Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction

Abstract

Leukotrienes may be involved in hypoxic pulmonary vasoconstriction, since they are pulmonary vasoconstrictors and cells capable of producing leukotrienes are located in the lung near resistance vessels. Whether 3 structurally unrelated blockers [diethylcarbamazine citrate (DEC), U-60257 and FPL 55712 [7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid]] of leukotriene synthesis or action block hypoxic pulmonary vasconstriction was investigated in isolated perfused rat lungs. DEC blocked ongoing and subsequent hypoxic pressor responses while minimally affecting the angiotensin II pressor response. The inhibition of the hypoxic pressor response by DEC was not affected by cyclooxygenase or H1-receptor blockers. K-induced vasoconstriction, which is dependent on Ca entry, was largely blocked by verapamil but not by DEC, suggesting that DEC was not acting primarily as a Ca-entry blocker. U-60257 blocked the hypoxic pressor response without inhibiting the pressor response to angiotensin II or KCl. FPL 55712, a leukotriene end-organ blocker, in a dose which inhibited vasoconstriction caused by exogenous leukotriene C4, inhibited the pressor response to hypoxia but not to angiotensin II. Leukotriene inhibitors preferentially inhibit hypoxic pulmonary vasoconstriction in isolated perfused adult rat lungs.