Sugiyama Tetsuhiro, Hatanaka Yukako, Iwatani Yukiko, Jin Xin, Kawasaki Hiromu
Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
J Pharmacol Sci. 2008 Mar;106(3):505-11. doi: 10.1254/jphs.fp0072259. Epub 2008 Mar 12.
Lafutidine is a histamine H(2)-receptor antagonist with gastric antisecretory and gastroprotective activity associated with activation of capsaicin-sensitive nerves. The present study examined the effect of lafutidine on neurotransmission of capsaicin-sensitive calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRPergic nerves) in rat mesenteric resistance arteries. Rat mesenteric vascular beds were perfused with Krebs solution and vascular endothelium was removed by 30-s perfusion with sodium deoxycholate. In preparations preconstricted by continuous perfusion of methoxamine (alpha(1) adrenoceptor agonist), perfusion of lafutidine (0.1 - 10 microM) concentration-dependently augmented vasodilation induced by the periarterial nerve stimulation (PNS, 1 Hz) without affecting vasodilation induced by exogenous CGRP (10 pmol) injection. Perfusion of famotidine (H(2)-receptor antagonist, 1 - 100 microM) had no effect on either PNS-induced or CGRP-induced vasodilation. Perfusion of lafutidine concentration-dependently augmented vasodilation induced by a bolus injection of capsaicin (vanilloid-1 receptor agonist, 30 pmol). The presence of a vanilloid-1 receptor antagonist, ruthenium red (10 microM) or capsazepine (5 microM), abolished capsaicin-induced vasodilation and significantly decreased the PNS-induced vasodilation. The decreased PNS-induced vasodilation by ruthenium red or capsazepine was not affected by perfusion of lafutidine. These results suggest that lafutidine facilitates CGRP nerve-mediated vasodilation by modulating the function of presynaptic vanilloid-1 receptors located in CGRPergic nerves.
拉呋替丁是一种组胺H(2)受体拮抗剂，具有胃抗分泌和胃保护活性，与辣椒素敏感神经的激活有关。本研究检测了拉呋替丁对大鼠肠系膜阻力动脉中辣椒素敏感的含降钙素基因相关肽（CGRP）的血管舒张神经（CGRP能神经）神经传递的影响。用Krebs溶液灌注大鼠肠系膜血管床，并用脱氧胆酸钠灌注30秒以去除血管内皮。在通过持续灌注甲氧明（α(1)肾上腺素能受体激动剂）预收缩的制剂中，灌注拉呋替丁（0.1 - 10微摩尔）浓度依赖性地增强了动脉周围神经刺激（PNS，1赫兹）诱导的血管舒张，而不影响外源性注射CGRP（10皮摩尔）诱导的血管舒张。灌注法莫替丁（H(2)受体拮抗剂，1 - 100微摩尔）对PNS诱导的或CGRP诱导的血管舒张均无影响。灌注拉呋替丁浓度依赖性地增强了辣椒素（香草酸受体-1激动剂，30皮摩尔）推注诱导的血管舒张。香草酸受体-1拮抗剂钌红（10微摩尔）或辣椒平（5微摩尔）的存在消除了辣椒素诱导的血管舒张，并显著降低了PNS诱导的血管舒张。钌红或辣椒平降低的PNSNS诱导血管舒张不受拉呋替丁灌注的影响。这些结果表明，拉呋替丁通过调节位于CGRP能神经中的突触前香草酸受体-1的功能来促进CGRP神经介导的血管舒张。
