Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London, UK.
Br J Pharmacol. 2010 Jun;160(3):594-603. doi: 10.1111/j.1476-5381.2009.00622.x. Epub 2010 Feb 5.
N-arachidonoyl glycine (NAGly) is an endogenous lipid that is structurally similar to the endocannabinoid, N-arachidonoyl ethanolamide (anandamide). While NAGly does not activate cannabinoid receptors, it exerts cannabimimetic effects in pain regulation. Here, we have determined if NAGly, like anandamide, modulates vascular tone.
In rat isolated small mesenteric arteries, the relaxant responses to NAGly were characterized. Effects of N-arachidonoyl serine and N-arachidonoyl gamma-aminobutyric acid were also examined.
In endothelium-intact arteries, NAGly-induced relaxation (pEC(50%)= 5.7 +/- 0.2; relaxation at 30 microM = 98 +/- 1%) was attenuated by l-NAME (a nitric oxide synthase inhibitor) or iberiotoxin [selective blocker of large conductance Ca(2+)-activated K(+) channels (BK(Ca))], and abolished by high extracellular K(+) concentration. Endothelial removal reduced the potency of NAGly, and the resultant relaxation was inhibited by iberiotoxin, but not l-NAME. NAGly responses were sensitive to the novel cannabinoid receptor antagonist O-1918 independently of endothelial integrity, whereas pertussis toxin, which uncouples G(i/o) proteins, attenuated NAGly relaxation only in endothelium-intact arteries. Treatments with antagonists for CB(1), CB(2) and TRPV1 receptors, or inhibitors of fatty acid amide hydrolase and COX had no effect. The two other arachidonoyl amino acids also induced iberiotoxin- and L-NAME-sensitive relaxations.
NAGly acts as a vasorelaxant predominantly via activation of BK(Ca) in rat small mesenteric arteries. We suggest that NAGly activates an unknown G(i/o)-coupled receptor, stimulating endothelial release of nitric oxide which in turn activates BK(Ca) in the smooth muscle. In addition, NAGly might also activate BK(Ca) through G(i/o)- and nitric oxide-independent mechanisms.
N-花生四烯酰甘氨酸（NAGly）是一种内源性脂质，其结构与内源性大麻素 N-花生四烯酰乙醇胺（大麻素）相似。虽然 NAGly 不能激活大麻素受体，但它在疼痛调节中发挥大麻样作用。在这里，我们确定 NAGly 是否像大麻素一样调节血管张力。
在大鼠分离的小肠系膜动脉中，研究了 NAGly 的舒张反应。还研究了 N-花生四烯酰丝氨酸和 N-花生四烯酰γ-氨基丁酸的作用。
在内皮完整的动脉中，NAGly 诱导的舒张（pEC（50％）= 5.7 +/- 0.2; 30 microM 时的舒张率为 98 +/- 1％）被 l-NAME（一氧化氮合酶抑制剂）或 iberiotoxin [选择性阻断大电导钙激活钾（BK（Ca））通道] 减弱，并被高细胞外钾浓度消除。内皮去除降低了 NAGly 的效力，并且由此产生的舒张被 iberiotoxin 抑制，但不受 l-NAME 抑制。NAGly 反应对新型大麻素受体拮抗剂 O-1918 敏感，而不依赖内皮完整性，而百日咳毒素（可使 G(i/o)蛋白解耦联）仅在完整内皮的动脉中减弱 NAGly 舒张。用 CB（1）、CB（2）和 TRPV1 受体拮抗剂、脂肪酸酰胺水解酶和 COX 抑制剂处理没有效果。另外两种花生四烯酰氨基酸也诱导了 iberiotoxin 和 L-NAME 敏感的舒张。
NAGly 主要通过激活大鼠小肠系膜动脉中的 BK（Ca）作为血管舒张剂。我们认为，NAGly 激活一种未知的 G(i/o)偶联受体，刺激内皮释放一氧化氮，进而在平滑肌中激活 BK(Ca)。此外，NAGly 可能还通过 G(i/o)和一氧化氮非依赖性机制激活 BK(Ca)。
