Fulton D, Quilley J
Department of Pharmacology and Molecular Cardiobiology Division, Boyer Center for Molecular Medicine, Yale University, New Haven, Connecticut, USA.
J Pharmacol Exp Ther. 1998 Sep;286(3):1146-51.
The mediator of nitric oxide-(NO) independent vasodilation attributed to endothelium-derived hyperpolarizing factor remains unidentified although there is evidence for a cytochrome P450-derived eicosanoid. Anandamide, the ethanolamide of arachidonic acid and an endogenous ligand for cannabinoid receptors, was proposed as an endothelium-derived hyperpolarizing factor-mediating mesenteric vasodilation to acetylcholine and the hypotensive effect of bradykinin. Using pharmacological interventions that attenuate responses to bradykinin, we examined the possibility of anandamide as a mediator of the NO-independent vasodilator effect of bradykinin in the rat perfused heart by determining responses to anandamide and arachidonic acid. Hearts were treated with indomethacin to exclude prostaglandins and nitroarginine to inhibit NO synthesis and elevate perfusion pressure. The cannabinoid receptor antagonist, SR 141716A (2 microM), reduced dose-dependent vasodilator responses to anandamide (1-10 microgram) but was without effect on responses to AA (1-10 microgram), bradykinin (10-1000 ng) or cromakalim (1-10 microgram). Inhibition of voltage-dependent Ca++ channels with nifedipine (5 nM) attenuated vasodilation to anandamide and arachidonic acid whereas inhibition of Ca++-activated K+ channels with charybdotoxin (10 nM) reduced responses to arachidonic acid but had no effect on vasodilation induced by anandamide. Inhibition of cytochrome P450 with clotrimazole (1 microM) greatly reduced vasodilator responses to bradykinin with less effect on those to anandamide. Finally, the time course of the coronary vasodilator responses to anandamide and bradykinin were dissimilar. These results argue against a role of anandamide in the vasodilator effect of bradykinin in the rat heart.
尽管有证据表明细胞色素P450衍生的类花生酸参与其中，但一氧化氮（NO）非依赖性血管舒张的介质，即内皮衍生超极化因子（endothelium-derived hyperpolarizing factor, EDHF）仍未明确。花生四烯酸乙醇胺（anandamide），作为花生四烯酸的乙醇酰胺以及大麻素受体的内源性配体，被认为是介导肠系膜血管舒张以应对乙酰胆碱以及介导缓激肽降压作用的内皮衍生超极化因子。通过使用减弱对缓激肽反应的药理学干预措施，我们通过测定对花生四烯酸乙醇胺和花生四烯酸的反应，研究了花生四烯酸乙醇胺作为缓激肽在大鼠灌注心脏中NO非依赖性血管舒张作用介质的可能性。心脏用吲哚美辛处理以排除前列腺素的影响，并用硝基精氨酸抑制NO合成并提高灌注压力。大麻素受体拮抗剂SR 141716A（2 microM）可降低对花生四烯酸乙醇胺（1 - 10微克）的剂量依赖性血管舒张反应，但对花生四烯酸（1 - 10微克）、缓激肽（10 - 1000纳克）或克罗卡林（1 - 10微克）的反应无影响。用硝苯地平（5 nM）抑制电压依赖性Ca++通道可减弱对花生四烯酸乙醇胺和花生四烯酸的血管舒张作用，而用蝎毒素（10 nM）抑制Ca++激活的K+通道可降低对花生四烯酸的反应，但对花生四烯酸乙醇胺诱导的血管舒张无影响。用克霉唑（1 microM）抑制细胞色素P450可大大降低对缓激肽的血管舒张反应，而对花生四烯酸乙醇胺的反应影响较小。最后，冠状动脉对花生四烯酸乙醇胺和缓激肽的血管舒张反应的时间进程不同。这些结果表明花生四烯酸乙醇胺在大鼠心脏缓激肽的血管舒张作用中不起作用。
