Pharmacological Evidence that Histamine H3 Receptors Mediate Histamine-Induced Inhibition of the Vagal Bradycardic Out-flow in Pithed Rats.

Abstract

In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. As vagal release of ACh may be modulated by autoreceptors (muscarinic M2 ) and heteroreceptors (including serotonin 5-HT1 ), this study has analysed the pharmacological profile of the receptors involved in histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pre-treated (i.v.) with 1mg/kg atenolol, followed by i.v. administration of physiological saline (1ml/kg), histamine (10, 50, 100 and 200μg/kg) or the selective histamine H1 (2-pyridylethylamine), H2 (dimaprit), H3 (methimepip) and H4 (VUF 8430) receptor agonists (1, 10, 50 and 100μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9Hz; 15±3V and 1ms) of the vagus nerve resulted in frequency-dependent bradycardic responses, which were (i) unchanged during the infusions of saline, 2-pyridylethylamine, dimaprit or VUF 8430; and (ii) dose-dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1-10μg/kg) was abolished by the H3 receptor antagonist JNJ10181457 (1mg/kg, i.v.). In conclusion, our results suggest that histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats is mainly mediated by pre-junctional activation of histamine H3 receptors, as previously demonstrated for the vasopressor sympathetic out-flow and the vasodepressor sensory CGRPergic (calcitonin gene-related peptide) out-flow.