Effect of chronic oral administration of the CCK receptor antagonist loxiglumide on exocrine and endocrine pancreas in normal rats.

Abstract

In normal adult rats, administration of a low dose of loxiglumide for 7 d had no significant effect on exocrine and endocrine pancreatic function, whereas a high dose of loxiglumide decreased pancreatic enzyme output without inducing insulin resistance and diabetes mellitus. There is a possibility that chronic administration of cholecystokinin receptor antagonists not only inhibits the growth of the pancreas but also alters exocrine and endocrine pancreatic function. Loxiglumide at a dose of 50, 100, or 200 mg/kg body weight, or the same volume of saline, was given by an orogastric tube twice daily for 7 d (13 successive times). Biochemical and functional changes were determined on d 8 at 24 h after the last administration of loxiglumide and 18 h fasting. Pancreatic exocrine and endocrine function was simultaneously determined following an intravenous injection of a mixed solution of 0.5 g/kg body weight glucose plus 100 ng/kg body weight cerulein. Pancreatic weight and protein content were dose-dependently decreased by loxiglumide, whereas DNA content was decreased only by the highest dose of loxiglumide. Loxiglumide caused dose-dependent decreases in pancreatic fluid and protein output. Total pancreatic insulin content in rats treated with loxiglumide was not significantly different from that in the control rats. However, insulin concentration relative to DNA content was significantly increased in rats treated with 200 mg/kg body weight loxiglumide compared with that in other groups of rats. Glucose-stimulated insulin release was significantly low in rats treated with the highest dose of loxiglumide compared with that in other groups of rats, although there was no difference of serum glucose concentrations among these four groups of rats.