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 microM) significantly reduces the contractile response to capsaicin (2 microM) 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 microM) and (S)-(N)-(1-(3-(1-benzoyl-3-(3, 4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidine-4-yl)-N -methylacetamide (SR 142804: 100 nM) (for blocking tachykinin NK1 and NK3 receptors, respectively). PPADS (30 microM) fails to influence submaximal cholinergic contractions evoked by cholecystokinin octapeptide (CCK-8; 2-3 nM) or senktide (1 nM), or the direct smooth muscle-contracting effect of histamine (100-200 nM). A higher concentration (300 microM) 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 microM) 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 microM) fails to influence the effect of capsaicin (2 microM) 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 microM) 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.
Barthó
L
L
Department of Pharmacology and Pharmacotherapy, University Medical School of Pécs, H-7643, Pécs, Hungary. lbartho@apacs.pote.hu
Lázár
Z
Z
Lénárd
L
L
Benkó
R
R
Tóth
G
G
Penke
B
B
Szolcsányi
J
J
Maggi
C A
CA
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D012844:Sincalide / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology / Q000502:physiology*
D004791:Enzyme Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D010446:Peptide Fragments; D010880:Piperidines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018042:Receptors, Neurokinin-3; C054724:senktide; C079014:GR 82334; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D019335:Nitroarginine; D010803:Physalaemin; D009569:Nitric Oxide; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; C091554:SR 142801; D012844:Sincalide; D000109:Acetylcholine; D002211:Capsaicin