HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs.

ABSTRACT

The activation of the ATP-sensitive potassium channel (KATP) during myocardial ischemia leads to potassium efflux, reductions in action potential duration and the formation of ventricular fibrillation (VF). Drugs that inactivate KATP should prevent these changes and thereby prevent VF. However, most KATP antagonists also alter pancreatic channels, which promote insulin release and hypoglycemia. Recently, a cardioselective KATP antagonist, HMR 1883, has been developed that may offer cardioprotection without the untoward side effects of existing compounds. Therefore, VF was induced in 13 mongrel dogs with healed myocardial infarctions by a 2-min coronary artery occlusion during the last minute of a submaximal exercise test. On subsequent days, the exercise-plus-ischemia test was repeated after pretreatment with HMR 1883 (3.0 mg/kg i.v., n = 13) or glibenclamide (1.0 mg/kg i.v., n = 7). HMR 1883 (P < .001) and glibenclamide (P < .01) prevented VF in 11 of 13 and 6 of 7 animals, respectively. Glibenclamide, but not HMR 1883, elicited increases in plasma insulin and reductions in blood glucose. Glibenclamide also reduced (P < .01) both mean coronary blood flow and left ventricular dP/dt maximum as well as the reactive hyperemia induced by 15-sec coronary occlusions (-30.3 +/- 11%), whereas HMR 1883 did not alter this increase in coronary flow (-3.0 +/- 4.7%). Finally, myocardial ischemia (n = 10) significantly (P < .01) reduced refractory period (control, 121 +/- 2 msec; occlusion, 115 +/- 2 msec), which was prevented by either glibenclamide or HMR 1883. Thus, the cardioselective KATP antagonist HMR 1883 can prevent ischemically induced reductions in refractory period and VF without major hemodynamic effects or alterations in blood glucose levels. These data further suggest that the activation of KATPs may play a particularly important role in both the reductions in refractory period and lethal arrhythmia formation associated with myocardial ischemia.