EMS-180448, A NOVEL GLYBURIDE-REVERSIBLE CARDIOPROTECTIVE AGENT, ENHANCES POSTISCHEMIC RECOVERY OF CONTRACTILE FUNCTION IN DOGS

BMS-180448 has been found to retain the cardioprotective potency of it s chemically related analog, cromakalim, although having significantly less peripheral vasodilating activity. The effect of the ATP-sensitiv e potassium channel opener, BMS-180448, on postischemic recovery of fu nction (segmental shortening) was determined in open chested, anesthet ized dogs instrumented with ultrasonic crystals. The plasma-concentrat ion of the effective and ineffective doses of BMS-180448 was compared to concentrations used in isolated rat hearts. BMS-180448 was given as a total dose of 4.2, 1.4 or 0.5 mg/kg over 30 min, starting 15 min be fore ischemia. Ischemia was initiated by a complete occlusion of the l eft anterior descending coronary artery for 15 min. Reperfusion was ma intained for 3 hr and segmental shortening was measured. During ischem ia, systolic bulging was observed in the ischemic region in drug and v ehicle-treated groups. Upon reperfusion, some contractile functional r ecovery was observed in vehicle-treated controls within minutes, but q uickly decreased so that slight bulging was observed up to 3 hr into r eperfusion. High dose BMS-180448 significantly improved the recovery o f contractile function such that, by 3 hr after reperfusion, segmental shortening had recovered to 60% of base line. The 1.4-mg/kg dose also significantly improved reperfusion function, but 0.5 mg/kg of BMS-180 448 was without effect. None of the doses of BMS-180448 significantly affected peripheral hemodynamic status or collateral blood flow. The p lasma concentration of the 1.4-mg/kg dose was approximately 3 mu M dur ing ischemia. In isolated rat hearts, BMS-180448 significantly increas ed postischemic function at 3 mu M and higher concentrations, which ag rees with the dog data. BMS-180448 was protective in a dose-dependent manner in a canine model of stunned myocardium, and the concentrations necessary for protection are similar to that for rats.