Quilley J, Fulton D, McGiff J C
Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
Biochem Pharmacol. 1997 Nov 15;54(10):1059-70. doi: 10.1016/s0006-2952(97)00039-7.
There is now overwhelming evidence for factors, other than nitric oxide (NO), that mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle via activation of Ca2+-activated K+ channels. Although the identity of endothelium-derived hyperpolarizing factor (EDHF) remains to be established, cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA), namely, the epoxides, fulfill several of the criteria required for consideration as putative mediators of endothelium-dependent hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elicit vasorelaxation via stimulation of Ca2+-activated K+ channels. Our studies in the rat indicate that, of the epoxides, 5,6-epoxyeicosatrienoic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is unaffected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the expression of CYP-dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP-dependent vasodilator mechanism may serve as a backup to a primary NO-dependent mechanism, although they may act in concert. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to be important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium-dependent vasodilator responsiveness.
现在有大量证据表明，除一氧化氮（NO）外，还有其他因素可通过激活钙激活钾通道使下层平滑肌超极化，从而介导内皮依赖性血管舒张。尽管内皮源性超极化因子（EDHF）的身份尚待确定，但花生四烯酸（AA）的细胞色素P450（CYP）依赖性代谢产物，即环氧化物，符合作为内皮依赖性超极化假定介质所需的几个标准。它们由内皮产生，对血管活性激素作出反应而释放，并通过刺激钙激活钾通道引起血管舒张。我们在大鼠身上的研究表明，在环氧化物中，5,6 - 环氧二十碳三烯酸（5,6 - EET）最有可能是对缓激肽作出反应的非NO依赖性但CYP依赖性冠状动脉舒张的介质。然而，在大鼠肾脏中的研究支持存在其他EDHF，因为乙酰胆碱也表现出非NO依赖性血管舒张，这种舒张不受CYP抑制剂的影响，而CYP抑制剂在减弱对缓激肽反应的浓度下会起作用。在一些血管中，NO可能会持续抑制CYP依赖性EDHF的表达。因此，在NO合成受损的情况下，CYP依赖性血管舒张机制可能作为主要的NO依赖性机制的备用机制，尽管它们可能协同作用。在其他血管，特别是微血管中，EDHF可能构成激素和其他生理刺激的主要血管舒张机制。EDHF似乎是血管张力的重要调节因子；在高血压和糖尿病等与内皮依赖性血管舒张反应性改变相关的疾病中，可以证明该系统的改变。
