ALTERATIONS OF INSULIN-RESPONSE TO DIFFERENT BETA-CELL SECRETAGOGUES AND PANCREATIC VASCULAR-RESISTANCE INDUCED BY N-OMEGA-NITRO-L-ARGININEMETHYL-ESTER

1 We studied a possible interplay of pancreatic NO synthase activity o n insulin secretion induced by different beta cell secretagogues and a lso on pancreatic vascular bed resistance. 2 This study was performed in the isolated perfused pancreas of the rat. Blockade of NO synthase was achieved with N-omega-nitro-L-arginine methyl ester (L-NAME); the specificity of the antagonist was checked by using its D-enantiomer as well as by substitutive treatments with sodium nitroprusside (SNP) as a NO donor in studies of glucose-induced insulin secretion. 3 Arginin e (5 mM) induced a monophasic insulin response which was, in the prese nce of L-NAME at equimolar concentration, very strongly potentiated an d converted into a 13 times higher biphasic one. D-NAME (5 mM) was onl y able to induce a 3 times higher response, but provoked a similar vas oconstrictor effect. 4 The small biphasic insulin secretion induced by L-leucine (5 mM) was also strongly enhanced, by 8 times, in the prese nce of L-NAME (5 mM) vs 2 times in the presence of D-NAME (5 mM). 5 be ta cell responses to KCl (5 mM) and tolbutamide (0.185 mM) were only s lightly increased by L-NAME (5 mM) to values not far from the sum of t he effects of L-NAME and of the two drugs alone. D-NAME (5 mM) was tot ally ineffective on the actions of both secretagogues. 6 L-NAME, infus ed 15 min before and during a rise in glucose concentration from 5 to 11 mM, was able in the low millimolar range (0.1-0.5 mM) to blunt the classical biphasic pattern of beta cell response to glucose and, at 5 mM, to convert it into a significantly greater monophasic one. In cont rast, D-NAME (5 mM) was unable to induce similar effects. 7 SNP alone at 3 mu M was ineffective but at 30 mu M substantially reduced the sec ond phase of insulin response to glucose; however, at both concentrati ons the NO donor partly reversed alterations in insulin secretion caus ed by L-NAME (5 mM) and restored a biphasic pattern of insulin respons e. At a high (300 mu M) concentration, SNP drastically reduced the sec ond phase of beta cell response, but in the presence of L-NAME, provok ed a significantly greater biphasic response. 8 When L-NAME was infuse d only for the 15 min before high glucose, an exaggerated first phase of beta cell response was followed by an abortive second one. SNP, at a low concentration (30 nM), given simultaneously with L-NAME, restore d a biphasic pattern and prevented the vasoconstrictor effect induced by the inhibitor. 9 L-NAME, when infused only during high glucose, mar kedly enhanced the second phase of insulin response which could be sig nificantly reduced by SNP (3 mu M). The NO donor induced a dilator eff ect significantly greater in L-NAME-treated pancreata than in non-trea ted ones. 10 In conclusion our data bring evidence that NO synthase ac tivity exerts an inhibitory control on pancreatic beta cell response t o various nutrient secretagogues and may, at least partly, be implicat ed in the generation of the biphasic pattern of insulin response to gl ucose.