Summary
The effects of the potassium channel openers (KCO), cromakalim or pinacidil, were evaluated in an anesthetized porcine model of pacing- and ischemia-induced ventricular fibrillation (VF). Hearts were paced at 180 bpm and the left anterior descending coronary artery was occluded until VF was induced.
Reproducible times to VF (in seconds) were obtained allowing at least 20 min recovery following defibrillation. Cromakalim (0.3 mg/kg) or pinacidil (3 mg/kg) produced equivalent drops in mean arterial blood pressure. At these doses, cromakalim reduced monophasic action potential duration measured at 90% repolarization (APD90). Although time to VF in the cromakalim group was significantly greater than the vehicle treated group, it was not significantly different from its predrug value. In contrast, pinacidil reduced APD90, and significantly increased time to VF from 134±5 to 322±62 s (p<0.05). Neither cromakalim nor pinacidil affected whole-cell calcium currents recorded in guinea pig myocytes. During ischemia, cromakalim or pinacidil further reduced APD90; however, pinacidil had a two-fold greater effect than did cromakalim. The Class III antiarrhythmic agent, dofetilide, prolonged APD90, but did not increase time to VF.
In conclusion, the increased time to VF observed with pinacidil coincides with its ability to shorten APD, and is consistent with activation of ATP-sensitive K+ channels (K+ ATP). It is suggested that indirect reduction of calcium influx through K+ ATP activation and APD shortening is sufficient to increase time to VF in this model. However, the inability of dofetilide to be effective suggests that this model would not be useful to test for Class III antiarrhythmic agents.
Similar content being viewed by others
References
Atwal KS, McCullough JR, Hedberg A, Conder ML, Ahmed SZ, Cucinotta G, Normandin DE (1992) The discovery of a novel calcium channel blocker related to the structure of potassium channel opener cromakalim. Bioor Med Chem Letters 2:1475–1478
Black SC, Chi L, Mu DX, Lucchesi BR (1991) The antifibrillatory actions of UK-68,798, a class III antiarrhythmic agent. J Pharmacol Exp Ther 258:416–423
Carmeliet E (1992) Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther 262:809–817
Chi L, Uprichard ACG, Lucchesi BR (1990) Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death. J. Cardiovasc Pharmacol 15:452–464
Chiu PJS, Tetzloff G, Ahn H-S, Sybertz EJ (1988) Effects of BRL 34915, a putative K channel opener, on transmembrane 45Ca movements in rabbit aortic smooth muscle. Eur J. Pharmacol 155:229–237
Cole WC, McPherson CD, Sontag D (1991) ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res 69:571–581
Conder ML, Zhu JL, Gonzales S, Byrne J, McCullough JR (1993) Comparison of the electrophysiological effects of P1075 and cromakalim in canine and guinea pig cardiac muscle. Biophys J 64:A310
D'Alonzo AJ, Darbenzio RB, Parham CS, Grover GJ (1992) Effects of intracoronary cromakalim on postischaemic contractile function and action potential duration. Cardiovasc Res 26:1046–1053
DiDiego JM, Antzelevitch C (1993) Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues — does activation of ATP-regulated potassium current promote phase-2 reentry. Circulation 88:1177–1189
Escande D, Thuringer D, Leguern S, Cavero I (1988) The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes. Biochemical Biophysical Research Communications 154:620–625
Franz MR, Burkhoff D, Spurgeon H, Weisfeldt ML, Lakatta EG (1986) In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Eur Heart J 7:34–41
Gautier P, Bertrand J-P, Guiraudou P (1991) Effects of SR 44866, a potassium channel opener, on action potentials of rabbit, guinea pig and human heart fibers. J Cardiovasc Pharmacol 17:692–700
Grover GJ, Dzwonczyk S, Parham CS, Sleph PG (1990) The protective effects of cromakalim and pinacidil on reperfusion function and infarct size in isolated perfused rat hearts and anesthetized dogs. Cardiovasc Drugs Ther 4:465–474
Grover GJ, McCullough JR, Henry DE, Conder ML, Sleph PG (1989) Antiischemic 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 251:98–104
Gwilt M, Blackburn KJ, Burges RA, Higgins AJ, Milne AA, Solca AM (1992) Electropharmacology of dofetilide, a new class III agent, in anaesthetized dogs. Eur J. Pharmacol 215:137–144
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp technique for high-resolution current recording from cells and cell-free membrane patches. Plüger's Arch 391:85–100
