R. Henningsson et al., Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia, AM J P-CELL, 280(5), 2001, pp. C1242-C1254
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.