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-ter minal 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/gas trin pharmacological profile. [Leu(11)]Gastrin-(5-17), CCK-8 and cioni n were found to induce [C-14]aminopyrine accumulation to 25% above the basal level. Under the same experimental conditions, histamine induce d a response twice as great as the response obtained with [Leu(11)]gas trin-(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 henyl-H-1,4-benzodiazepin-3-y l)-N-(3-methylphenyl) urea), L-364,718 nyl-1-H-1,4-benxodiazepin-3-yl) -N-(3-methylphenyl) urea), L-364,718 H-1,4-benxodiazepin-3-yl)-1H-indo le-2-carboximide) ( a selective CCKA receptor antagonist), PD-135,158 yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl] amino-4-oxo-[1S-1 a lpha.2 beta[S(S*)]4 alpha]]-butanoate N-mehtyl-D-glucamine) (bicyclo system 1S-endo), YM-022 H-1,4,-benzodiazepin-3-yl]-3-(3-methylphenyl)u rea) and JMV-180 (Boc-Tyr(SO H)-Nle-Gly-Trp-Nle-Asp-O-CH2-C6H5) exhibi ted the same profile for inhibition of [Leu(11)]gastrin-(5-17) or CCk- 8-induced [C-14]aminopyrine accumulation in rabbit gastric glands. The se 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 b y about 40% by the histamine H-2 receptor blocker cimetidine. These re sults are consistent with there being cooperativity between [Leu(11)]g astrin-(5-17) (or CCK-8) and histamine in the acid secretory pathway. Similarly, the CCKB/gastrin receptor antagonists were tested against h istamine-induced [C-14]aminopyrine accumulation and surprisingly, only compound L-365,260 appeared active and even more potent than cimetidi ne.