INVESTIGATION ON THE MECHANISM OF INHIBIT ION OF INSULIN-SECRETION INDUCED BY A PERIPHERAL-TYPE BENZODIAZEPINE, 4'-CHLORDIAZEPAM

We have previously shown that the selective peripheral-type benzodiaze pine agonist 4'-chlordiazepam inhibited glucose-induced insulin secret ion from rat pancreatic islets. The present work was designed to furth er investigate the mechanism of this effect. Since interactions have b een described between benzodiazepines and purinergic modulators. such as adenosine, we studied the effect of the adenosine receptor antagoni st 8-phenyltheophylline. This substance, which on its own had no effec t on insulin release, prevented the inhibiting effect of 4'-chlordiaze pam. We then performed experiments in the presence of forskolin, which directly stimulates adenylyl-cyclase, and dibutyryl-cyclic AMP, which enhances the intracellular cAMP content. The inhibiting effect of 4'- chlordiazepam was prevented neither by forskolin nor dibutyryl-cAMP, i n contrast to the inhibiting effect of adenosine, which has been previ ously shown to be prevented by dibutyryl-cAMP. In conclusion, the inhi biting effect of 4'-chlordiazepam on glucose-induced insulin secretion is antagonized by 8-phenyltheophylline; the signalling mechanism of t his effect appears to be independent of the adenylyl cyclase/cAMP path way.