Cholecystokinin CCK2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway.
OBJECTIVE
Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK(1)). However, the role played by cholecystokinin 2 (CCK(2)) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK(2) receptors on the contractile activity of human distal colon.


METHODS
The effects of compounds acting on CCK(2) receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation.


RESULTS
Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK(2) receptor antagonist; +57% at 0.01 microM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N(omega)-nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 microM).


CONCLUSIONS
CCK(2) receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK(2) receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.
Fornai
M
M
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Vioa Roma 55, 56126 Pisa, Italy.
Colucci
R
R
Antonioli
L
L
Crema
F
F
Buccianti
P
P
Chiarugi
M
M
Baschiera
F
F
Ghisu
N
N
Tuccori
M
M
Blandizzi
C
C
Del Tacca
M
M
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D003106:Colon / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011189:Potassium Chloride; D043887:Receptor, Cholecystokinin B / Q000187:drug effects / Q000502:physiology*; D012844:Sincalide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013779:Tetrodotoxin
C090019:8-sulfocholecystokinin octapeptide; C111554:GV 150013X; C109599:N(omega)-propylarginine; D018697:Nootropic Agents; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D009569:Nitric Oxide; D013779:Tetrodotoxin; D011189:Potassium Chloride; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D012844:Sincalide; D000218:Adamantane; D019331:NG-Nitroarginine Methyl Ester