The myocardial infarct size-limiting and antiarrhythmic effects of acyl-CoA:Cholesterol acyltransferase inhibitor VULM 1457 protect the hearts of diabetic–hypercholesterolaemic rats against ischaemia/reperfusion injury both in vitro and in vivo

Abstract

The study was designed to characterise the influence of a novel acyl-CoA:cholesterol acyltransferase inhibitor, VULM 1457, on the severity of myocardial ischaemia–reperfusion injury in a model of diabetes mellitus and hypercholesterolaemia induced by co-administration of streptozotocin and a high fat-cholesterol diet. We used Langendorff-perfused rat hearts to measure the size of myocardial infarction after 30 min of regional ischaemia, followed by a 2-h reperfusion period, and open-chest rats were exposed to 6 min of ischaemia and 10 min of reperfusion to analyse ventricular arrhythmias. In addition to the high fat-cholesterol diet, VULM 1457 was administered to the diabetic–hypercholesterolaemic rats for 5 days. Decreased plasma and liver cholesterol levels and a significantly reduced occurrence of ventricular fibrillation (29% vs. 100%, P < 0.01), determined via the mean number and duration of episodes (0.6 ± 0.4 and 2.1 ± 1.4 s vs. 2.8 ± 0.8 and 53.5 ± 14.4 s in diabetic–hypercholesterolaemic rats, both P < 0.01), were observed in these animals. Lethal ventricular fibrillation was suppressed, and arrhythmia severity was also significantly decreased in these animals as compared to the non-treated animals (2.9 ± 0.6 vs. 4.9 ± 0.2; P < 0.05). A smaller infarct size, normalised to the size of area at risk, was observed in the treated diabetic–hypercholesterolaemic group as compared to the non-treated group (16.3 ± 1.9% vs. 37.3 ± 3.1%; P < 0.01). Aside from remarkable hypolipidaemic activity, VULM 1457 improved the overall myocardial ischaemia–reperfusion injury outcomes in the diabetic–hypercholesterolaemic rats by suppressing arrhythmogenesis as well as by reducing myocardial necrosis.