Leukotriene antagonists attenuate thromboxane-inducible pulmonary hypertension

Abstract

Leukotrienes C4 and D4 and thromboxane A2 are potent vasoconstrictors that may mediate pulmonary vasoconstriction in many clinical situations. There is a complex interaction among leukotrienes and thromboxane A2, because inhibition of thromboxane synthesis prevents some of the hemodynamic effects of exogenous leukotrienes. Similarly, if leukotrienes mediate thromboxane A2-induced pulmonary vasoconstriction, then leukotriene antagonists should attenuate the effects of a thromboxane A2-mimetic such as U46619. First, dose response curves for the hemodynamic effects of U46619 were performed on seven spontaneously breathing newborn lambs. Then a putative leukotriene receptor antagonist, FPL57231,1 mg/ kg/min, or a putative leukotriene synthesis antagonist, U60257, 30 mg/kg, was given before infusing U46619 (1 μg/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p < 0.05) and significant dose-dependent decreases in cardiac output and heart rate (p < 0.05). A 1 μg/kg/min infusion of U46619 increased pulmonary arterial pressure by 155.4% ± 8.9 and systemic arterial pressure by 8.9% ± 7.7 and decreased cardiac output by 19.7% ± 12.2 and heart rate by 9.9% ± 10.6. FPL57231 attenuated the effects of U46619. U60257 had similar effects. Therefore, the hemodynamic effects of thromboxane A2, an important mediator of the pulmonary vasoconstriction produced, for example, by group B streptococci and Escherichia coli, may be mediated by the secondary production of leukotrienes. © 1989 International Pediatric Research Foundation, Inc.