Summary
Nitric oxide, which is produced from l-arginine by a nitric oxide-synthase enzyme, has been shown to be a ubiquitous messenger molecule. Recently, it has been suggested that nitric oxide might influence insulin secretion by activating the soluble guanylate cyclase and generating cyclic guanosine monophosphate (cGMP). We have investigated the role of the nitric oxide pathway in insulin secretion by evaluating the insulin response to several secretagogues in rats in which nitric oxide-synthase was chronically inhibited by oral administration of the l-arginine analogue, NG-nitro-l-arginine methyl ester (l-NAME). Blood pressure and aortic wall cGMP content were used as indices of nitric oxide-synthase blockade. Insulin secretion was evaluated after an intravenous bolus of d-glucose, l-arginine or d-arginine. Chronic l-NAME administration induced a 30% increase in blood pressure and a seven-fold drop in arterial cGMP content. Body weight, fasting plasma glucose and insulin were not influenced by l-NAME administration. First-phase insulin secretion (1+3 min) in response to glucose was not significantly different in l-NAME and control rats. The areas under the insulin curve were similar in both groups. Insulin secretion in response to d-arginine or l-arginine in l-NAME-treated and control rats were also similar. In conclusion, chronic nitric oxide-synthase blockade increases blood pressure and decreases aortic cGMP content, but does not alter insulin secretion in response to several secretagogues. Chronic oral administration of l-NAME in the rat provides an adequate animal model for studying the l-arginine nitric oxide-pathway.
Article PDF
Similar content being viewed by others
Abbreviations
- NO:
-
Nitric oxide
- cGMP:
-
guanosine 3′: 5′ cyclic monophosphate
- l-NMMA:
-
NG-monomethyl-l-arginine
- l-NAME:
-
NG-nitro-l-arginine-methyl-ester
- NOD mice:
-
non obese diabetic mice
References
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524–526
Dinerman JL, Lowenstein CJ, Snyder SH (1993) Molecular mechanisms of nitric oxide regulation. Circ Res 73: 217–222
Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43: 109–142
Bredt DS, Hwang PM, Snyder SH (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347: 768–770
Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxydation of sulfhydryls: the cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266: 4244–4250
Nussler AK, Billiar TR (1993) Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 54: 171–178
Lowenstein CJ, Synder SH (1992) Nitric oxide, a novel biologic messenger. Cell 70: 705–707
Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298: 249–258
Schmidt HHHW, Warner TD, Ishii K, Sheng H, Murad F (1992) Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides. Science 255: 721–723
Laychock SG, Modica ME, Cavanaugh CT (1991) L-arginine stimulates cyclic guanosine 3′5′-monophosphate formation in rat islet of Langerhans and RINm5F insulinoma cells: evidence for L-arginine: nitric oxide synthase. Endocrinology 129: 3043–3052
Jones PM, Persaud SJ, Bjaaland T, Pearson JD, Howell SL (1992) Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans. Diabetologia 35: 1020–1027
Vincent SR (1992) Nitric oxide and arginine-evoked insulin secretion. Science 258: 1376
Corbett JA, Wang JL, Misko TP, Zhao WG, Hickeky WF, McDaniel ML (1993) Nitric oxide mediates IL-1 β induced islet dysfunction and destruction. Prevention by dexamethasone. Autoimmunity 15: 145–153
Lambert LE, Whitten JP, Baron BM, Cheng HC, Doherty NS, McDonald IA (1991) Nitric oxide synthesis in the CNS, endothelium and macrophages differs in its sensitivity to inhibition by arginine analogues. Life Sci 48: 69–75
Southern C, Schulster D, Green IC (1990) Inhibition of insulin secretion by interleukin-1β and tumor necrosis factor-α via an L-arginine-dependent nitric oxide generating mechanism. FEBS Lett 276: 42–44
Eizirik DL, Cagliero E, Björklund A, Welsh N (1992) Interleukin-1 β induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which is similar to that observed in activated macrophages. FEBS Lett 308: 249–252
Arnal JF, Warin L, Michel JB (1992) Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. J Clin Invest 90: 647–652
Moro MA, Michelena P, Sanchez-García P, Palmer R, Moncada S, García AG (1993) Activation of adrenal medullary L-arginine: nitric oxide pathway by stimuli which induce the release of catecholamines. Eur J Pharmacol 246: 213–218
Causon RC, Carruthers ME, Rodnight R (1981) Assay of plasma catecholamines by liquid chromatography with electrochemical detection. Anal Biochem 116: 223–226
Blachier F, Leclercq-Meyer V, Marchand J et al. (1989) Stimulus-secretion coupling of arginine-induced insulin release. Functional response of islets to L-arginine and ornithine. Biochem Biophys Acta 1013: 144–151
Malaisse WJ, Blanchier F, Mourtada A et al. (1989) Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of L-arginine and L-ornithine in pancreatic islets. Biochem Biophys Acta 1013: 133–143
Sener A, Blanchier F, Rasschaert J, Malaisse WJ (1990) Stimulus-secretion coupling of arginine-induced insulin release. Comparison with histidine-induced insulin release. Endocrinology 127: 107–113
Arnal JF, El Amrani AI, Michel JB (1993) Atrial natriuretic factor influences in vivo plasma, lung and aortic wall cGMP concentrations differently. Eur J Pharmacol 237: 265–273
Verspohl AJ, Ammon HPT (1989) Atrial natriuretic peptide acts via specific binding sites of cGMP system of rat pancreatic islets without affecting insulin release. Naunyn Schmiedebergs Arch Pharmacol 339: 348–353
Granger DL, Hibbs JB, Perfect JR, Durack DT (1990) Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages. J Clin Invest 85: 264–273
Bogle RG, Moncada S, Pearson JD, Mann GE (1992) Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transporter. Br J Pharmacol 105: 768–770
Jansson L, Sandler S (1991) The nitric oxide synthase II inhibitor NG-nitro-L-arginine stimulates pancreatic islet insulin release in vitro, but not in the perfused pancreas. Endocrinology 128: 3081–3085
Gardiner SM, Kemp PA, Bennett T (1993) Regional haemodynamics in Brattleboro rats during chronic ingestion of NG-nitro-L-arginine methyl ester. Blood Pressure 2: 228–232
Kaech C, Zhu JS, Brechtel G, Baron AD (1993) Acute hypertension induced by L-NMMA causes insulin resistance in rats. Hypertension 22: 470 (Abstract)
Krönke KD, Rodriguez ML, Kolb H, Kolb-Bachofen V (1993) Cytotoxicity of activated rat macrophages against syngeneic islets cells is arginine-dependent, correlates with citrulline and nitrite concentrations and is identical to lysis by the nitric oxide donor nitroprusside. Diabetologia 36: 17–24
Corbett JA, Wang JL, Hugher JH et al. (1992) Nitric oxide and cyclic GMP formation induced by interleukin-1 β in islets of Langerhans. Biochem J 287: 229–235
Corbett JA, Mikhael A, Shimizu J et al. (1993) Nitric oxide production in islets from nonobese diabetic mice: aminoguanidine-sensitive and -resistant stages in the immunological diabetic process. Proc Natl Acad Sci USA 90: 8992–8995
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pueyo, M.E., Gonzalez, W., Pussard, E. et al. Insulin secretion in rats with chronic nitric oxide synthase blockade. Diabetologia 37, 879–884 (1994). https://doi.org/10.1007/BF00400942
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400942