1 The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal musclemyenteric plexus preparations of guinea-pig ileum, preincubated with [ 3 H]-noradrenaline. 2 In the presence of rauwolscine, electrically-induced [ 3 H]-noradrenaline release was inhibited by histamine or R-a-methylhistamine, whereas it was unaected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory eects of histamine or R-amethylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modi®ed the release of [ 3 H]-noradrenaline. 3 The modulatory action of histamine was attenuated by pertussis toxin and abolished by Nethylmaleimide. Tetraethylammonium or 4-aminopyridine enhanced the evoked tritium out¯ow and counteracted the inhibitory eect of histamine. However, the blocking eects of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca 2+ concentration in the superfusion medium. 4 Histamine-induced inhibition of tritium output was enhanced by o-conotoxin or low Ca 2+ concentration, whereas it was not modi®ed by nifedipine, forskolin, rolipram, phorbol myristate acetate, H7 or lavendustin A. 5 The present results indicate that presynaptic H 3 receptors, located on sympathetic nerve endings, mediate an inhibitory control on intestinal noradrenergic neurotransmission. It is suggested that these receptors are coupled to G i /G o proteins which modulate the activity of N-type Ca 2+ channels through a direct link, thus reducing the availability of extracellular Ca 2+ at the level of noradrenergic nerve terminals.

The present study investigates the mechanisms through which prejunctional histamine H3 receptors modulate intestinal cholinergic neurotransmission. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea pig ileum, preincubated with [3H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation. The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. The electrically induced [3H]acetylcholine release was inhibited by histamine (EC50)=33.5 nM) or the H3 receptor agonist R-alpha-methylhistamine (EC50=41.6 nM), whereas it was not affected by pyridylethylamine (H1 agonist), impromidine (H2 agonist), pyrilamine (H1 antagonist), cimetidine (H2 antagonist), thioperamide or clobenpropit (H3 antagonists). The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide (pKd= 8.31 and 8.53, respectively) or clobenpropit (pKd=9.44 and 9.32, respectively), but not by pyrilamine or cimetidine. The modulatory action of histamine on the evoked tritium outflow was attenuated by pertussis toxin and abolished by N-ethylmaleimide, two selective blockers of Gi/Go proteins. Tetraethylammonium or 4-aminopyridine, acting as inhibitors of voltage-dependent K+ channels, enhanced the evoked tritium outflow when tested alone, and apparently counteracted the inhibitory effect of histamine. However, the blocking actions of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by appropriate reductions of Ca2+ concentration in the superfusion medium. Histamine-induced inhibition of evoked tritium output was enhanced by omega-conotoxin, a selective blocker of N-type Ca2+ channels, or low Ca2+ concentration, whereas it was not modified by nifedipine, an antagonist of L-type Ca2+ channels. In addition, the inhibitory effect of histamine was not significantly affected by forskolin (activator of adenylyl cyclase), 8-bromo-cyclic AMP (a stable analog of cyclic AMP), rolipram (a selective blocker of type IV phosphodiesterase), phorbol myristate acetate (activator of protein kinase C), H-89 (N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide, inhibitor of protein kinase A), Ro-31-8220 (2-(1-[3-(amidinothio)propyl]-1H-indol-3-yl)-3-(1-methylindol-3-yl)-maleimide, inhibitor of protein kinase C), KT5823 (N-methyl-(8R*,9S*,11S*)-(-)-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]cycloocta[c,d,e]-trinden-1-one, inhibitor of protein kinase G), or lavendustin A (inhibitor of tyrosine kinase). The present results indicate that histamine inhibits intestinal cholinergic neurotransmission through presynaptic H3 receptors coupled to Gi/Go proteins. It is suggested that adenylyl cyclase, serine-threonine protein kinase and tyrosine kinase pathways are not implicated in this regulatory action, and that Gi/Go proteins modulate the activity of N-type Ca2+ chann...

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