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Reperfusion-induced arrhythmias and myocardial ion shifts: A pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts

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Summary

Pinacidil is a member of the new antihypertensive drug family possessing an action that involves an increased, potassium efflux in vascular and cardiac muscle. We investigated the contribution of opening of ATP-sensitive potassium channel to the development of reperfusion-induced arrhythmias and myocardial ion shifts, particularly that of Na+, K+, Ca2+ and Mg2+ in isolated rat hearts. After 30 min of normothermic global ischemia, pinacidil with 1 to 60 μmol/l failed to reduce the incidence of reperfusion-induced arrhythmias, even on the postischemic/reperfused myocardium in a subset of hearts unresponsive to reperfusion-induced arrhythmias (the duration of ischemia was reduced to 25 min), pinacidil treatment was associated with a greater incidence of reperfusion-induced arrhythmias (100%) as compared to the control value (50%). These proarrhythmic effects of pinacidil were also reflected in a maldistribution of myocardial ion contents both in nonischemic and ischemic/reperfused hearts. Cicletanine, a furopyridine antihypertensive agent that has no effect on coronary resistance, reduced the incidence of reperfusion arrhythmias, and its antiarrhythmic effect was antagonized by pinacidil. The same observation was made in relation to myocardial ion content, e.g., pinacidil-induced K+ loss and Ca2+ gain were antagonized by cicletanine, both in nonischemic and ischemic/reperfused hearts. It is hypothesized that the increased tendency to develop reperfusion-induced ventricular fibrillation is associated with the pinacidil-induced K+ efflux. The present study does not attempt to address the question of specific ionic currents; however, it has been suggested that proarrhythmic and antiarrhythmic effects of pinacidil and cicletanine, respectively, may relate to same receptor sites in which the latter may reflect a specific blockade of the outward K+ ion current via ATP-sensitive K+ channels. If this is so, the use of K+ channel openers as antihypertensive agents may be of particular concern in that population of postinfarction patients who are known to be at high risk of sudden coronary death.

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  1. A. Tosaki

    Present address: Surgery L/1087, School of Medicine, University of Connecticut Health Center, 06030, Farmington, Connecticut, USA

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  1. Biological Research Center, Szeged, Hungary

    A. Tosaki

  2. Central Research Laboratories, Medical School, Szeged, Hungary

    P. Szerdahelyi

  3. Surgery L/1087, School of Medicine, University of Connecticut Health Center, 06030, Farmington, Connecticut, USA

    D. K. Das

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Tosaki, A., Szerdahelyi, P. & Das, D.K. Reperfusion-induced arrhythmias and myocardial ion shifts: A pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts. Basic Res Cardiol 87, 366–384 (1992). https://doi.org/10.1007/BF00796522

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