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.
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.
Adameová
Adriana
A
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovak Republic. adameova@fpharm.uniba.sk
Ravingerová
Tána
T
Svec
Pavel
P
Faberová
Viera
V
Kuzelová
Magdaléna
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D002994:Clofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000889:Anti-Arrhythmia Agents; D002791:Cholesterol, Dietary; D000960:Hypolipidemic Agents; C505646:VULM 1457; D002785:Sterol O-Acyltransferase; D002994:Clofibrate