We have previously shown that the selective peripheral-type benzodiazepine agonist 4'-chlordiazepam inhibited glucose-induced insulin secretion from rat pancreatic islets. The present work was designed to further investigate the mechanism of this effect. Since interactions have been described between benzodiazepines and purinergic modulators such as adenosine, we studied the effect of the adenosine receptor antagonist 8-phenyltheophylline. This substance, which on its own had no effect on insulin release, prevented the inhibiting effect of 4'-chlordiazepam. 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, in contrast to the inhibiting effect of adenosine, which has been previously shown to be prevented by dibutyryl-cAMP. In conclusion, the inhibiting effect of 4'-chlordiazepam on glucose-induced insulin secretion is antagonized by 8-phenyltheophylline; the signalling mechanism of this effect appears to be independent of the adenylyl cyclase/cAMP pathway.
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