Abstract
Nitric oxide (NO) has been implicated to regulate pancreatic circulation, promote capillary integrity, and inhibit leukocyte adhesion. We investigated the role of NO in the development of pancreatitis. Nitro-l-arginine, an inhibitor of NO synthase, in total dose of 35 mg/kg body wt was infused in the rats with edematous pancreatitis induced by two intraperitoneal injections of cerulein (20 μg/kg).l-Arginine (125 or 250 mg/kg), a NO donor was intravenously administered twice in the rats with hemorrhagic pancreatitis induced by waterimmersion stress plus two intraperitoneal injections of cerulein (40 μg/kg). The degree of pancreas edema, serum amylase levels, and histologic alterations were investigated. Nitro-l-arginine exacerbated cerulein-induced pancreatitis and caused a decrease in pancreatic blood flow.l-Arginine ameliorated the severity of hemorrhagic pancreatitis dose dependently and improved the pancreatic blood flow. These findings suggest that NO could confer protection against the development of hemorrhagic pancreatitis, probably through improvement of the pancreatic microcirculation.
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Popper HL, Necheles H, Russel KC: Transition of pancreatic edema into pancreatic necrosis. Surg Gynecol Obstet 87:79, 1948
Bockman DE: Microvasculature of the pancreas: Relation to pancreatitis. Int J Pancreatol 12:11–21, 1992
Klar E, Rattner DW, Compton C, Stanford G, Chernow B, Warsha AL: Adverse effect of therapeutic vasoconstrictors in experimental acute pancreatitis. Ann Surg 214:168–174, 1991
Yamaguchi H, Kimura T, Nawata H: Does stress play a role in the development of severe pancreatitis in rats? Gastroenterology 98:1682–1688, 1990
Takano S, Kimura T, Kawabuchi M, Yamaguchi H, Nawata H: Ultrastructural study of the effects of stress on the development of acute hemorrhagic pancreatitis in rats. Gastroenterol Jpn 26:236, 1991
Furukawa M, Kimura T, Sumii T, Yamaguchi H, Kinjoh M, Nawata H: Role of local pancreatic blood flow in development of hemorrhagic pancreatitis induced by stress in rats. Pancreas 8:499–505, 1993
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: Endothelin: a novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415, 1988
Hahahan DJ: Platelet activating factor: A biologically active phosphoglyceride. Annu Rev Biochem 35:493–509, 1986
Reynolds EE, Mok LLS: Role of thromboxane A2/prostaglandin H2 receptor in the vasoconstrictor response of rat aorta to endothelin. J Pharmacol Exp Ther 21:309–315, 1989
Palmer RMJ, Ashton DS, Moncada S: Vascular endothelial cell synthesize nitric oxide froml-arginine. Nature 333:664–666, 1988
Clancy RM, Leszczynska-Piziak J, Abramson SB: Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 90:1116–1121, 1992
Konturek SJ, Dembinski A, Konturek PJ, Warzecha Z, Jaworek J, Gustaw P, Tomaszewska R, Stachura J: Role of platelet activating factor in pathogenesis of acute pancreatitis in rats. Gut 33:1268–1274, 1992
Closa D, Rosello-Catafau J, Martrat A, Hotter G, Bulbena O, Fernander-Cruz L, Gelpi E: Changes of systemic prostacyclin and thromboxane A2 in sodium taurocholate- and ceruleininduced acute pancreatitis in rats. Dig Dis Sci 38:33–38, 1993
Liu XH, Kimura T, Ishikawa H, Yamaguchi H, Furukawa M, Nakano I, Kinjoh M, Nawata H: Effect of endothelin-1 on the development of hemorrhagic pancreatitis in rats. Scans J Gastroenterol 30:276–282, 1995
Katsuki S, Arnold W, Mittal C, Murad F: Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 3:23–25, 1977
Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 86:3375–3378, 1989
Vallance P, Collier J, Moncada S: Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2:997–1000, 1989
