischaemic actions of potassium channel openers in experimental myocardial ischaemia/reperfusion injury in dogs.Eur Heart J 1993;14(Suppl B):10–15.

    Google Scholar 

  13. Shen WK, Tung RT, Machulda MM, Kurachi Y. Essential role of nucleotide diphosphates in nicorandil-mediated activation of cardiac ATP-sensitive K+ channel. A comparison with pinacidil and lemakalim.Circ Res 1991;69:1152–1158.

    PubMed  Google Scholar 

  14. Lodge NJ, Colatsky TJ, Cullinan CA, Follmer CH. Electromechanical effects of the putative potassium channel activator celikalim (WAY 120,491) on feline atrial and ventricular muscle.J Pharmacol Exp Ther 1992;261:1153–1159.

    PubMed  Google Scholar 

  15. Wickenden AD, Grimwood S, Grant TL, Todd MH. Comparison of the effects of the K+-channel openers cromakalim and minoxidil sulphate on vascular smooth muscle.Br J Pharmacol 1991;103:1148–1152.

    PubMed  Google Scholar 

  16. Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system.Am J Physiol 1991;261:H1675-H1689.

    Google Scholar 

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

    PubMed  Google Scholar 

  18. Takano M, Noma A. Selective modulation of the ATP-sensitive K+ channel by nicorandil in guinea-pig cell membrane.Arch Pharmacol 1990;342:592–597.

    PubMed  Google Scholar 

  19. Hiraoka M, Fan Z. Activation of ATP-sensitive outward K+ current by nicorandil in isolated ventricular myocytes.J Pharmacol Exp Ther 1989;250:278–285.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  21. Erne P, Hermsmeyer K. Actions of pinacidil on calcium release in single vascular muscle cells of rat veins.Physiologist 1987;30:129.

    Google Scholar 

  22. Meisheri KD, Swirtz MA, Purohit SS, Cipkus-Dubray LA, Khan SA, Oleynek JJ. Characterization of K+ channel dependent as well as independent components of pinacidil-induced vasodilatation.J Pharmacol Exp Ther 1991;256:492–499.

    PubMed  Google Scholar 

  23. Anabuki J, Hori M, Ozaki H, Kato I, Karaki H. Mechanisms of pinacidil-induced vasodilatation.Eur J Pharmacol 1990;190:373–379.

    PubMed  Google Scholar 

  24. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators.Am J Cardiol 1989;63:18J-24J.

    PubMed  Google Scholar 

  25. Gross GJ, Warltier DC, Hardman HF, Lamping KA. Enhanced subendocardial perfusion distal to a flow-limiting coronary artery stenosis in dogs: Comparative effects of nicorandil, a potential new antianginal agent, and nitroglycerin.J Cardiovasc Pharmacol 1985;7:977–982.

    PubMed  Google Scholar 

  26. Suryapranta H. Coronary haemodynamics and vasodilatory profile of a potassium channel opener in patients with coronary artery disease.Eur Heart J 1993;14(Suppl B):16–21.

    Google Scholar 

  27. Why H, Richardson PJ. A potassium channel opener as monotherapy in chronic stable angina pectoris: Comparison with placebo.Eur Heart J 1993;14(Suppl B):25–29.

    Google Scholar 

  28. Kato K, Asanoi H, WakaBayashi C, et al. Effect of nicorandil on exercise performance in patients with effort angina: A multicenter trial using a treadmill exercise test.J Cardiovasc Pharmacol 1987;10(Suppl):S98-S103.

    PubMed  Google Scholar 

  29. Meeter K, Kelder JC, Tijssen J, et al. Efficacy of nicorandil versus propranolol in mild stable angina pectoris of effort: A long-term, double-blind randomized study.J Cardiovasc Pharmacol 1992;20(Suppl 3):S59-S66.

    Google Scholar 

  30. Guermonprez JL, Blin P, Peterlongo F. A double-blind comparison of the long-term efficacy of a potassium channel opener and a calcium antagonist in stable angina pectoris.Eur Heart J 1993;14(Suppl B):30–34.

    Google Scholar 

  31. Raftery EB, Lahiri A, Hughes LO, Rose EL. A double-blind comparison of a beta-blocker and a potassium channel opener in exercise induced angina.Eur Heart J 1993;14(Suppl B):35–39.

    PubMed  Google Scholar 

  32. Smallwood JK, Steinberg MI. Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: Relationship to antihypertensive activity.J Cardiovasc Pharmacol 1988;12:102–109.

    PubMed  Google Scholar 

  33. Steinberg MI, Ertel P, Smallwood JK, Wyss V, Zimmermann K. The relation between vascular relaxant and cardiac electrophysiological effects of pinacidil.J Cardiovasc Pharmacol 1988;12(Suppl 2):30–40.

