PLATELETS, NEUTROPHILS, AND VASOCONSTRICTION AFTER ARTERIAL INJURY BYANGIOPLASTY IN PIGS - EFFECTS OF MK-886, A LEUKOTRIENE BIOSYNTHESIS INHIBITOR

1 Leukotrienes constitute a class of potent bioactive mediators known to play a pivotal role in inflammation. Since their biosynthesis has b een shown to be enhanced by platelet-neutrophil interactions, leukotri enes may be involved in these interactions and the arterial response t o injury. Therefore, we investigated the effects of the selective leuk otriene biosynthesis inhibitor lthio-5-isopropylindol-2-yl]-2,2-dimeth ylpropanoic acid (MK-886) on the acute thrombo tic and vasomotor respo nses after arterial injury by angioplasty. 2 Carotid arterial injury w as produced by balloon dilatation in control (molecusol vehicle; n = 1 0) and treated (MK-886, 10 mg kg(-1), i.v.; n = 9) pigs. The acute thr ombotic reaction following deep arterial wall injury was quantified wi th Cr-51 labelled platelets and In-111 labelled neutrophils, and the v asomotor response was determined angiographically. 3 Platelet depositi on at the site of deep arterial wall injury averaged 56.4 +/- 11.0 x 1 0(6) platelets cm(-2) in the control group, and was significantly redu ced to 18.2 +/- 3.8 x 10(6) platelets cm(-2) (P < 0.005) by treatment with MK-886. Neutrophil deposition was also decreased by MK-886, from 242.8 +/- 36.8 to 120.9 +/- 20.3 x 10(3) neutrophils cm(-2) (P < 0.01) . MK-886-treated animals had a significant decrease in the postangiopl asty vasoconstrictive response at the site of endothelial injury dista lly, from 37.5 +/- 3.1% in the control group to 13.5 +/- 2.5% (P < 0.0 01). 4 The effects of MK-886 were associated with a profound inhibitio n of ex vivo leukotriene B-4 (LTB4) synthesis in blood stimulated by t he calcium ionophore A23187 and a significant reduction of neutrophil aggregation in whole blood (P < 0.01), whereas neutrophil superoxide a nion production, serum thromboxane B-2 and platelet aggregation in who le blood were not influenced. 5 The relevant effects of MK-886 are pri marily related to inhibition of neutrophil function and suggest an imp ortant modulatory role for leukotrienes in the pathophysiological resp onse associated with platelet and neutrophil interactions following ar terial injury in vivo.