CARDIOPROTECTIVE PROFILE OF THE CARDIAC-SELECTIVE ATP-SENSITIVE POTASSIUM CHANNEL OPENER BMS-180448

ATP-sensitive potassium channel (K-ATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference K-ATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective K-ATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC(25) for increasing time to contracture = 2.5 mu M), with potency equal to that of cromakalim (EC(25) = 4.9 mu M) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the K-ATP blockers glyburide and sodium 5-hydroxydecanoate, indicating K-ATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single K-ATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was >100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available K-ATP openers.