Protective effect of a novel thromboxane antagonist, BAY-U3405, on canine myocardial damage after coronary artery occlusion and reperfusion.
The effects of a novel thromboxane antagonist, (3R)-3-(4-fluorophenylsulfonmido)-1,2,3,4-tetrahydro-9-carbazol epropanoic acid (BAY-U3405), on myocardial damage due to ischemia and reperfusion (added to accelerate the initiated injury) were studied in anesthetized dogs. The left anterior descending (LAD) coronary artery was occluded for 6 hours and reperfused for 30 minutes. BAY-U3405, 1 mg/kg, was injected intravenously 15 minutes after LAD occlusion, followed by continuous infusion of 10 mg/kg/hour starting at 30 minutes after occlusion. The drug had no hemodynamic effects. During the experiments 6 of 14 animals died of ventricular fibrillation (VF) in the placebo-vehicle controls (3 during occlusion and 3 during reperfusion); in the drug-treated group 5 of 13 dogs died of VF (all during occlusion none during reperfusion). This difference in total mortality and cause was not statistically significant. Reperfusion arrhythmias were largely suppressed by BAY-U3405: 201 +/- 43 versus 689 +/- 98 irregular beats during 30 minutes (p less than 0.001) in the experimental and control groups, respectively. Coronary collateral flow, obtained from a load-line analysis by measurement of retrograde coronary flow, and collateral index were similar in both groups. Therefore, BAY-U3405 did not alter collateral blood supply to the ischemic myocardium. Infarct size, determined with tetrazolium staining, was reduced by 65% (p less than 0.01) after its administration. These results suggest that thromboxane antagonism by BAY-U3405 may delay infarct expansion and reduce the frequency of ventricular arrhythmias during reperfusion of previously ischemic myocardium.
Fiedler
V B
VB
Department of Pharmacology, Pharma Research Center, Bayer AG, Wuppertal, Germany.
Perzborn
E
E
Seuter
F
F
D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000503:physiopathology
D002227:Carbazoles; D013449:Sulfonamides; D013931:Thromboxanes; C063119:ramatroban