Coruzzi G, Gambarelli E, Bertaccini G, Timmerman H
Institute of Pharmacology, University of Parma, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Jun;351(6):569-75. doi: 10.1007/BF00170155.
The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.
在麻醉大鼠中研究了一系列选择性组胺H3受体激动剂（R）α-甲基组胺、碘替丁和依美匹哌以及选择性拮抗剂硫丙酰胺、氯苯丙哌和氯芬丙哌对心血管系统的反应。静脉注射剂量为0.003 - 1 μmol/kg时，H3激动剂未能使基础血压和心率产生任何显著变化。较大剂量的（R）α-甲基组胺可升高血压和心率，较高剂量的碘替丁引起血管减压反应并降低心率，而依美匹哌实际上无活性。虽然（R）α-甲基组胺诱导的效应未被组胺H1、H2和H3受体拮抗剂阻断，但可被咪唑克生和普萘洛尔减弱，这表明涉及的机制是肾上腺素能的。碘替丁诱导的效应与组胺H3受体无关，而是由间接（通过5HT3受体）胆碱能机制介导，因为这些效应可被静脉注射1 mg/kg阿托品和0.1 mg/kg昂丹司琼阻止。同样，H3拮抗剂本身在静脉注射剂量高达10 μmol/kg时未能改变基础心血管功能，仅在静脉注射30 μmol/kg时观察到血压和心率显著下降，去甲肾上腺素的效应也显著降低。这些数据表明，在麻醉大鼠中，组胺H3受体激活或阻断对基础心血管功能无影响。给予大剂量（R）α-甲基组胺和碘替丁后记录到的效应显然与组胺H3受体无关，在将这些化合物用作“体内”实验的H3配体时应予以考虑。
