Muscarinic cholinergic induced secretin subsensitivity in rat isolated pancreatic acini. Effects on amylase release, cyclic adenosine monophosphate and inositol phosphate formation

Abstract

In this study, dispersed rat pancreatic acini exhibited secretin subsensitivity in their capacity to release amylase after preexposure to increasing concentrations of the muscarinic cholinergic agonist carbamylcholine. The present study also explores the potential mechanisms involved in this cellular desensitization phenomenon. Secretin subsensitivity of pancreatic acini pre-exposed to 10(-4) M carbamylcholine was observed only at secretin concentrations above 10(-8) M. The desensitized cells had not recovered 3 h after the cholinergic agonist exposure. In these acini, the adenylate cyclase pathway remained unaltered because cholera toxin, forskolin, and 8-Br-cAMP still induced weak, but normal, amylase release when compared with control acini. In vivo administration of pertussis toxin failed to protect the dispersed pancreatic acini against carbamylcholine-induced secretin subsensitivity. Moreover, cAMP production by these acini in response to secretin, cholera toxin, and forskolin was similar to that observed in control acini. Secretin stimulation of inositol phosphate (InsP1, InsP2, InsP3) production after carbamylcholine pre-exposure remained equivalent to that observed in acini that had never been exposed to the cholinergic agonist. Thus, after muscarinic cholinergic agonist exposure, pancreatic acini showed secretin subsensitivity in their capacity to release enzyme. This phenomenon appears to result from modifications at post-second messenger loci.