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.

• Authors: Adriana Adameová, Tána Ravingerová, Pavel Svec, Viera Faberová, Magdaléna Kuzelová
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 576 Issue 1-3 Pg. 114-21 (Dec 08 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17764671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Cholesterol, Dietary
• Hypolipidemic Agents
• VULM 1457
• Sterol O-Acyltransferase
• Clofibrate

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Cholesterol, Dietary (administration & dosage)
• Clofibrate (analogs & derivatives, pharmacology)
• Diabetes Mellitus, Experimental (complications, drug therapy, physiopathology)
• Hypercholesterolemia (complications, drug therapy, etiology, physiopathology)
• Hypolipidemic Agents (pharmacology)
• Male
• Myocardial Infarction (drug therapy, etiology, physiopathology)
• Rats
• Rats, Wistar
• Reperfusion Injury (prevention & control)
• Sterol O-Acyltransferase (antagonists & inhibitors)