Cholecystokinin-mediated ileal electrolyte transport in the guinea pig. Characterization of receptor subtype.
Cholecystokinin (CCK) receptors are currently divided into at least two subtypes: a CCK-A subtype, responsive to the sulfated form of cholecystokinin octapeptide (CCK-8) and selectively antagonized by L-364,718, and a CCK-B subtype, which shares equal affinities for gastrin and CCK-8. In the present study the receptor subtype that mediates guinea pig ileal secretion by evaluating the potencies of CCK- and gastrin-related peptides to evoke increases in transmucosal short-circuit current was characterized. The antagonist potencies of L-365,260 (CCK-B selective) and L-364,718 (CCK-A selective) against CCK-8 were also determined. Both CCK-8 and cerulein, when added to the serosal side of the tissue, evoked increases in the short-circuit current, having EC50 values of 0.8 and 0.2 nmol/L, respectively. Desulfated (SO3) CCK-8, CCK-4, gastrin17-I, pentagastrin, gastrin17-II, and gastrin13-I were relatively weak agonists (EC50 greater than 1000 nmol/L. Cholecystokinin octapeptide-induced short-current responses were competitively antagonized by L-364,718 (pA2, 10.3) and L-365,260 (pA2, 7.4). The high selectivity of the tissue for sulfated CCK-8 suggests that the secretory effect of CCK-8 on guinea pig ileal electrolyte transport is mediated by a CCK-A receptor. The potent effect of L-364,718 against CCK-8 is also consistent with an action at the A-subtype receptor.
Gastrointestinal Diseases Research, Searle Research and Development, Skokie, Illinois.
J F
JF
Kachur
S X
SX
Wang
G W
GW
Gullikson
T S
TS
Gaginella
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D020109:Devazepide; D004573:Electrolytes / Q000493:pharmacokinetics*; D004594:Electrophysiology; D005755:Gastrins / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D012844:Sincalide / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001570:Benzodiazepinones; D004573:Electrolytes; D005755:Gastrins; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D020109:Devazepide; D012844:Sincalide