    Google Scholar 

  34. Imanishi S, Arita M, Kiyosue T, Aomine M. Effects of SG-75 (nicorandil) on electrical activity of canine cardiac Purkinje fibers: Possible increase in potassium conductance.J Pharmacol Exp Ther 1983;225:198–205.

    PubMed  Google Scholar 

  35. Di Diego JM, Antzelevitch C. Pinacidil-induced reentrant arrhythmias in isolated canine ventricular epicardium.Circulation 1990;82(Suppl III):III-528.

    Google Scholar 

  36. Bril A, Man R. Effects of the potassium channel activator, BRL 34915, on the action potential characteristics of canine cardiac Purkinje fibers.J Pharmacol Exp Ther 1990;253:1090–1096.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  38. Conder ML, McCullough JR. Purported K+ channel opener, BRL 34915, blocks inwardly rectifying K+ current in isolated guinea pig ventricular myocytes.Biophys J 1987;51:258.

    Google Scholar 

  39. Yanagisawa T, Satoh K, Tiara N. Circumstantial evidence of increased potassium conductance of the membrane of cardiac muscle by 2-nicotinamidoethyl nitrate (SG-75).Jpn J Pharmacol 1979;29:687–694.

    PubMed  Google Scholar 

  40. Furukawa Y, Akahane K, Ogiwara Y, Chiba S. K+ channel blocking and antimuscarinergic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium.Eur J Pharmacol 1991;193:217–222.

    PubMed  Google Scholar 

  41. Yang T, Tande PM, Lathrop PM, Refsum H. Class III antiarrhythmic action by potassium channel blockade: Dofetilide attentuates hypoxia induced electromechanical changes.Cardiovasc Res 1992;26:1109–1115.

    PubMed  Google Scholar 

  42. Lathrop DA, Varro A. Modulation of the effects of sotalol on Purkinje strand electromechanical characteristics.Can J Physiol Pharmacol 1989;67:1463–1467.

    PubMed  Google Scholar 

  43. Spinelli W, Follmert C, Parson 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.

    PubMed  Google Scholar 

  44. Chi L, Uprichard A, Lucchesi R. Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.J Cardiovasc Pharmacol 1990;15:452–464.

    PubMed  Google Scholar 

  45. Yoneyama F, Satoh K, Taira N. Nicorandil increases coronary blood flow predominantly by K+-channel mechanism.Cardiovasc Drugs Ther 1990;4:1119–1126.

    PubMed  Google Scholar 

  46. Padrini R, Bova S, Cargnelli G, Piovan D, Ferrari M: Effects of pinacidil on guinea-pig isolated perfused heart with particular reference to the proarrhythmic effect.Br J Pharmacol 1992;105:715–719.

    PubMed  Google Scholar 

  47. Le Grand GB, Hatem S, Le HJY, Deroubaix E, Benitah JP, Coraboeuf E. Proarrhythmic effect of nicorandil in isolated rabbit and its suppression by tolbutamide and quinidine.Eur J Pharmacol 1992;229:91–96.

    PubMed  Google Scholar 

  48. 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.

    PubMed  Google Scholar 

  49. 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.

    PubMed  Google Scholar 

  50. Carlsson L, Abrahamsson C, Drews L, Duker G. Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed afterdepolarizations.Circulation 1992;85:1491–1501.

    PubMed  Google Scholar 

  51. Takahasi N, Ito M, Saikawa T, Arita M. Nicorandil suppresses early afterdepolarizations and ventricular arrhythmias induced by caesium chloride in rabbits in vivo.Cardiovasc Res 1991;25:445–452.

    PubMed  Google Scholar 

  52. 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.

    PubMed  Google Scholar 

  53. Gross GJ, Pieper G, Farber NE, Warltier D, Hardman H. Effects of nicorandil on coronary circulation and myocardial ischemia.Am J Cardiol 1989;63:11J-17J.

    PubMed  Google Scholar 

  54. Gross GJ, Auchampach JA, Maruyama M, Warltier DC, Pieper GM. Cardioprotective effects of nicorandil.J Cardiovasc Pharmacol 1992;20(Suppl 3):S22-S28.

    Google Scholar 

  55. Lamping KA, Gross GJ. Improved recovery of myocardial segment function following a short coronary occlusion in dogs by nicorandil, a potential new antianginal agent, and nifedipine.J Cardiovasc Pharmacol 1985;7:158–166.

    Google Scholar 

  56. Pieper GM, Gross GJ. Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during ischemia and on postischemic function in a canine preparation of brief, repetitive coronary artery occlusions.Circulation 1987;76:916–928.

    PubMed  Google Scholar 

  57. Hanaki Y, Sugiyama S, Ajioka M, Kondo T, Fukushima A, Ozawa T. Acceleration of recovery of mitochondria function after coronary reperfusion by various coronary dilating drugs in canine heart.J Cardiovasc Pharmacol 1989;13:336–341.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  59. Grover GJ, Sleph PG, Dzwonczyk S. Pharmacological profile of cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs.J Cardiovasc Pharmacol 1990;16:853–864.

