Vasoactive intestinal polypeptide mediates cholecystokinin-induced relaxation of the sphincter of Oddi.
This study evaluates the hypothesis that cholecystokinin (CCK) relaxes the sphincter of Oddi via vasoactive intestinal polypeptide (VIP). Isolated canine sphincter of Oddi were suspended in organ baths under standard conditions. Responses to cholecystokinin octapeptide (CCK-8) and VIP were recorded on a pen recorder via an isometric transducer. 10(-11)-10(-7) M CCK-8 and 4 X 10(-11)-5 X 10(-7) M VIP generated dose-related sphincter of Oddi relaxation, which was unaffected by atropine, propranolol, and phentolamine. The effect of CCK-8 was antagonized by dibutyryl cGMP (Bt2 cGMP) (10(-3) M), the VIP-antagonist (N-Ac-Tyr1, D-Phe2)-growth hormone-releasing factor-(1-29)-NH2, and abolished by tetrodotoxin. In contrast, VIP's relaxing action was tetrodotoxin insensitive. 10(-11)-10(-7) M CCK-8 stimulated dose-dependent release of VIP (0.5-2.2 fm/ml.mg tissue), which was not inhibited by atropine, propranolol, and phentolamine, but was antagonized by 10(-3) M Bt2 cGMP and tetrodotoxin. In addition CCK-8 and VIP generated dose-related (10(-10)-10(-7) M) increases in sphincter of Oddi cAMP levels that were not affected by atropine, propranolol, and phentolamine. Furthermore, 10(-5)-10(-2) M 8-bromo-cAMP caused dose-dependent relaxation of the sphincter of Oddi. In separate studies, a 2-h incubation in physiological solution containing 12 parts/1,000 of rabbit VIP antiserum antagonized sphincter relaxation caused by 4 nM CCK-8 and 6 nM VIP. The antiserum also significantly decreased the sphincter of Oddi cAMP level stimulated by 4 nM CCK-8 by 48 +/- 15%. These studies demonstrate that CCK-8 relaxes the canine sphincter of Oddi via a noncholinergic, nonadrenergic neural pathway involving VIP. The intracellular mechanism mediating CCK/VIP relaxation involves generation of cAMP.
Wiley
J W
JW
University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor 48109.
O'Dorisio
T M
TM
Owyang
C
C
D014670:Ampulla of Vater / Q000502:physiology*; D000818:Animals; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009924:Organ Culture Techniques; D009803:Sphincter of Oddi / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism* / Q000494:pharmacology
D003995:Dibutyryl Cyclic GMP; D014660:Vasoactive Intestinal Peptide; D013779:Tetrodotoxin; D002766:Cholecystokinin