Vallance P, Collier J, Moncada S: Nitric oxide synthesized froml-arginine mediates endothelium dependent dilatation in human vein in vivo, Cardiovasc Res 23:1053–1057, 1989
Konturek SJ, Bliski J, Konturek PK, Cieszkowski M, Pawlik W: Role of endogenous nitric oxide in the control of canine pancreatic secretion and blood flow. Gastroenterology 104:896–902, 1993
Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142, 1991
Arndt H, Russell JB, Kurose I, Kubes P, Granger DN: Mediators of leukocyte adhesion in rat mesenteric venules elicited by inhibition of nitric oxide synthesis. Gastroenterology 105:675–680, 1993
Ialenti A, Ianaro A, Moncada S, Di Rosa M: Modulation of acute inflammation by endogenous nitric oxide. Eur J Pharmacol 211:177–182, 1992
Warzecha Z, Dembinski A, Szlachcic A, Jaworek J, Konturek SJ: Role of nitric oxide in pancreatic secretion and pancreatitis. Gastroenterology 104:A342, 1993
Yamaguchi H, Kimura T, Mimura K, Nawata H: Activation of proteases in cerulein-induced pancreatitis. Pancreas 4:565–571, 1989
Reber HA, Karanjia ND, Alvarez C, Widdison AL, Leung FW, Ashley SW, Lutrin FJ: Pancreatic blood flow in cats with chronic pancreatitis. Gastroenterology 103:652–659, 1992
Ceska M, Birath K, Brown B: A new and rapid method for the clinical determination of α-amylase activities in human serum and urine. Clin Chim Acta 26:437–444, 1969
Pizcueta P, Piqué JM, Fernández M, Bosch J, Rodés J, Whittle BJR, Moncada S: Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 103:1909–1915, 1992
Furukawa M, Kimura T, Yamaguchi H, Kinjoh M, Nawata H: Role of oxygen-derived free radicals in hemorrhagic pancreatitis induced by stress and cerulein in rats. Pancreas 9:67–72, 1994
Lerch MM, Adler G: Experimental pancreatitis. Curr Opin Gastroenterol 9:752–759, 1993
Whittle BJ, Lopez-Belmonte J, Moncada S: Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol 99:607–711, 1990
MacNaughton WK, Cirino G, Wallace JL: Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 45:1869–1876, 1989
Ogle CW, Qui BS: Nitric oxide inhibition intensifies coldrestraint induced gastric ulcers in rats. Experientia 49:304–307, 1993
Caplan MS, Hedlund E, Hill N, Mackendrick W: The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats. Gastroenterology 106:346–352, 1994
Emanuelli G, Montrucchio G, Gaia E, Dughera L, Corvetti G, and Gubetta L: Experimental acute pancreatitis induced by platelet activating factor in rabbits. Am J Pathol 134:315–326, 1989
Kald B, Kald A, Ihse I, Tagesson C: Release of platelet-activating factor in acute experimental pancreatitis. Pancreas 8:440–442, 1993
Lopez-Belmonte J, Whittle BJR, Moncada S: The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 108:73–78, 1993
Boughton-Smith NK, Deakin AM, Whittle BJR: Actions of nitric oxide on the acute gastrointestinal damage induced by PAF in the rat. Agents Actions 35(special conference issue):C3–C9, 1992
Tani S, Itoh H, Okabayashi Y, Nakamura T, Fujii M, Fujisawa T, Koide M, Otsuki M: New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Dig Dis Sci 35:367–374, 1990
Milner JA, Stepanovich LV: Inhibitory effect of dietary arginine on growth of Erlich ascites tumor cells in mice. J Nutr 109:489–494, 1979
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This study was supported by the research fund of the “Research Committee on Intractable Diseases of the Pancreas” of the Japanese Ministry of Health and Welfare, and by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science and Culture, Japan.
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Liu, X., Nakano, I., Yamaguchi, H. et al. Protective effect of nitric oxide on development of acute pancreatitis in rats. Digest Dis Sci 40, 2162–2169 (1995). https://doi.org/10.1007/BF02209000
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DOI: https://doi.org/10.1007/BF02209000