BM 13.505, a selective thromboxane receptor antagonist, reduces myocardial infarct size following coronary artery reperfusion.
This study was designed to assess the effectiveness of the thromboxane receptor antagonist, BM 13.505, in limiting myocardial infarct size in rats subjected to 30 min of coronary artery occlusion followed by reperfusion for 5.5 hr (MI/R). Myocardial infarct size was determined histochemically with triphenyltetrazolium chloride staining of the left ventricle. BM 13.505 (30 mg/kg, i.p.) was administered 1 min prior to coronary artery occlusion. In MI/R-vehicle treated animals, myocardial infarct size was 39 +/- 6% of the left ventricle. In MI/R-BM 13.505 treated animals, reperfusion injury was reduced by 50% to 19 +/- 7% of the left ventricle (p less than 0.05, compared to the MI/R-vehicle group). There were no significant differences in mean arterial blood pressure, heart rate, platelet count or white blood cell count between the treatment groups. Incubation of cultured L929 cells with the thromboxane/endoperoxide mimetic U 46619 produced a cytolytic effect, with an EC50 value of 125 microM. Addition of BM 13.505 at concentrations up to 30 microM did not protect against the cytolytic effect of U 46619, suggesting a non-receptor-mediated mechanism. These data indicate that hemodynamic, hematologic or cytoprotective factors do not explain the cardioprotective effects of BM 13.505. These results provide further evidence that antagonism of thromboxane receptors is beneficial in myocardial ischemia/reperfusion injury.
Smith
E F
EF
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406.
Earl
C Q
CQ
Egan
J W
JW
D000818:Animals; D002478:Cells, Cultured; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015425:Myocardial Reperfusion; D010648:Phenylacetates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D010648:Phenylacetates; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; C051762:daltroban