Cisapride and structural analogs selectively enhance 5-hydroxytryptamine (5-HT)-induced purinergic neurotransmission in the guinea pig proximal colon.
In the guinea pig proximal colon, 5-hydroxytryptamine (5-HT) stimulates neuronal 5-HT1-like receptors to induce relaxations that are mediated by nitric oxide and ATP. In the current study, the effects of cisapride and structural analogs on these 5-HT-induced relaxations were investigated. In the continuous presence of ketanserin (0.3 microM) and tropisetron (3 microM) to block contractions via 5-HT2A, 5-HT3 and 5-HT4 receptors, 5-HT induced relaxations that yielded a biphasic concentration-response curve. Cisapride (0.1-1 microM) enhanced the second phase of the concentration-response curve to 5-HT by about 20% to 40%, whereas from 0.3 microM onwards, it inhibited the first phase. Also in the presence of cisapride (0.3 microM), tetrodotoxin (0.3 microM) abolished the relaxations to 5-HT. Cisapride (0.3 microM) did not affect the concentration-response curves to isoprenaline, nitroglycerin, nitroprusside or exogenous ATP, which demonstrated its specificity. The 5-HT relaxation-enhancing effects of cisapride were not mimicked by phentolamine (1 microM), NAN-190 (0.03 microM), spiperone (1 microM), citalopram (0.3 microM), paroxetine (0.3 microM), pargyline (100 microM) or SDZ 205-557 (0.3 microM). In the presence of the inhibitor of nitric oxide synthesis, NG-nitro-L-arginine (100 microM), cisapride (0.3 microM) still enhanced the remaining relaxations to 5-HT (2-3-fold). However, in the presence of the P2-purinoceptor antagonist suramin (300 microM), cisapride did not enhance the relaxations to 5-HT. In the presence of NG-nitro-L-arginine, the cisapride-enhanced relaxations to 5-HT were inhibited by about 90% by suramin. We conclude that in the guinea pig colon, cisapride selectively facilitates the suramin-sensitive, ATP-mediated part of the relaxation to 5-HT via an unidentified effect on intramural nerves.
Briejer
M R
MR
Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Veen
G J
GJ
Akkermans
L M
LM
Lefebvre
R A
RA
Schuurkes
J A
JA
D000255:Adenosine Triphosphate / Q000502:physiology*; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D020117:Cisapride; D003106:Colon / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D058669:Adrenergic alpha-2 Receptor Antagonists; D001549:Benzamides; D010880:Piperidines; D011985:Receptors, Serotonin; D009569:Nitric Oxide; D012701:Serotonin; D000255:Adenosine Triphosphate; D020117:Cisapride