Amelioration of ischemia/reperfusion injury in isolated rats hearts by the ATP-sensitive potassium channel opener BMS-180448.

Abstract

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.

• Authors: T M Monticello, C A Sargent, J R McGill, D S Barton, G J Grover
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 31 Issue 1 Pg. 93-101 (Jan 1996) ISSN: 0008-6363 [Print] England
• PMID: 8849593 (Publication Type: Journal Article)

Chemical References

• Benzopyrans
• Guanidines
• Potassium Channels
• BMS 180448

Topics

• Animals
• Benzopyrans (therapeutic use)
• Guanidines (therapeutic use)
• Male
• Microscopy, Electron
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Myocardium (pathology, ultrastructure)
• Perfusion
• Potassium Channels (drug effects)
• Rats
• Rats, Sprague-Dawley
• Time Factors