Premium
Pharmacological Evidence that Histamine H 3 Receptors Mediate Histamine‐Induced Inhibition of the Vagal Bradycardic Out‐flow in Pithed Rats
Author(s) -
García Mónica,
GarcíaPedraza José Ángel,
Villalón Carlos M.,
Morán Asunción
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12475
Subject(s) - histamine , dimaprit , endocrinology , medicine , chemistry , histamine h3 receptor , bradycardia , histamine h2 receptor , muscarinic acetylcholine receptor , vagus nerve , compound 48/80 , histamine h1 receptor , stimulation , antagonist , pharmacology , receptor , biology , heart rate , degranulation , blood pressure
Abstract In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine ( AC h) release. As vagal release of AC h may be modulated by autoreceptors (muscarinic M 2 ) and heteroreceptors (including serotonin 5‐HT 1 ), 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 H 1 (2‐pyridylethylamine), H 2 (dimaprit), H 3 (methimepip) and H 4 (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 H 3 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 H 3 receptors, as previously demonstrated for the vasopressor sympathetic out‐flow and the vasodepressor sensory CGRPergic (calcitonin gene‐related peptide) out‐flow.