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

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 1 mg/kg atenolol, followed by i.v. administration of physiological saline (1 ml/kg), histamine (10, 50, 100 and 200 μg/kg) or the selective histamine H₁ (2‐pyridylethylamine), H₂ (dimaprit), H₃ (methimepip) and H₄ (VUF 8430) receptor agonists (1, 10, 50 and 100 μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9 Hz; 15 ± 3 V and 1 ms) 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 50 μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1–10 μg/kg) was abolished by the H₃ receptor antagonist JNJ 10181457 (1 mg/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.