Leukotriene antagonists attenuate thromboxane-inducible pulmonary hypertension.
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 microgram/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p less than 0.05) and significant dose-dependent decreases in cardiac output and heart rate (p less than 0.05). A 1 microgram/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.
Soifer
S J
SJ
Cardiovascular Research Institute, University of California, San Francisco 94143.
Schreiber
M D
MD
Heymann
M A
MA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology; D016859:Lipoxygenase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors*; D012756:Sheep; D013928:Thromboxane A2 / Q000494:pharmacology*
D002867:Chromones; D016859:Lipoxygenase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D013189:SRS-A; D013928:Thromboxane A2; C034338:FPL 57231; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; C035296:piriprost