Heme oxygenase and carbon monoxide:: Regulatory roles in islet hormone release -: A biochemical, immunohistochemical, and confocal microscopic study

Carbon monoxide (CO) has been suggested as a novel messenger molecule in the brain. We now report on the cellular localization and hormone secretory function of a GO-producing constitutive heme oxygenase. (HO-2) in mouse islets, Islet homogenates produced large amounts of CO which were suppressed dose-dependently by the HU inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets, A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, somatostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhibited? whereas hemin enhanced, both insulin and glucagon secretion fi om glucose-stimulated islets, Stimulation or inhibition of CO production was accompanied by corresponding changes fn islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated Islets, whereas exogenous nitric oxide (NO) inhibited insulin and stimulated glucagon release, Islets stimulated by glucose or L-arginine displayed a marked increase in their NO-synthase (NOS) activity Such an increase was suppressed by hemin, conceivably because NOS activity was inhibited by hemin-derived CO, Consequently, hemin enhanced L-arginine-induced insulin secretion, Insulin release stimulated by either hemin-derived CO or exogenous Cf) was strongly inhibited try the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnPP-IX, Glucagon release induced by CO (but not by hemin) was inhibited by ODQ and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway which constitutes a novel regulatory system of physiological importance for the stimulation of insulin and glucagon release,This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays Interaction with islet NOS activity.