Reduced Myocardial Neutrophil Accumulation and Infarct Size Following Thromboxane Synthetase Inhibitor or Receptor Antagonist

Abstract

Since thromboxane A₂ (TXA₂) re lease may relate to the extension of myocardial injury following coro nary ligation, the authors examined the effects of pretreatment with a se lective TXA ₂ synthetase inhibitor U- 63,557A, or a TXA₂ receptor anta gonist SQ-29,548, on myocardial in farct 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 con trol animals to 34±4% (P < 0.05) in U-63,557A-treated animals and to 32±4% (P < 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 un treated 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 < 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 in dices of myocardial oxygen demand (heart rate and arterial pressure). However, neutrophil accumulation in the infarcted myocardium was mark edly decreased by U-63,557A and SQ-29,548 pretreatment. Myocardial myeloperoxidase activity, a specific marker of neutrophil infiltration, was also decreased (P < 0.02) in U- 63,557A- and SQ-29,548-treated ani mals (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 simi lar reduction in f-MLP-induced neu trophil 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 recep tor inhibitors may, in part, relate to a decrease in neutrophil accumulation in the infarcted tissue. In spite of dif ferences in mechanisms of action of U-63,557A and SQ-29,548, both agents exert a similar protective ef fect on the extent of myocardial in jury following coronary ligation. Reduction in neutrophil accumula tion in the infarcted zone, as well as in f-MLP-directed chemotaxis in vi tro, suggests that TXA₂ inhibition may modulate neutrophil migration.