Jurkiewicz NK, Sanguinetti MC (1993) Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide Class III antiarrhythmic agent: Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res 72:75–83
Kameyama M, Hofmann F, Trautwein W (1985) On the mechanism of β-adrenergic regulation of the Ca channel in the guinea-pig heart. Pflügers Arch 405:285–293
Lauer MR, Liem LB, Young C, Sung RJ (1992) Cellular and clinical electrophysiology of verapamilsensitive ventricular tachycardias. J Cardiovasc Electrophysicol 3:500–514
Levy MN (1989) Role of calcium in arrhythmogenesis. Circulation 80:IV23-IV30
Liu B, McCullough JR, Vassalle M (1990) On the mechanism of increased potassium conductance by the potassium channel opener BRL 34915 in isolated ventricular myocytes. Drug Dev Res 19:409–423
Maxwell MP, Hearse DJ, Yellon DM (1987) Species variation in the coronary collateral circulation during regional myocardial ischaemia: A critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res 21:737–746
McCullough JR, Conder ML, Griffel LH (1990) Electrophysiological actions of BRL 34915 in isolated guinea pig ventricular myocytes. Drug Dev Res 19:141–151
Meisheri KD, Swirtz MA, Purohit SS, Cipkus-Dubray LA, Kahn SA, Oleynek JJ (1991) Characterization of K+ channel-dependent as well as-independent components of pinacidil-induced vasodilation. J Pharmacol Exp Ther 256:492–499
Merillat JC, Lakatta EG, Hano O, Guarnieri T (1990) Role of calcium and the calcium channel in the initiation and maintenance of ventricular fibrillation. Circ Res 67:1115–1123
Okabe K, Kajioka S, Nakao K, Kitamura K, Kuriyama H, Weston AH (1990) Actions of cromakalim on ionic currents recorded from single smooth muscle cells of the rat portal vein. J Pharmacol Exp Ther 252:832–839
Pasnani JS Ferrier GR (1992) Differential effects of glyburide on premature beats and ventricular tachycardia in an isolated tissue model of ischemia and reperfusion. J Pharmacol Exp Ther 262:1076–1084
Post JM, Stevens RJ, Sanders KM, Hume JR (1991) Effect of cromakalim and lemakalim on slow waves and membrane currents in colonic smooth muscle. Am J Physiol 260:C375-C382
Sargent CA, Grover GJ, Antonaccio MJ, McCullough JR (1993) The cardioprotective, vasorelaxant and electrophysiological profile of the maxi-K channel opener NS-004. J Pharmacol Exp Ther 266:1422–1429
Sargent CA, Vesterqvist O, McCullough JR, Ogletree ML, Grover GJ (1992) Effect of phospholipase A2 inhibitors quinacrine and 7,7-dimethyleicosadienoic acid in isolated globally ischemic rat hearts. J Pharmacol Exp Ther 262:1161–1167
Timour Q, Larbre JP, Aupetit JF, Gerentes-Chassagne I, Loufoua-Moundanga J, Kioueh I, Faucon G (1991) Protection against ischaemic ventricular fibrillation by blocking agents of myocardial cell calcium influx. Electrophysiological study in the pig in situ heart. Fund Clin Pharmacol 5:641–644
Timour Q, Larbre JP, Kioueh I, Aupetit JF, Loufoua-Moundanga L, Vialle A, Faucon G (1992) Calcium channel modulators and susceptibility to ischaemic ventricular fibrillation: Modification of cellular calcium overload. Arch Intern Pharmacodyn Ther 315:30–46
vanderGiessen WJ, Mooi W, Rutterman AM, Vliet HHV, Slager CJ, Verdouw PD (1983) A new model for coronary thrombosis in the pig: Preliminary results with thrombolysis. Eur Heart J 4:69–76
Verdouw PD, Wolfenbuttel BH, Cate FJT (1983) Nifedipine with and without propranolol in the treatment of myocardial ischemia. Eur Heart J 4:101–108
Weir SW, Weston AH (1986) Effects of apamin on responses to BRL 34915 and nicorandil and other relaxants in the guinea-pig taenia caeci. Br J Pharmacol 88:113–120
Weir SW, Weston AH (1986) The effects of BRL 34915 and nicorandil on electrical and mechanical activity on86Rb efflux in rat blood vessels. Br J Pharmacol 88:121–128
Zuanetti G, Corr PB (1990) Antiarrhythmic efficacy of a new class III agent, UK-68,798, during chronic myocardial infarction: Evaluation using three-dimensional mapping. J Pharmacol Exp Ther 256:325–334
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
D'Alonzo, A.J., Hess, T.A., Darbenzio, R.B. et al. Effects of cromakalim or pinacidil on pacing- and ischemia-induced ventricular fibrillation in the anesthetized pig. Basic Res Cardiol 89, 163–176 (1994). https://doi.org/10.1007/BF00788735
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00788735