Cromakalim is a member of the new antihypertensive drug family possessing an action that involves an increased K efflux in vascular and cardiac muscle. We studied the contribution of opening of ATP-sensitive K channel to the development of reperfusion-induced arrhythmias and myocardial ion shifts, particularly that of Na, K, Ca and Mg in isolated rat hearts. After 30 min of global ischemia, cromakalim (1 to 30 μM) failed to reduce reperfusion arrhythmias. On the postischemic-reperfused 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 ventricular fibrillation (VF) and ventricular tachycardia (VT) as compared to the controls (100% VF and 100% VT in treated vs. 41% VF and 50% VT in controls, P < .05). Proarrhythmic effects of cromakalim were also reflected in a maldistribution of myocardial ions. At concentrations of 3, 10 and 30 μM of glibenclamide, a K channel blocker, a significant reduction in the incidence of reperfusion-induced VF and VT was observed, and an attenuation in the maldistribution of myocardial ion contents induced by ischemia/reperfusion was found. The reduction in myocardial contractility was detected at relatively high concentrations (10 and 30 μM) in both cromakalim- and glibenclamide-treated groups. The proarrhythmic effect of cromakalim (30 μM) was abolished by 3 μM of glibenclamide, suggesting that the increased tendency to develop reperfusion arrhythmias is associated with the cromakalim-induced K efflux. Cromakalim- induced vasodilation was also prevented by glibenclamide, indicating 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 channel openers as antihypertensive agent might be of particular concern in that population of postinfarction patients who are known to be at high risk of arrhythmias.
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Dec 1 1993|
ASJC Scopus subject areas
- Molecular Medicine