EFFECT OF TIMING OF TREATMENT OF THE GLYBURIDE-REVERSIBLE CARDIOPROTECTIVE ACTIVITY OF BMS-180448

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and fe rret models of ischemia and reperfusion. In rat hearts, 10 mu M BMS-18 0448, given before and after global ischemia as well as only during re flow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less ef fective. Cromakalim (10 mu M) and bimakalim (10 mu M) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and posttreatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++](i)) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BM S-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interva l beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administra tion of BMS-180448 was associated with a 35% reduction in infarct dama ge from that recorded in vehicle-treated control ferrets. Drug adminis tered at the midpoint of ischemia reduced infarct size similar to 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated wit h changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during r eperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-1804 48.