vulm-1457 and Hypercholesterolemia

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.

Topics: Animals; Anti-Arrhythmia Agents; Cholesterol, Dietary; Clofibrate; Diabetes Mellitus, Experimental; Hypercholesterolemia; Hypolipidemic Agents; Male; Myocardial Infarction; Rats; Rats, Wistar; Reperfusion Injury; Sterol O-Acyltransferase

This study examined the effects of simvastatin (10 mg/ kg) and VULM 1457 (50 mg/kg), an ACAT inhibitor, in the heart model of 6 min ischemia followed by 10 min reperfusion injury in the diabetic-hypercholesterolaemic (DM-HCH) rats. In the DM-HCH rats, the incidence of ventricular tachycardia (VT) had a tendency to be increased, while ventricular fibrillation (VF) occurred in all diseased rats (p < 0.01). Simvastatin and VULM 1457 with the shown hypolipidemic effect, significantly (p < 0.01) suppressed a formation of VF (38% and 29%; respectively).

Topics: Animals; Arrhythmias, Cardiac; Blood Glucose; Cholesterol; Cholesterol, Dietary; Clofibrate; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Reperfusion Injury; Simvastatin; Sterol O-Acyltransferase

The use of inhibitors of enzyme acyl-CoA: cholesterol acyltransferase (ACAT) seems to be a novel potential approach for a therapeutic treatment of dyslipidaemias and atherosclerosis. VULM 1457 is an ACAT inhibitor, which has expressed potent hypolipidemic and antiatherosclerotic effects in previous studies. In this study, we used streptozocin-induced diabetic rats, which were fed a fat-cholesterol diet to evaluate the affect of VULM 1457 on the atherogenic lipids levels in both plasma and liver. VULM 1457, with a slight influence on triglyceride levels, significantly reduced plasma and hepatic cholesterol concentrations (p < 0.05, p < 0.001; respectively) in the diabetic-hypercholesterolaemic rats.

Topics: Animals; Blood Glucose; Cholesterol; Cholesterol, Dietary; Clofibrate; Diabetes Mellitus, Experimental; Dietary Fats; Enzyme Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Liver; Rats; Rats, Wistar; Sterol O-Acyltransferase; Triglycerides