Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R
Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Circulation. 1996 Dec 15;94(12):3341-7. doi: 10.1161/01.cir.94.12.3341.
The contribution of the endothelium-derived hyperpolarizing factor (EDHF), proposed to be a cytochrome P450-derived metabolite of arachidonic acid, to endothelium-dependent dilatation under physiological conditions has yet to be established, because its effect can be detected only after inhibition of NO synthase and cyclooxygenase. The possibility that NO exerts a feedback inhibition on EDHF formation was studied in isolated perfused arterial segments.
Under combined blockade of NO synthase and cyclooxygenase, the EDHF-mediated vasodilatation elicited by receptor-dependent agonists in rabbit carotid and porcine coronary arteries was significantly attenuated by the NO donors C87-3786 and CAS 1609. The endothelium-independent dilatation elicited by isoproterenol was not altered by either NO donor. In NG-nitro-L-arginine-treated carotid artery segments, C87-3786 significantly attenuated the acetylcholine-induced increase in 6-keto-prostaglandin F1 alpha release, which was taken as an index of arachidonic acid liberation. In parallel experiments using cultured human endothelial cells, C87-3786 attenuated the Ca2+ response to bradykinin. The release of EDHF from a luminally perfused porcine coronary artery was detected by recording the membrane potential of downstream-situated cultured rat aortic smooth muscle cells. The NO donor C87-3786 had no effect on the hyperpolarization elicited by preformed EDHF but markedly inhibited its release from bradykinin-stimulated donor segments.
These findings indicate that under physiological conditions, the production of EDHF is damped by NO. Therefore, it follows that when NO synthesis is impaired, alleviation of this intrinsic inhibition may, at least in part, maintain endothelial vasodilator function.
内皮衍生超极化因子（EDHF）被认为是花生四烯酸的细胞色素P450衍生代谢产物，其在生理条件下对内皮依赖性舒张的作用尚未明确，因为只有在抑制一氧化氮合酶和环氧化酶后才能检测到其作用。在离体灌注动脉段中研究了一氧化氮对EDHF形成的反馈抑制可能性。
在一氧化氮合酶和环氧化酶联合阻断的情况下，一氧化氮供体C87-3786和CAS 1609可显著减弱受体依赖性激动剂在兔颈动脉和猪冠状动脉中引发的EDHF介导的血管舒张。异丙肾上腺素引发的非内皮依赖性舒张不受任何一种一氧化氮供体的影响。在经N-硝基-L-精氨酸处理的颈动脉段中，C87-3786可显著减弱乙酰胆碱诱导的6-酮-前列腺素F1α释放增加，该释放增加被视为花生四烯酸释放的指标。在使用培养的人内皮细胞的平行实验中，C87-3786减弱了对缓激肽的Ca2+反应。通过记录下游培养的大鼠主动脉平滑肌细胞的膜电位来检测从管腔灌注的猪冠状动脉中释放的EDHF。一氧化氮供体C87-3786对预先形成的EDHF引起的超极化没有影响，但显著抑制其从缓激肽刺激的供体段中的释放。
这些发现表明，在生理条件下，一氧化氮会抑制EDHF的产生。因此，可以推断，当一氧化氮合成受损时，减轻这种内在抑制可能至少部分维持内皮舒张功能。
