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

在经细胞色素P450(CP450)诱导剂处理的大鼠肺灌流中，对低氧或苯肾上腺素的升压反应显著减弱，而对血栓素类似物Kc1或U46619的升压反应不明显，而对乙酰胆碱的血管扩张反应增强。由于在离体肺动脉(PA)实验中这种作用不明显，CP450引起的肺血管张力改变似乎选择性地发生在阻力血管上。5，6-环二十碳三烯酸(5，6-EET)，一种花生四烯酸衍生的CP450环氧化物，以及白毒素(LX)，一种亚油酸衍生的CL450环氧化物，扩张的PA环被苯肾上腺素预先收缩，但环氧合酶抑制剂抵消了前者的血管扩张作用，而不是后者。此外，LX还可减弱对缺氧、Kc1和ET-1的升压反应。内皮剥离或加入EDRF抑制剂LNMMA可显著抑制LX的血管扩张作用，提示LX的血管扩张作用主要依赖于EDRF的释放。在培养的大鼠主动脉平滑肌实验中，LX还能扩张去氧肾上腺素或内皮素-1预先收缩的PA环，并能抑制内皮素-1或佛波酯刺激的大鼠主动脉对钙的摄取。由于钙通道阻滞剂(地尔硫卓或镍)不干扰LX的血管扩张作用，LX可增加细胞内钙离子的外流。最后，大剂量LX引起肺损伤，而LNMMA可抑制肺损伤，提示LX诱导的EDRF(NO)的大量释放导致了肺损伤。因此，CP450(代谢产物)具有调节肺血管张力的潜力。

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.