Amelioration of ischemia/reperfusion injury in isolated rats hearts by the ATP-sensitive potassium channel opener BMS-180448.
OBJECTIVE
Aims of this study were: (1) Evaluate by morphology and specific physiological and biochemical parameters, the protective effects of the cardioselective ATP-sensitive potassium channel opener BMS-180448 on ischemic/reperfused isolated rat heart, and (2) Determine the earliest time point ischemia-induced myocardial injury is observed by light microscopy.


METHODS
Hearts from Sprague-Dawley rats were perfused on a Langendorff apparatus. After equilibration, hearts were treated with BMS-180448 (10 micro M) or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. Four hearts/group were collected following 10, 18, or 25 min of ischemia. A nonischemic control group was also evaluated. 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 semi-quantitatively evaluated together with physiological (i.e., heart rate, left ventricular diastolic pressure, time to contracture formation) and biochemical (i.e., lactate dehydrogenase, LDH, release) endpoints.


RESULTS
Cardioprotective effects of BMS-180448 following ischemia/reperfusion consisted of a reduced rate of contracture formation, reduced LDH release, and enhanced recovery of contractile function during reperfusion (P < 0.05). Light microscopic evidence of myocardial damage was detected following 18 min of ischemia. Morphological changes in ischemic/reperfused hearts included interstitial edema, myofiber degeneration, and hypercontraction band formation. Ultrastructurally, swollen myofibrils, swollen mitochondria with disrupted cristae and electron-dense deposits, myofibrillar lysis, and contraction bands, were observed. Light and electron microscopic severity scores were significantly 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 evidence of ischemia/reperfusion myocardial damage in the isolated rat heart model, in agreement with physiological and biochemical parameters.
Monticello
T M
TM
Department of Experimental Pathology, The Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Sargent
C A
CA
McGill
J R
JR
Barton
D S
DS
Grover
G J
GJ
D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; C084684:BMS 180448