Histamine H(3) 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 [(3)H]-noradrenaline. 2. In the presence of rauwolscine, electrically-induced [(3)H]-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 [(3)H]-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 Ca(2+) concentration in the superfusion medium. 4. Histamine-induced inhibition of tritium output was enhanced by omega-conotoxin or low Ca(2+) 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 Ca(2+) channels through a direct link, thus reducing the availability of extracellular Ca(2+) at the level of noradrenergic nerve terminals.
Blandizzi
C
C
Division of Pharmacology and Chemotherapy, Department of Oncology, University of Pisa, Via Roma 55, I-56126, Pisa, Italy.
Tognetti
M
M
Colucci
R
R
Del Tacca
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005033:Ethylmaleimide / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000294:innervation; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D037342:Pertussis Toxin; D010636:Phenols / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D017442:Histamine Agonists; D006633:Histamine Antagonists; D010636:Phenols; D018100:Receptors, Histamine H3; D010566:Virulence Factors, Bordetella; D020960:omega-Conotoxins; D005576:Colforsin; D015016:Yohimbine; C062898:lavendustin A; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D006632:Histamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015761:4-Aminopyridine; D037342:Pertussis Toxin; D009543:Nifedipine; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate; D005033:Ethylmaleimide; D002118:Calcium; D009638:Norepinephrine