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Modulation of neurotransmitter release via histamine H 3 heteroreceptors

Modulation of neurotransmitter release via histamine H 3 heteroreceptors Summary— Presynaptic H3 receptors occur on histaminergic neurones of the CNS (autoreceptors) and on non‐histaminergic neurones of the central and autonomic nervous system (heteroreceptors). H3 heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H3 heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H3 receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H3 receptor agonist imetit exceeded that of R‐(‐)‐α‐methylhistamine (the reference H3 receptor agonist) by one log unit and that of histamine by almost two log units. Clobenpropit was shown to be a competitive H3 receptor antagonist, exhibiting a pA2 as high as 9.6 (exceeding the pA2 of the reference H3 receptor antagonist thioperamide by one log unit). The irreversible antagonism of N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) was also studied. Interactions of the H3 heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the α2‐autoreceptor in mouse brain cortex slices could be demonstrated. Activation of α2‐autoreceptors decreases the H3 receptor‐mediated effect. Blockade of α2‐autoreceptors increases the H3 receptor‐mediated effect only if the α2‐autoreceptors are simultaneously activated by endogenous noradrenaline. The H3 receptor‐mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H3 receptors are not coupled to voltage‐sensitive K+ channels. Pertussis toxin and N‐ethylmaleimide attenuated the H3 receptor‐mediated effect in the mouse brain cortex, suggesting that the H3 receptors are coupled to a G protein (eg Gi or Go). However, negative coupling to an adenylate cyclase does not appear to exist since an H3 receptor‐mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of diseases of the gastrointestinal and bronchial system and the CNS. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Fundamental & Clinical Pharmacology Wiley

Modulation of neurotransmitter release via histamine H 3 heteroreceptors

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References (61)

Publisher
Wiley
Copyright
1994 Société Française de Pharmacologie et de Thérapeutique
ISSN
0767-3981
eISSN
1472-8206
DOI
10.1111/j.1472-8206.1994.tb00789.x
Publisher site
See Article on Publisher Site

Abstract

Summary— Presynaptic H3 receptors occur on histaminergic neurones of the CNS (autoreceptors) and on non‐histaminergic neurones of the central and autonomic nervous system (heteroreceptors). H3 heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H3 heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H3 receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H3 receptor agonist imetit exceeded that of R‐(‐)‐α‐methylhistamine (the reference H3 receptor agonist) by one log unit and that of histamine by almost two log units. Clobenpropit was shown to be a competitive H3 receptor antagonist, exhibiting a pA2 as high as 9.6 (exceeding the pA2 of the reference H3 receptor antagonist thioperamide by one log unit). The irreversible antagonism of N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) was also studied. Interactions of the H3 heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the α2‐autoreceptor in mouse brain cortex slices could be demonstrated. Activation of α2‐autoreceptors decreases the H3 receptor‐mediated effect. Blockade of α2‐autoreceptors increases the H3 receptor‐mediated effect only if the α2‐autoreceptors are simultaneously activated by endogenous noradrenaline. The H3 receptor‐mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H3 receptors are not coupled to voltage‐sensitive K+ channels. Pertussis toxin and N‐ethylmaleimide attenuated the H3 receptor‐mediated effect in the mouse brain cortex, suggesting that the H3 receptors are coupled to a G protein (eg Gi or Go). However, negative coupling to an adenylate cyclase does not appear to exist since an H3 receptor‐mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of diseases of the gastrointestinal and bronchial system and the CNS.

Journal

Fundamental & Clinical PharmacologyWiley

Published: Mar 4, 1994

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