Are C-terminal octapeptide of cholecystokinin and [Leu(11)]gastrin-(5-17) different in stimulating acid secretion in isolated rabbit gastric glands?

In the present study we compared various CCK, receptor antagonists and tried to detect a difference in biological activity between the C-terminal octapeptides of cholecystokinin (CCK-8) and [Leu(11)]gastrin-(5-17) in isolated rabbit gastric glands. Binding experiments showed that different CCKB/gastrin receptor agonists bound with high affinity and that antagonists inhibited this binding in accordance with a CCKB/gastrin pharmacological profile. [Leu(11)]Gastrin-(5-17), CCK-8 and cionin were found to induce [C-14]aminopyrine accumulation to 25% above the basal level. Under the same experimental conditions, histamine induced a response twice as great as the response obtained with [Leu(11)]gastrin-(5-17) or CCK-8. [Leu(11)]Gastrin-(5-17) (10(-7) M), CCK-8 (10(-8) M) and cionin (10(-8) M) appeared to be full agonists. CCKB/gastrin receptor antagonists including L-365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-H-1,4-benzodiazepin-3-yl)-N-(3-methylphenyl) urea), L-364,718 (3S-(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1-H-1,4-benxodiazepin-3-yl)-N-(3-methylphenyl) urea), L-364,718 (3S-(-)_N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benxodiazepin-3-yl)-1H-indole-2-carboximide) ( a selective CCKA receptor antagonist), PD-135,158 (4([2-[[#-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl] amino-4-oxo-[1S-1 alpha.2 beta[S*(S*)]4 alpha]]-butanoate N-mehtyl-D-glucamine) (bicyclo system 1S-endo), YM-022 ((R)-1-[2,3-dihydro-1-(2'-methylpehnacyl)-2-oxo-5-phenyl-1H-1,4,-benzodiazepin-3-yl]-3-(3-methylphenyl)urea) and JMV-180 (Boc-Tyr(SO H)-Nle-Gly-Trp-Nle-Asp-O-CH2-C6H5) exhibited the same profile for inhibition of [Leu(11)]gastrin-(5-17) or CCk-8-induced [C-14]aminopyrine accumulation in rabbit gastric glands. These results suggested that [Leu(11)]gastrin-(5-17) and CCk-8 induced [C-14]aminopyrine accumulation by the same mechanism. [Leu(11)]gastrin-(5-17)- or CCK-8-induced [C-14]aminopyrine accumulation was inhibited by about 40% by the histamine H-2 receptor blocker cimetidine. These results are consistent with there being cooperativity between [Leu(11)]gastrin-(5-17) (or CCK-8) and histamine in the acid secretory pathway. Similarly, the CCKB/gastrin receptor antagonists were tested against histamine-induced [C-14]aminopyrine accumulation and surprisingly, only compound L-365,260 appeared active and even more potent than cimetidine.