Suzuki Hideaki, Mobarakeh Jalal Izadi, Nunoki Kazuo, Sukegawa Jun, Watanabe Haruo, Kuramasu Atsuo, Watanabe Takeshi, Yanai Kazuhiko, Yanagisawa Teruyuki
Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai 980-8575, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Feb;371(2):99-106. doi: 10.1007/s00210-005-1031-0. Epub 2005 Feb 26.
To elucidate the central roles of histamine receptors in cardiovascular regulatory system, systolic, mean, and diastolic blood pressures (BPs) and heart rate (HR) were examined in conscious H(1) receptor gene knockout (H(1)KO) mice, H(2) receptor gene knockout (H(2)KO) mice, H(1) and H(2) receptor gene double knockout (DKO) mice, and their respective control mice by the tail-cuff system. Histamine, histamine-trifluoromethyl-toluidine derivative (HTMT, an H(1) agonist), dimaprit (an H(2) agonist), and immepip (an H(3) agonist) were intrathecally administered to these KO mice and control mice. Basal BPs and HR were not different among these three KO mice and their control or wild-type mice. Intrathecal administration of histamine significantly increased BPs and decreased HR in control mice. The increases in BPs were produced by histamine in H(1)KO and H(2)KO mice and by HTMT and dimaprit in C57BL mice. The pressor responses by HTMT and dimaprit in C57BL mice were greater than those by histamine in H(1)KO and H(2)KO mice, although the same decreases in HR were induced by histamine in C57BL and H(1)KO mice and by dimaprit in C57BL mice. The selective stimulation of H(3) receptors by immepip produced a consistent decrease in BPs in control mice. These results obtained with the exogenous selective agonists of three histamine receptors suggest that the pressor responses to histamine are mediated through the stimulation of both H(1) and H(2) receptors, whereas the atropine-sensitive decrease in heart rate is mainly due to H(2) receptors which activate the vagal output to the heart.
为阐明组胺受体在心血管调节系统中的核心作用，通过尾套法对清醒的H(1)受体基因敲除（H(1)KO）小鼠、H(2)受体基因敲除（H(2)KO）小鼠、H(1)和H(2)受体基因双敲除（DKO）小鼠及其各自的对照小鼠的收缩压、平均压和舒张压以及心率进行了检测。向这些基因敲除小鼠和对照小鼠鞘内注射组胺、组胺-三氟甲基-甲苯胺衍生物（HTMT，一种H(1)激动剂）、二甲双胍（一种H(2)激动剂）和依美哌啶（一种H(3)激动剂）。这三种基因敲除小鼠与其对照或野生型小鼠之间的基础血压和心率并无差异。鞘内注射组胺可使对照小鼠的血压显著升高并使心率降低。组胺使H(1)KO和H(2)KO小鼠血压升高，HTMT和二甲双胍使C57BL小鼠血压升高。尽管C57BL和H(1)KO小鼠中组胺诱导的心率降低程度相同，C57BL小鼠中二甲双胍诱导的心率降低程度相同，但C57BL小鼠中HTMT和二甲双胍引起的升压反应大于H(1)KO和H(2)KO小鼠中组胺引起的升压反应。依美哌啶对H(3)受体的选择性刺激使对照小鼠的血压持续降低。这三种组胺受体外源性选择性激动剂的这些结果表明，对组胺的升压反应是通过H(1)和H(2)受体的刺激介导的，而阿托品敏感的心率降低主要归因于激活心脏迷走神经输出的H(2)受体。
