Protective effect of a novel thromboxane synthetase inhibitor, CV-4151, on myocardial damage due to coronary occlusion and reperfusion in the hearts of anesthetized dogs.
The protective effect of a novel thromboxane (TX) synthetase inhibitor, (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), on myocardial damage due to an ischemic episode and reperfusion was investigated in anesthetized, open-chested dogs. The left anterior descending coronary artery (LAD) was occluded for 60 min and subsequently reperfused for 60 min. CV-4151 was infused i.v. at a dose of 1 mg/kg over a 10-min period starting 20 min before the LAD occlusion. The agent had no acute hemodynamic effects. Within 30 min after LAD occlusion, 15.6-33.3% of dogs experienced ventricular fibrillation (VF); CV-4151 had no significant effect on the incidence of VF. After reperfusion, the frequency of ventricular extrasystoles (PVCs) was markedly increased, and 33.3% (9 of 27 dogs) died of VF in the control group. CV-4151 suppressed the exaggerated PVCs, and the incidence of VF in the group was 0% (0/18, p less than 0.05). Myocardial infarct size determined 60 min after reperfusion by a p-nitroblue tetrazolium (p-NBT) staining technique was significantly reduced by CV-4151. Increase in TXB2 release into the great coronary vein during reperfusion was completely inhibited by CV-4151, whereas release of 6-keto-PGF1 alpha tended to increase during occlusion and reperfusion. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was significantly increased throughout occlusion and reperfusion periods. These results suggest that inhibition of TXA2 synthesis is beneficial for protection of the myocardium during reperfusion from ischemic damage.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003097:Collateral Circulation; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000473:pathology*; D004285:Dogs; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000517:prevention & control
D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D011725:Pyridines; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; C045446:isbogrel