Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat

The cardiovascular responses to a series of selective histamine H₃ receptor agonists, (R) -methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003–1 mol/kg i.v. doses, H₃ agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) -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) -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 mol/kg i.v. and only at 30 mol/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) -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.