    PubMed  Google Scholar 

  60. Harris AS, Bisteni A, Russell RA, et al. Excitatory factors in ventricular tachycardia in the early phase of myocardial ischemia. Potassium a major excitant.Science 1954;119:200–203.

    PubMed  Google Scholar 

  61. Kleber AG. Extracellular potassium accumulation in acute myocardial ischemia.J Mol Cell Cardiol 1984;16:389–394.

    PubMed  Google Scholar 

  62. Opie LH, Coetzee WA. Metabolic components of ischemia and fibrillation. In: Zipes DP, Jalife J, eds.Cardiac Electrophysiology. From Cell to Bedside. Philadelphia: WB Saunders, 1990:456–462.

    Google Scholar 

  63. Kantor PF, Coetzee WA, Carmeliet EE, Dennis SC, Opie LH. Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea.Circ Res 1990;66:478–485.

    PubMed  Google Scholar 

  64. Bekheit SS, 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 arrhythm.Am Heart J 1990;119:1025–1033.

    PubMed  Google Scholar 

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

    Google Scholar 

  66. Kempsford RD, Hawgood BJ. Assessment of the antiarrhythmic activity of nicorandil during myocardial ischemia and reperfusion.Eur J Pharmacol 1989;163:61–68.

    PubMed  Google Scholar 

  67. Chi L, Black SC, Kuo PI, Fagbemi SO, Lucchesi BR. Actions of pinacidil at a reduced potassium concentration: A direct cardiac effect possibly involving the ATP-dependent potassium channel.J Cardiovasc Pharmacol 1993;21:179–190.

    PubMed  Google Scholar 

  68. Tosaki A, Engelman RM, Rousou J, Das DK. Aggravation of reperfusion-induced arrhythmias by pinacidil, a potassium channel opener.Circulation 1992;86(Suppl I):I4.

    Google Scholar 

  69. Tosaki A, Szerdahelyi P, Das DK. Reperfusion-induced arrhythmias and myocardial ion shifts: a pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts.Basic Res Cardiol 1992;87:366–384.

    PubMed  Google Scholar 

  70. 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.

    PubMed  Google Scholar 

  71. Belz GG, Matthews J, Heinrich J, Wagner G. Controlled comparison of the pharmacodynamic effects of nicorandil (SG-75) and isosorbide dinitrate in man.Eur J Clin Pharmacol 1984;26:681–685.

    PubMed  Google Scholar 

  72. Belz GG, Matthews JH, Beck A, Wagner G, Schneider B. Hemodynamic effects of nicorandil, isorbide dinitrate, and dihydralazine in healthy volunteers.J Cardiovasc Pharmacol 1985;7:1107–1112.

    PubMed  Google Scholar 

  73. Mitrovic V, Neuss H, Kindler M. Elektrophysiologische Auswirkungen einer Vasodilatation durch Nicorandil.Herz Kreisl 1986;18:403–408.

    Google Scholar 

  74. Chikamatsu H, Hishida H, Yxasui N, et al. Electrophysiologic effects and antiarrhythmic action of nicorandil in human.Ther Res 1989;10:191–197.

    Google Scholar 

  75. Tsuchioka Y, Yamagata T, Amioka H, et al. Clinical electrophysiological effects of nicorandil on the conduction systems in humans.Kokyo Junkan 1990;38:683–690.

    Google Scholar 

  76. Fenici RR, Melillo G. Effect of nicorandil on human cardiac electrophysiological parameters.Cardiovasc Drugs Ther 1991;5(Suppl 3):367.

    Google Scholar 

  77. Goldberg MR, Rockhold FW. T-wave changes during therapy with pinacidil: A potassium channel activator.Clin Res 1987;35:442A.

    Google Scholar 

  78. Hall D, Froer KL, Rudolph W. Serial electrocardiographic changes during long-term treatment of renal hypertension with minoxidil.J Cardiovasc Pharmacol 1980;2(Suppl 2):S200–205.

    PubMed  Google Scholar 

  79. Roland E. Safety profile of an anti-anginal agent with potassium channel opening activity: An overview.Eur Heart J 1993;14(Suppl B):48–52.

    Google Scholar 

  80. Takahashi N, Ito M, Inoue T, et al. Effects of oral nicorandil on ventricular premature contractions.Ther Res 1990;11:115–120.

    Google Scholar 

  81. Antzelevitch C, Di Diego JM. Role of K+ channel activators in cardiac electrophysiology and arrhythmias.Circulation 1992;85:1627–1629.

    PubMed  Google Scholar 

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Haverkamp, W., Borggrefe, M. & Breithardt, G. Electrophysiologic effects of potassium channel openers. Cardiovasc Drug Ther 9 (Suppl 2), 195–202 (1995). https://doi.org/10.1007/BF00878466

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