Nitric oxide and hydroperoxide affect islet hormone release and Ca2+ efflux

We have investigated the influence of the intracellular free radical donors hydroxylamine (giving nitric oxide [NO]) and tert-butylhydroperoxide (givi ng hydroperoxide ["H2O2"]) on glucose- and cyclic adenosine monophosphate ( cAMP)-induced transduction signaling in islet hormone release. Both donors dose dependently inhibited glucose-stimulated insulin release and induced m odest (hydroxylamine) or profound (tert-butylhydroperoxide) suppression of Ca-45(2+)-efflux from perifused islets. By contrast, both donors stimulated glucagon release. Similar effects on hormone release were displayed after K+-depolarization. Insulin and glucagon release stimulated by activation of the cAMP system through isobutylmethylxanthine (IBMX) at basal glucose was modestly potentiated by low concentrations of both donors. These effects w ere still observed, although less pronounced, in K+-depolarized islets. In vitro as well as in vivo, the NO-synthase inhibitor N-G-nitro-L-arginine me thyl ester inhibited IBMX-induced glucagon release, but did not affect insu lin release. The results suggest that NO and hydroperoxide inhibit glucose- stimulated insulin release by perturbing Ca2+ fluxes and probably acting th rough S-nitrosylation (NO) or oxidation (hydroperoxide) of thiol groups cri tical to the secretory process. These effects are largely independent of de polarization events. By contrast, both NO and hydroperoxide can potentiate cAMP-stimulated hormone release presumably at a distal site in the stimulus -secretion coupling.