title: Reduced myocardial neutrophil accumulation and infarct size following thromboxane synthetase inhibitor or receptor antagonist.
abstract: 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.
authors.affiliation: Veterans Administration Medical Center, Gainesville, Florida.
authors.forename: W W
authors.initials: WW
authors.lastname: Nichols
authors.forename: J
authors.initials: J
authors.lastname: Mehta
authors.forename: T J
authors.initials: TJ
authors.lastname: Wargovich
authors.forename: D
authors.initials: D
authors.lastname: Franzini
authors.forename: D
authors.initials: D
authors.lastname: Lawson
mesh_terms: 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*
chemical_list: 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