Evidence for the involvement of ATP, but not of VIP/PACAP or nitric oxide, in the excitatory effect of capsaicin in the small intestine

The contractile effect of capsaicin in the guinea-pig small intestine involves an activation of enteric cholinergic neurons. Our present data show that the P-2 purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 30 mu M) significantly reduces the contractile response to capsaicin (2 mu M) in the presence, but not in the absence, of the tachykinin receptor antagonists [O-Pro(9), (Spiro-gamma-lactam)Leu(10), Trp(11)]physalaemin (1-11) (GR 82334; 3 mu M) and (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichloro- phenyl)piperidin-3-yl)propyl)-4-phenylpiperidine-4-yl)-N-methylacetamide (SR 142801; 100 nM) (for blocking tachykinin NK1 and NK3 receptors, respectively). PPADS (30 mu M) fails to influence submaximal cholinergic contractions evoked by cholecystokinin octapeptide (CCK-g; 2-3 nM) or senktide (1 nM), or the direct smooth muscle-contracting effect of histamine (100-200 nM). A higher concentration (300 mu M) of PPADS is also without effect against the stimulatory action of cholecystokinin octapeptide. This means that PPADS can probably be safely used as a purinoceptor antagonist in intestinal preparations. The putative pituitary adenylate cyclase activating peptide (PACAP) receptor antagonist PACAP-(6-38) (3 mu M) significantly reduces the contractile effect of PACAP-(1-38) (10 nM) and abolishes that of vasoactive intestinal polypeptide (VIP; 10 nM). PACAP-(6-38) (3 mu M) fails to influence the effect of capsaicin (2 mu M) both in the absence and in the presence of tachykinin receptor antagonists. The nitric oxide (NO) synthase inhibitor N-G-nitro-L-arginine (L-NOARG; 100 mu M) also fails to inhibit the capsaicin-induced motor response. We conclude that an endogenous ligand of PPADS-sensitive P-2 purinoceptors (possibly ATP), but not a VIP/PACAP-like peptide or NO, is involved in the nontachykininergic activation of cholinergic neurons in the course of the capsaicin-induced contraction. (C) 2000 Elsevier Science B.V. All rights reserved.