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

Abstract

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.

Pharmacological evidence that histamine H3 receptors inhibit the vasodepressor responses by selective stimulation of the rat perivascular sensory CGRPergic outflow

“…In fact, in agreement with the lack of effect of immepip on the methoxamine-induced vasopressor response (Fig. 1), Coruzzi et al, 1995 showed in anaesthetized rats that, unlike R-(-)-α-methylhistamine and imetit, immepip did not significantly change basal blood pressure and heart rate. In contrast, R-(-)-α-methylhistamine has been reported to produce a direct vasopressor response in pithed rats, which is not mediated by histamine H 1 , H 2 or H 3 receptors (Malinowska and Schlicker, 1991).…”

Histamine H3‐receptor stimulation is unable to modulate noradrenaline release by the isolated rat heart during ischaemia‐reperfusion

“…Conflicting results are seen concerning the prejunctional effects of H3-receptors in the rat, with some studies reporting a lack of action [4] and others an inhibition of electrically evoked noradrenaline release [ 141 and vasopressor response [MI. It has been suggested that prejunctional H3-receptors are functionally inactive under basal conditions in the rat [13]. Our results show that they also appear to play a minor role on noradrenaline release in the context of myocardial ischaemia in this species.…”

In vivo demonstration of H3‐histaminergic inhibition of cardiac sympathetic stimulation by R‐α‐methyl‐histamine and its prodrug BP 2.94 in the dog

“…Basal cardiovascular effects of H 3 agonists vary according to the species. In the guinea‐pig and in the rabbit, R‐α‐methyl‐histamine induces bradycardia and hypotension ( McLeod et al ., 1994 ) while in the rat, H 3 agonists have no effects ( Corruzzi et al ., 1995 ) at least not at the doses where they are selective for H 3 ‐receptors. Our results show that, in the dog, H 3 ‐receptor activation by BP 2.94 decreased heart rate and tended to reduce contractility and arterial pressure.…”

“…Our results show that, in the dog, H 3 ‐receptor activation by BP 2.94 decreased heart rate and tended to reduce contractility and arterial pressure. H 3 ‐antagonists fail to induce cardiovascular effects in the guinea‐pig, rabbit and rat ( Corruzzi et al ., 1995 ). We observed that, in the dog, SC 359 induced an important vasopressive response and a tachycardia after R‐α‐methyl‐histamine or BP 2.94.…”