Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis.
It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guinea-pig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 microM) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 microM), GR-94,800 (0.3 microM) and SR-48,968 (0.1 microM) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5-20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only.(ABSTRACT TRUNCATED AT 250 WORDS)
Holzer
P
P
University Department of Pharmacology, Graz, Austria.
Maggi
C A
CA
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006584:Hexamethonium Compounds / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010528:Peristalsis / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000187:drug effects*
D001549:Benzamides; D006584:Hexamethonium Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011950:Receptors, Cholinergic; D018041:Receptors, Neurokinin-2; C073839:SR 48968; D001285:Atropine; D015288:Neurokinin A; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol