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Influence of nitric oxide modulators on cholinergically stimulated hormone release from mouse islets

Björn Åkesson and Ingmar Lundquist

We have investigated, with a combined in vitro and in vivo approach, the influence on insulin and glucagon release stimulated by the cholinergic, muscarinic agonist carbachol of different NO modulators, i.e. the nitric oxide synthase (NOS) inhibitors N^G-nitro-L-arginine methyl ester (L-NAME), N^G-monomethyl-L-arginine (L-NMMA) and 7-nitroindazole as well as the intracellular NO donor hydroxylamine.

At basal glucose (7 mM) carbachol dose-dependently stimulated insulin release from isolated islets with a half-maximal response at approximately 1 µM of the agonist. In the presence of 5 mM L-NAME (a concentration that did not influence basal insulin release) the insulin response was markedly increased along the whole dose-response curve and the threshold for carbachol stimulation was significantly lowered.

Carbachol-stimulated islets displayed an increased insulin release and a suppressed glucagon release in the presence of L-NAME, L-NMMA or 7-nitroindazole. Significant suppression of glucagon release (except for L-NAME) was achieved at lower concentrations (approximately 0·1-0·5 mM) of the NOS inhibitors than the potentiation of insulin release (1·0-5·0 mM). The intracellular NO donor hydroxylamine dose-dependently inhibited carbachol-induced insulin release but stimulated glucagon release only at a low concentration (3 µM).

In islets depolarized with 30 mM K⁺ in the presence of the K_ATP channel opener diazoxide, NOS inhibition by 5 mM L-NAME still markedly potentiated carbachol-induced insulin release (although less so than in normal islets) and suppressed glucagon release.

In vivo pretreatment of mice with L-NAME was followed by a markedly increased insulin release and a reduced glucagon release in response to an i.v. injection of carbachol.

The data suggest that NO is a negative modulator of insulin release but a positive modulator of glucagon release induced by cholinergic muscarinic stimulation. These effects were also evident in K⁺ depolarized islets and thus NO might exert a major influence on islet hormone secretion independently of membrane depolarization events.

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				R. Henningsson, A. Salehi, and I. Lundquist Role of nitric oxide synthase isoforms in glucose-stimulated insulin release Am J Physiol Cell Physiol, July 1, 2002; 283(1): C296 - C304. [Abstract] [Full Text] [PDF]

				R. Henningsson, P. Alm, E. Lindstrom, and I. Lundquist Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E95 - E107. [Abstract] [Full Text] [PDF]