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

We investigated, by acombined in vivo and in vitro approach, the temporal changes of isletnitric oxide synthase (NOS)-derived nitric oxide (NO) and hemeoxygenase (HO)-derived carbon monoxide (CO) production in relation toinsulin and glucagon secretion during acute endotoxemia induced bylipopolysaccharide (LPS) in mice. Basal plasma glucagon, islet cAMP andcGMP content after in vitro incubation, the insulin response to glucosein vivo and in vitro, and the insulin and glucagon responses to theadenylate cyclase activator 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) inislet tissue. Immunocytochemistry revealed a marked expression of iNOSin many -cells, but only in single -cells after LPS. Moreover,biochemical analysis showed a time dependent and markedly increasedproduction of NO and CO in these islets. Addition of a NOS inhibitor tosuch islets evoked a marked potentiation of glucose-stimulated insulinrelease. Finally, after incubation in vitro, a marked suppression of NOproduction by both exogenous CO and glucagon was observed in controlislets. This effect occurred independently of a concomitant inhibitionof guanylyl cyclase. We suggest that the impairing effect of increasedproduction of islet NO on insulin secretion during acute endotoxemia isantagonized by increased activities of the islet cAMP and HO-COsystems, constituting important compensatory mechanisms against thenoxious and diabetogenic actions of NO in endocrine pancreas.