THE CHOLECYSTOKININ CCK1 RECEPTOR AGONIST SR146131 DOES NOT ACTIVATE LOW-AFFINITY RECEPTOR SITES IN VIVO.

Abstract

Cholecystokinin CCK1 receptors have two affinity states, which are activated by appropriate concentrations of CCK or analogs like cerulein (CRL). With respect to pancreatic function, activation of high affinity sites stimulates enzyme secretion into the pancreatic ducts, while activation of low affinity sites inhibits this effect and induces acute pancreatitis in vivo. We have investigated whether the selective CCK1 agonist SR146131 (Bignon et al., J. Pharmacol. Exp. Ther., 1999; 289: 742–751 and 752–761) would discriminate between the two affinity states of the receptor. Intraperitoneal injection of CRL (0.25–7.5 nmol/kg) in anesthetized rats stimulated amylase output via the biliopancreatic duct in a dose-dependent manner, but enzyme secretion was completely blocked at a supramaximal dose (25 nmol/kg). SR146131 (18–180 nmol/kg) also dose-dependently stimulated amylase secretion; however, secretion did not decline even at doses of 1800 nmol/kg. The effect of SR146131 was blocked by the CCK1 antagonist dexloxiglumide, but not by the CCK2 antagonist itriglumide. A supramaximal dose of CRL (25 nmol/kg given twice i.p. at an interval of 1 h) induced acute edematous pancreatitis, quantified by water content of the pancreatic tissue and increases in amylase activities in the blood serum and in the pancreatic interstitial space. The effects of CRL were prevented by dexloxiglumide, but not by itriglumide. SR146131 (60–1800 nmol/kg twice i.p.) did not induce any signs of inflammation, as all measured parameters remained at control values which were obtained in animals injected with saline instead of CRL or SR146131. Histological evaluation showed that even the highest dose of SR146141 did not induce any signs of acinar cell damage. In summary, the CCK1 agonist SR146131 stimulates pancreatic exocrine function in vivo without exhibiting inhibition at supramaximal doses. Unlike the CCK analog cerulein, SR146131 does not induce acute pancreatitis even when applied at supramaximal dose levels. We conclude that in contrast to CCK and cerulein, SR146131 is an agonist only at the high affinity site of the CCK1 receptor. The investigation was supported by the Jubilee Funds of the Austrian National Bank (grant 9314).