Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia

We investigated, by a combined in vivo and in vitro approach, the temporal changes of islet nitric oxide synthase (NOS)-derived nitric oxide (NO) and heme oxygenase (HO)-derived carbon monoxide (CO) production in relation to insulin and glucagon secretion during acute endotoxemia induced by lipopoly saccharide (LPS) in mice. Basal plasma glucagon, islet cAMP and cGMP conten t after in vitro incubation, the insulin response to glucose in vivo and in vitro, and the insulin and glucagon responses to the adenylate cyclase act ivator forskolin were greatly increased after LPS. Immunoblots demonstrated expression of inducible NOS (iNOS), inducible HO (HO-1), and an increased expression of constitutive HO (HO-2) in islet tissue. Immunocytochemistry r evealed a marked expression of iNOS in many beta -cells, but only in single alpha -cells after LPS. Moreover, biochemical analysis showed a time depen dent and markedly increased production of NO and CO in these islets. Additi on of a NOS inhibitor to such islets evoked a marked potentiation of glucos e-stimulated insulin release. Finally, after incubation in vitro, a marked suppression of NO production by both exogenous CO and glucagon was observed in control islets. This effect occurred independently of a concomitant inh ibition of guanylyl cyclase. We suggest that the impairing effect of increa sed production of islet NO on insulin secretion during acute endotoxemia is antagonized by increased activities of the islet cAMP and HO-CO systems, c onstituting important compensatory mechanisms against the noxious and diabe togenic actions of NO in endocrine pancreas.