Histamine H3 receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves

1 The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea-pig ileum, preincubated with [H-3]-noradrenaline. 2 In the presence of rauwolscine, electrically-induced [H-3]-noradrenaline release was inhibited by histamine or R-alpha-methylhistamine, whereas it was unaffected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modified the release of [H-3]- noradrenaline. 3 The modulatory action of histamine was attenuated by pertussis toxin and abolished by N-ethylmaleimide. Tetraethylammonium or 4-aminopyridine enhanced the evoked tritium outflow and counteracted the inhibitory effect of histamine. However, the blocking effects of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca2+ concentration in the superfusion medium. 4 Histamine-induced inhibition of tritium output was enhanced by omega-conotoxin or low Ca2+ concentration, whereas it was not modified 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 Ca2+ channels through a direct link, thus reducing the availability of extracellular Ca2+ at the level of noradrenergic nerve terminals.