POTASSIUM CHANNEL OPENERS AND BLOCKERS - DO THEY POSSESS PROARRHYTHMIC OR ANTIARRHYTHMIC ACTIVITY IN ISCHEMIC AND REPERFUSED RAT HEARTS

Cromakalim is a member of the new antihypertensive drug family possess ing an action that involves an increased K efflux in vascular and card iac muscle. We studied the contribution of opening of ATP-sensitive K channel to the development of reperfusion-induced arrhythmias and myoc ardial ion shifts, particularly that of Na, K, Ca and Mg in isolated r at hearts. After 30 min of global ischemia, cromakalim (1 to 30 muM) f ailed to reduce reperfusion arrhythmias. On the postischemic-reperfuse d myocardium in a subset of hearts unresponsive to reperfusion-induced arrhythmias (duration of ischemia was reduced to 25 min), cromakalim treatment was associated with a higher incidence of reperfusion ventri cular fibrillation (VF) and ventricular tachycardia (VT) as compared t o the controls (100% VF and 100% VT in treated vs. 41% VF and 50% VT i n controls, P < .05). Proarrhythmic effects of cromakalim were also re flected in a maldistribution of myocardial ions. At concentrations of 3, 10 and 30 muM of glibenclamide, a K channel blocker, a significant reduction in the incidence of reperfusion-induced VF and VT was observ ed, and an attenuation in the maldistribution of myocardial ion conten ts induced by ischemia/reperfusion was found. The reduction in myocard ial contractility was detected at relatively high concentrations (10 a nd 30 muM) in both cromakalim- and glibenclamide-treated groups. The p roarrhythmic effect of cromakalim (30 muM) was abolished by 3 muM of g libenclamide, suggesting that the increased tendency to develop reperf usion arrhythmias is associated with the cromakalim-induced K efflux. Cromakalim-induced vasodilation was also prevented by glibenclamide, i ndicating that proarrhythmic and antiarrhythmic effects of cromakalim and glibenclamide, respectively, may relate to the same receptor sites in which the latter may reflect a specific blockade of the outward K current via ATP-sensitive K channels. If this is so, the use of K chan nel openers as antihypertensive agent might be of particular concern i n that population of postinfarction patients who are known to be at hi gh risk of arrhythmias.