piperidines and fenamic-acid

Acetylcholine (ACh) stimulates ion secretion in the small intestine and colon. The purpose of the present study was to characterize the ACh-induced electrogenic ion transport in human duodenum and determine the muscarinic receptor subtypes functionally involved.. Biopsies from the second part of duodenum were obtained from 28 patients during endoscopy. Biopsies were mounted in modified Ussing chambers with air-suction for measurements of short-circuit current by a previously validated technique. Short-circuit current was measured after application of chloride/bicarbonate transport inhibitors bumetanide, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), diphenylamine-2-carboxylate (DPC), and acetazolamide. 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and two mamba toxins MT3 and MT7 were used to characterize the mAChR receptor subtypes involved. The effects of transport inhibitors and receptor antagonists were measured by comparing two consecutive responses of ACh on short-circuit current in the same biopsy specimen.. Bumetanide and 4-DAMP significantly inhibited ACh-induced short-circuit current, whereas SITS, DPC, acetazolamide, mamba toxin MT3, and mamba toxin MT7 all failed to show any significant effect.. In conclusion, our results indicate that muscarinic receptor subtype M3 acts as the main mediator of bumetanide-sensitive ACh-induced secretion in human duodenum.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Acetazolamide; Acetylcholine; Bumetanide; Calcium Channel Blockers; Diuretics; Duodenum; Elapid Venoms; Humans; Intercellular Signaling Peptides and Proteins; Ion Transport; Muscarinic Antagonists; Neurotoxins; ortho-Aminobenzoates; Peptides; Piperidines; Receptors, Muscarinic

Previous studies demonstrated neurally mediated recurrent increases in short-circuit current (Isc) suggestive of anion secretion in guinea pig distal colon. To determine the neural pathways involved, segments of distal colon from guinea pigs were mounted in flux chambers. In muscle-stripped or whole thickness preparations, serosal addition of the histamine H2 receptor agonist, dimaprit, caused cyclical increases in Isc, which were reduced by the chloride channel blocker, N-phenylanthranilic acid, but not by the sodium channel blocker amiloride. Dimaprit stimulated release of [3H]acetylcholine and vasoactive intestinal polypeptide (VIP) from submucosal/mucosal sheets. Dimaprit caused recurrent increases in Isc, which were significantly decreased by mecamylamine, a nicotinic receptor antagonist, and nearly abolished by the muscarinic antagonist, atropine (M3 > M1 = M2). The muscarinic antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, M3 > M1), was more potent than pirenzepine (M1 > M3) in reducing recurrent increases in Isc. Dimaprit- and electrically evoked secretion were inhibited by the VIP antagonists [4Cl-D-Phe6, Leu17]VIP and VIP hybrid. The results suggest the involvement of VIP-ergic and cholinergic neurons utilizing nicotinic and muscarinic synapses in mediating secretion.

Topics: Acetylcholine; Amiloride; Animals; Atropine; Choline; Colon; Dimaprit; Electric Conductivity; Guinea Pigs; Histamine Release; Intestinal Mucosa; Male; ortho-Aminobenzoates; Piperidines; Pirenzepine; Receptors, Histamine H2; Vasoactive Intestinal Peptide