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

Abstract

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.

H 3 receptor-mediated inhibition of intestinal acetylcholine release: pharmacological characterization of signal transduction pathways

“…In keeping with this view, the present results, showing that the inhibitory action of histamine on [ 3 H]acetylcholine release was attenuated by pertussis toxin and abolished by N-ethylmaleimide, suggest that the H 3 receptors, located on cholinergic nerve endings of guinea pig ileum, are coupled to G proteins belonging to G i /G o subtypes. This finding is consistent with the results of previous studies where the involvement of G i /G o proteins was demonstrated for the H 3 receptor-mediated modulation of noradrenergic neurotransmission (Nozaki and Sperelakis 1989;Endou et al 1994;Schlicker et al 1994b;Blandizzi et al 2000).…”

“…In addition, experiments performed on cell lines transfected with human or rat H 3 receptor cDNA indicated a negative coupling of these receptors with adenylyl cyclase in both species (Lovenberg et al 2000). However, studies dealing with histamine-mediated modulation of noradrenergic neurotransmission failed to demonstrate an involvement of cyclic AMP in the signaling pathway of prejunctional H 3 receptors at both central and peripheral level (Schlicker et al 1994b;Celuch 1995;Blandizzi et al 2000).…”

Histamine H3-Receptor-Induced Attenuation of Norepinephrine Exocytosis: A Decreased Protein Kinase A Activity Mediates a Reduction in Intracellular Calcium

“…Preliminary evidence from our laboratory had suggested that G i /G o may be involved in the H 3 R-mediated attenuation of adrenergic inotropic responses in the heart (Endou et al, 1994). Other investigators had also suggested a G i /G o involvement in the H 3 Rmediated inhibition of NE release from intestinal sympathetic nerves (Blandizzi et al, 2000). We therefore determined whether the H 3 R-mediated inhibition of NE exocytosis elicited by K ϩ or forskolin is attenuated by PTX, a Fig.…”

Lack of evidence for histamine H 3 receptor function in rat ileum and human colon

“…Subsequently, activation of the H 3 receptor has been shown to inhibit nerve transmission via cholinergic, noradrenergic and NANC neurons in the ileum, jejunum, duodenum and colon of the guinea-pig gastrointestinal tract (Trzeciakowski 1987;Coruzzi et al 1991;Leurs et al 1991;Poli et al 1991;Taylor and Kilpatrick 1992;Vollinga et al 1992;Hemedah and Mitchelson 1997;Blandizzi et al 2000), human bronchus and guinea-pig trachea (Ichinose and Barnes 1989a;Ichinose et al 1989) as well as from sensory nerves in various tissues (Ichinose and Barnes 1989b;Ohkubo et al 1995).…”