AMELIORATION OF ISCHEMIA REPERFUSION INJURY IN ISOLATED RAT HEARTS BYTHE ATP-SENSITIVE POTASSIUM CHANNEL OPENER BMS-180448/

Objective: Aims of this study were: (1) Evaluate by morphology and spe cific physiological and biochemical parameters, the protective effects of the cardioselective ATP-sensitive potassium channel opener BMS-180 448 on ischemic/reperfused isolated rat heart, and (2) Determine the e arliest time point ischemia-induced myocardial injury is observed by l ight microscopy. Methods: Hearts from Sprague-Dawley rats were perfuse d on a Langendorff apparatus. After equilibration, hearts were treated with BMS-180448 (10 mu M) or vehicle (0.04% DMSO) for 10 min before t he onset of ischemia, Four hearts/group were collected following 10, 1 8, or 25 min of ischemia. A nonischemic control group was also evaluat ed. Following 25 min of ischemia, another set of hearts was reperfused with oxygenated Krebs-Hensleit solution and allowed to recover for 30 min. Light and electron microscopic changes of the myocardium were se mi-quantitatively evaluated together with physiological (i.e., heart r ate, left ventricular diastolic pressure, time to contracture formatio n) and biochemical (i.e., lactate dehydrogenase, LDH, release) endpoin ts. Results: Cardioprotective effects of BMS-180448 following ischemia /reperfusion consisted of a reduced rate of contracture formation, red uced LDH release, and enhanced recovery of contractile function during reperfusion (P < 0.05). Light microscopic evidence of myocardial dama ge was detected following 18 min of ischemia. Morphological changes in ischemic/reperfused hearts included interstitial edema, myofiber dege neration, and hypercontraction band formation. Ultrastructurally, swol len myofibrils, swollen mitochondria with disrupted cristae and electr on-dense deposits, myofibrillar lysis, and contraction bands, were obs erved. Light and electron microscopic severity scores were significant ly less (P < 0.05) in BMS-180448-treated hearts at the 25 min ischemic time point and in reperfused hearts, as compared to similarly-treated vehicle hearts, Conclusions: BMS-180448 ameliorates morphological evi dence of ischemia/reperfusion myocardial damage in the isolated rat he art model, in agreement with physiological and biochemical parameters.