ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP 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 KATP opener with less
vasorelaxant activity led to identification of the arylcyanoguanidine analogue
BMS-180448. In globally ischemic rat hearts,
BMS-180448 was cardioprotective (EC25 for increasing time to
contracture = 2.5 microM), with potency equal to that of
cromakalim (EC25 = 4.9 microM) 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 KATP blockers
glyburide and
sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP 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 KATP openers.