BM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis.
The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A2 receptor antagonist and thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals (n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 +/- 2.2 and 36.9 +/- 2.1% of the left ventricular mass, respectively. In the BM-573-treated group (n = 6), a drug infusion (10 mg. kg-1. h-1) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction.
Rolin
S
S
Department of Pharmacy, University of Namur, 61, rue de Bruxelles, 5000 Namur, Belgium.
Petein
M
M
Tchana-Sato
V
V
Dogne
J M
JM
Benoit
P
P
Lambermont
B
B
Ghuysen
A
A
Kolh
P
P
Masereel
B
B
D000818:Animals; D003328:Coronary Thrombosis / Q000150:complications*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D013552:Swine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D013930:Thromboxane-A Synthase