Inhibitory effects of NO on insulin secretion
Suppression of mouse islet NOS activity (by L-NAME, L-NMMA, or 7-nitroindazole), is accompanied by an increase in GSIS (Panagiotidis et al., 1995[100]; Akesson et al., 1999[1]; Henningsson et al., 2000[49], 2002[52]; Eckersten and Henningsson, 2012[28]), indicating the negative role of NO in insulin secretion. In addition, GSIS has been shown to be suppressed by different concentrations of NO donors in isolated mouse (Panagiotidis et al., 1995[100]; Akesson and Lundquist, 1999[2]) and rat (Antoine et al., 1996[5]) pancreatic islets.
Concerning the mechanism, by which NO inhibits insulin secretion, there is evidence showing that NO acts through the formation of S-nitrosothiols (Stamler et al., 1992[121]), as well as changes in transmembrane ionic movements (Figure 2(Fig. 2)) (Antoine et al., 1996[5]). Hydroxylamine was shown to decrease Ca2+ entry through voltage-sensitive Ca2+ channels and increase K+ outflow from pancreatic islets, an effect which is impaired by glibenclamide (Antoine et al., 1996[5]). Hydroxylamine, however, does not affect Ca2+ outflow and [Ca2+]i rises evoked by K+-induced depolarization; the enhancing effect of hydroxylamine on K+ outflow as well as its lack of effect on the cationic responses to K+ stimulation, indicate that the decrease of Ca2+ entry can be regarded as the consequence of K+ channel activation (Antoine et al., 1996[5]). In addition, NO reacts with a number of sulfhydryl containing proteins (Stamler et al., 1992[121]), and functionally essential SH groups in the glucose-binding site of glucokinase is a target for oxidizing agents (Lenzen et al., 1988[73]). Furthermore, NO by formation of ironnitrosyl complexes with FeS containing enzymes such as aconitase, causes reversible inactivation of the mitochondrial enzyme (Lancaster and Hibbs, 1990[69]). Such mechanisms have been proposed by studies on the inducible form of NO synthase in insulin producing cells (Eizirik and Leijerstam, 1994[29]).