Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release

Islet production of nitric oxide (NO) and CO in relation to islet hormone s ecretion was investigated in mice given the NO synthase (NOS) inhibitor N-G -nitro-L-arginine methyl ester (L-NAME) in their drinking water. In these m ice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and imm unoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in L-NAM E-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after L-NAME drinking. G lucagon secretion was increased in vitro. Control islets incubated with dif ferent NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimu lated insulin release also from islets of L-NAME-drinking mice. In contrast , glucagon release was suppressed. In islets from L-NAME drinking mice, cyc lic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusi on, chronic NOS blockade evoked iNOS-derived NO production in pancreatic is lets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the is let cAMP and HO-CO systems.