Reduced myocardial neutrophil accumulation and infarct size following thromboxane synthetase inhibitor or receptor antagonist.
Since thromboxane A2 (TXA2) release may relate to the extension of myocardial injury following coronary ligation, the authors examined the effects of pretreatment with a selective TXA2 synthetase inhibitor U-63,557A, or a TXA2 receptor antagonist SQ-29,548, on myocardial infarct size forty-eight hours following left coronary ligation in rats. Myocardial infarct size (as percent of left ventricle, LV) was decreased from 44 +/- 3% in saline-treated control animals to 34 +/- 4% (P less than 0.05) in U-63,557A-treated animals and to 32 +/- 4% (P less than 0.05) in SQ-29,548 treated animals (U-63,557A-treated vs SQ-29,548-treated, P = NS). LV creatine kinase (CK) was 5.08 +/- 0.42 IU/mg protein in noninfarcted untreated rats and 1.79 +/- 0.21 IU/mg protein in saline-treated infarcted rats. LV CK was 2.86 +/- 0.40 IU/mg protein in U-63,557A-treated rats and 3.11 +/- 0.51 IU/mg protein in SQ-29,548-treated infarcted rats (both P less than 0.05 compared with saline-treated rats). The beneficial effects of U-63,557A and of SQ-29,548 were not accompanied by reduction in indices of myocardial oxygen demand (heart rate and arterial pressure). However, neutrophil accumulation in the infarcted myocardium was markedly decreased by U-63,557A and SQ-29,548 pretreatment. Myocardial myeloperoxidase activity, a specific marker of neutrophil infiltration, was also decreased (P less than 0.02) in U-63,557A- and SQ-29,548-treated animals (0.09 +/- 0.03 and 0.07 +/- 0.02 units/100 mg, respectively) compared with saline-treated infarcted rats (0.19 +/- 0.04 units/100 mg). In vitro incubation of U-63,557A and SQ-29,548 caused a significant and similar reduction in f-MLP-induced neutrophil chemotaxis, and U-63,557A increased prostacyclin formation in whole blood. These data suggest that reduction in the extent of myocardial injury by TXA2 synthetase or receptor inhibitors may, in part, relate to a decrease in neutrophil accumulation in the infarcted tissue. In spite of differences in mechanisms of action of U-63,557A and SQ-29,548, both agents exert a similar protective effect on the extent of myocardial injury following coronary ligation. Reduction in neutrophil accumulation in the infarcted zone, as well as in f-MLP-directed chemotaxis in vitro, suggests that TXA2 inhibition may modulate neutrophil migration.
Nichols
W W
WW
Veterans Administration Medical Center, Gainesville, Florida.
Mehta
J
J
Wargovich
T J
TJ
Franzini
D
D
Lawson
D
D
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000201:enzymology / Q000473:pathology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D013929:Thromboxane B2; D013928:Thromboxane A2; C045749:SQ 29548; D011464:Epoprostenol; D009195:Peroxidase; D003402:Creatine Kinase; D013930:Thromboxane-A Synthase; C039936:furegrelate