Reduction of myocardial damage and polymorphonuclear leukocyte accumulation following coronary artery occlusion and reperfusion by the thromboxane receptor antagonist BM 13.505.
This study was designed to assess the effect of the thromboxane receptor antagonist, BM 13.505, in limiting myocardial damage and polymorphonuclear leukocyte accumulation in rats subjected to coronary artery occlusion for 30 min with reperfusion for 24 h (MI/R). Myocardial injury and polymorphonuclear leukocyte infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the left ventricular free wall (LVFW). Myocardial CPK levels were 8.24 +/- 0.33 U/mg protein in sham MI/R-vehicle-treated animals (n = 18), and were significantly decreased to 6.51 +/- 0.44 U/mg protein in MI/R-vehicle animals (n = 22). Myocardial MPO values were 2.4 +/- 0.5 U/g LVFW in sham MI/R animals, and significantly increased to 10.9 +/- 1.3 U/g LVFW in MI/R-vehicle animals. Administration of BM 13.505 (30 mg/kg, i.p.) 1 min prior to coronary occlusion resulted in CPK values of 7.83 +/- 0.45 U/mg protein and MPO levels of 6.1 +/- 0.9 U/g LVFW (p less than 0.05, compared to the MI/R-vehicle group). The survival rate in the MI/R-BM 13.505 group was 74 and 65% at 2 and 24 h, respectively, and was not different from the MI/R-vehicle group. There were no significant differences in mean arterial blood pressure or heart rate between the MI/R-vehicle and MI/R-BM 13.505 groups, indicating that changes in myocardial oxygen demand do not explain the protective effects. A lower dose did not reduce myocardial injury, indicating that the effects of BM 13.505 were dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
E F
EF
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406.
Griswold
D E
DE
Egan
J W
JW
Hillegass
L M
LM
DiMartino
M J
MJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003402:Creatine Kinase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D010648:Phenylacetates; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D013931:Thromboxanes; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D009195:Peroxidase; D003402:Creatine Kinase; C051762:daltroban