Cholecystokinin stimulates neuronal receptors to produce contraction of the canine colon.
The motor effects of cholecystokinin 26-33-amide (CCK octapeptide; CCK-OP) and several purported CCK receptor antagonists on canine colonic circular muscle were determined in pentobarbital anesthetized dogs. Intravenous injections of CCK-OP had no effect on colonic motility at doses that contracted the gallbladder, stomach and duodenum. CCK-OP delivered by intraarterial injection to a small segment of the proximal colon produced a dose related increase in colonic motility with one-half maximum response at 12 ng/Kg and maximum response at 50 ng/Kg. The effects of intraarterial injections of several established CCK-receptor antagonists on proximal colonic responses to intraarterial injections of CCK-OP were determined. Proglumide, 10 mg/Kg, did not produce colonic contractions itself, but antagonized CCK-OP-induced responses. Carbobenzyloxy (CBZ)-CCK27-32-amide antagonized CCK-OP-induced colonic responses and also had no effect on basal colonic motility (0.1-1 and 5 micrograms/Kg). Neither compound antagonized acetylcholine- induced colonic responses. Butoxycarbonyl (BOC)-CCK31-33-amide increased basal colonic motility, but did not alter CCK-OP-induced responses at doses of 0.1 and 0.2 mg/Kg. Dibutyryl-cGMP at a dose of 0.1 mg/Kg did not affect basal motility or CCK-OP-induced contractions. At a dose of 1.0 mg/kg it increased basal colonic motility but did not affect CCK-OP-induced contractions. Pentagastrin increased colonic motor activity only at a dose of 5 micrograms/Kg, i.a., a much higher dose than effective doses of CCK-OP. The mechanism of CCK-OP-induced colonic motor effects also was determined. Atropine sulfate, 100 micrograms/Kg, i.v. significantly reduced both intraarterial acetylcholine-and CCK-OP-induced maximum colonic contractions. Tetrodotoxin, at intravenous doses that completely block neuronal activity, did not affect maximum acetylcholine-induced contractions but practically eliminated maximum CCK-OP-induced maximum colonic responses. In conclusion, intraarterial CCK-OP produces circular muscle contraction of the canine proximal colon that is mediated by stimulation of specific CCK receptors which produce the release of acetylcholine from cholinergic enteric neurons. Proglumide and CBZ-CCK27-32-amide are effective CCK receptor antagonists at these colonic neuronal receptors.
Barone
F C
FC
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406.
Bondinell
W E
WE
Labosh
T J
TJ
White
R F
RF
Ormsbee
H S
HS
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002766:Cholecystokinin / Q000031:analogs & derivatives / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D010418:Pentagastrin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011377:Proglumide / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D012844:Sincalide / Q000008:administration & dosage / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology
D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; D003995:Dibutyryl Cyclic GMP; D013779:Tetrodotoxin; C058799:cholecystokinin (31-33) amide, butyloxycarbonyl-; D001285:Atropine; D002766:Cholecystokinin; C058798:cholecystokinin (27-32) amide, benzoyloxycarbonyl-; D010418:Pentagastrin; D011377:Proglumide; D012844:Sincalide; D000109:Acetylcholine