External pancreatic secretion in the rat: Supramaximal inhibition induced by the cholecystokinin octapeptide [CCK(26–33)] and analogs altered on the 28–29 bond

Abstract

Supramaximal doses of cholecystokinin induce in vitro submaximal biological responses, desensitization and residual stimulation. In vivo, supramaximal inhibition and oedematous pancreatitis have been reported. The aim of this study was to analyze the in vivo response of the pancreatic secretion of the rat to a wide range of doses of CCK8 and analogs prepared by alterations of the Met(28)-Gly(29) bond, a modification that may lead to potent agonists. We used Boc-[Nle 28-Nle 31]-CCK(26–33) (1) and derivatives of (1) with the 28–29 peptide bond replaced by CH 2-NH (2), CO-CH 2 (3), CH 2-CH 2 (4), NH-CO (5). On infusions, the ED 50's (pmol/kg·min) for protein output were 4 for CCK8 and (1), 11 for (3), 40 for (2) and (4), and 860 for (5). The relative order of the in vivo potencies was near to the one determined in vitro on isolated rat acini. On bolus injections, the maximal response was observed with 300 pmol/kg of CCK8, and peaked 10–15 min after the injection. With higher doses of CCK8, the secretory peak was smaller, and was delayed relative to the monment of the injection. Supramaximal doses of CCK analogs induced the same pattern of response; however, the peak injection delay was in some cases smaller than after CCK8. Determination of the plasma CCK levels indicated that the time of peak effect after supramaximal doses of CCK8 was delayed relative to the time of effective maximal plasma CCK levels. This suggests a slow dissociation of CCK8 from one of its pancreatic binding sites in vivo. These data indicate that agonists with high in vivo potency can be obtained by altering the Met(28)-Gly(29) bond, that supramaximal doses of CCK and analogs induce both a decrease and a delay of the peak effect, and suggest that the delay may be related to the rate of dissociation of the peptides from one of their receptor sites.