The effect of cytochrome P450 (metabolites) on pulmonary vascular tone

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In isolated perfused lungs from rats treated with cytochrome P450 (CP450) inducer, pulmonary arterial pressor response to hypoxia or phenylephrine but not KC1 or U46619, a thromboxane mimic, was attenuated significantly and vasodilatory response to acetylcholine was augmented. Because such effects were never obvious in the case of isolated pulmonary arterial (PA) experiment, CP450 induced modification of pulmonary vascular tone seemed to occur selectively at the resistance vessel. A 5,6 epoxyeicosatrienoic acid (5,6 EET), an arachidonate derived CP450 epoxide, and leukotoxin (Lx), a linoleate derived CL450 epoxide dilated PA ring preconstricted with phenylephrine, though cyclooxygenase inhibitor offset the vasodilatory effect due to the former but not that of the latter. Further, Lx attenuated the pressor response to hypoxia, KC1 and endothelin 1. Vasodilatory effect of Lx was largely inhibited by the endothelium denudation or addition of LNMMA, an EDRF inhibitor, suggesting that major part of Lx-induced vasodilation depend on EDRF release. Lx also dilated denuded PA ring precontracted with phenylephrine or endothelin 1 and inhibited ^<45>Ca^<2+> up take in cultured rat aortic smooth muscle experiment stimulated with endothelin 1 or phorbol myristate acetate. Since Ca channel blocker (Diltiazem or nickel) did not interfere the vasodilatory effect of Lx, Lx may augment Ca^<2+> eflux from the cell. Finally, large dose of Lx caused lung injury which was suppressed by the pretreatment of LNMMA, suggesting that Lx-induced massive release of EDRF (NO) caused lung injury. Thus, CP450 (methabolites) have a potential of modulation of pulmonary vascular tone.