Arachidonic acid-induced endothelial-dependent relaxations of canine coronary arteries: contribution of a cytochrome P-450-dependent pathway.
Arachidonic acid-induced endothelial-dependent relaxations of canine coronary arteries: contribution of a cytochrome P-450-dependent pathway.
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发表时间：
1987-03
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通讯作者：
A. Pinto;N. Abraham;K. Mullane
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作者：
A. Pinto;N. Abraham;K. Mullane
花生四烯酸(AA，10(-8)-5×10(-6)M)对用地诺前列素预收缩的犬冠状动脉环具有剂量依赖性的松弛作用，在内皮完整的情况下，这种松弛作用显著大于(P<0.001)。用消炎痛抑制环氧合酶使AA的剂量-反应曲线右移，但不能阻止脂肪酸的松弛作用。细胞色素P-450依赖的酶的抑制剂SKF-525A也减弱了对AA的反应，尽管SKF-525A和吲哚美辛的组合阻止了任何松弛作用。3-甲基胆蒽和β-萘黄酮体内注射(40 mg/kg/d，连用3天)或用氯化钴(24 mg/kg/d，连用2天)阻断细胞色素P-450依赖酶，可分别增强或减弱AA诱导的内皮依赖松弛作用。这些结果表明，犬冠状动脉对AA的内皮依赖性松弛过程中存在一种依赖于细胞色素P-450的混合功能氧化酶。与地诺前列素相比，U46619的冠脉预收缩不能表现出对AA的内皮依赖性松弛，而对缓激肽和乙酰胆碱的反应也部分减弱。通过环氧合酶和细胞色素P-450依赖的单加氧酶对AA代谢的药物调控表明，缓激肽诱导的内皮依赖性松弛部分依赖于AA的代谢物，而乙酰胆碱产生的松弛不依赖于AA代谢物，提示内皮可能释放了一些潜在的松弛因子。
Arachidonic acid (AA, 10(-8)-5 X 10(-6) M) induced dose-dependent relaxations of canine coronary arterial rings precontracted with dinoprost that were significantly greater (P less than .001) if the endothelium was intact. Cyclooxygenase inhibition with indomethacin displaced the dose-response curve to AA to the right but did not prevent the relaxant effects of the fatty acid. SKF-525A, an inhibitor of cytochrome P-450-dependent enzymes, also attenuated the response to AA although the combination of SKF-525A and indomethacin prevented any relaxant effect. Induction of cytochrome P-450-dependent enzymes in the coronary artery with 3-methylcholanthrene and beta-naphthoflavone given in vivo (40 mg/kg/day for 3 days) or depletion of these enzymes with cobalt chloride (24 mg/kg/day for 2 days) resulted in an enhancement or diminution, respectively, of AA-induced endothelial-dependent relaxations. These results implicate a cytochrome P-450-dependent mixed function oxidase in the endothelial-dependent relaxations to AA in the canine coronary artery. Precontraction of coronary arteries with U46619 in contrast to dinoprost failed to display endothelial-dependent relaxations to AA, whereas the responses to bradykinin and acetylcholine were also partially attenuated. Pharmacologic manipulations of AA metabolism via cyclooxygenase and cytochrome P-450-dependent monooxygenases indicate that the endothelial-dependent relaxations induced by bradykinin are partially dependent upon metabolites of AA, whereas the relaxations produced by acetylcholine are independent of AA metabolites, suggesting that a number of potential relaxing factors may be released from the endothelium.