Increased Salivary Nitrite and Nitrate Excretion in Rats with Cirrhosis
Increased nitric oxide (NO) formation is mechanistically linked to pathophysiology of the extrahepatic complications of cirrhosis. NO is formed by either enzymatic or non-enzymatic pathways. Enzymatic production is catalyzed by NO synthase (NOS) while entero-salivary circulation of nitrate and nitrite is linked to non-enzymatic formation of NO under acidic pH in the stomach. There is no data on salivary excretion of nitrate and nitrite in cirrhosis. This study was aimed to investigate salivary levels of nitrate and nitrite in a rat model of biliary cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Four weeks after the operation, submandibular ducts of anesthetized BDL and control rats were cannulated with polyethylene microtube for saliva collection. Assessment of pH, nitrite and nitrate levels was performed in our research. We also investigated NOS expression by real time RT-PCR to estimate eNOS, nNOS and iNOS mRNA levels in the submandibular glands. Salivary pH was significantly lower in BDL rats in comparison to control animals. We also observed a statistically significant increase in salivary levels of nitrite as well as nitrate in BDL rats while there was no elevation in the mRNA expression of nNOS, eNOS, and iNOS in submandibular glands of cirrhotic groups. This indicates that an increased salivary level of nitrite/nitrate is less likely to be linked to increased enzymatic production of NO in the salivary epithelium. It appears that nitrate/nitrite can be transported from the blood stream by submandibular glands and excreted into saliva as entero-salivary circulation, and this mechanism may have been exaggerated during cirrhosis.
El-Sherif AM, Abou-Shady MA, Al-Bahrawy AM, et al. Nitric oxide levels in chronic liver disease patients with and without oesophageal varices. Hepatol. Int 2008;2(3):341-5.
Moal F, Veal N, Vuillemin E, et al. Hemodynamic and antifi brotic effects of a selective liver nitric oxide donor V-PYRRO/NO in bile duct ligated rats. World J Gastroenterol 2006;12(41):6639-45.
Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin Liver Dis 2001;21(3):337-49.
Reynaert H, Thompson MG, Thomas T, et al. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut 2002;50(4):571-81.
McCuskey RS. Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver 2000;20(1):3-7.
Kato Y, Katsuta Y, Zhang X, et al. Inhibition of nitric oxide synthase in hyperdynamic circulation of rats with early or late cirrhosis secondary to common bile duct ligation. J Nippon Med Sch 2011;78(3):146-55.
Schweyer S, Mihm S, Radzun HJ, et al. Liver infiltrating T lymphocytes express interferon gamma and inducible nitric oxide synthase in chronic hepatitis C virus infection. Gut 2000;46(2):255-9.
Kandemir O, Polat A, Kaya A. Inducible nitric oxide synthase expression in chronic viral hepatitis and its relation with histological severity of disease. J Viral Hepatol 2002;9(6):419-23.
de Lucas S, Bartolome J, Amaro MJ, et al. Hepatitis C virus core protein transactivates the inducible nitric oxide synthase promoter via NF-kappaB activation. Antiviral Res 2003;60(2):117-24.
Sanchez-Rodriguez A, Criado M, Rodriguez-Lopez AM, et al. Increased nitric oxide synthesis and inducible nitric oxide synthase expression in patients with alcoholic and non-alcoholic liver cirrhosis. Clin Sci (Lond) 1998;94(6):637-43.
Barak N, Zemel R, Ben-Ari Z, et al. Nitric oxide metabolites in decompensated liver cirrhosis. Dig Dis Sci 1999;44(7):1338-41.
Bakaar G, Sorbi D, Mazzoccoli V. Nitric oxide and chronic HCV and HIV infections. Dig Dis Sci 2001;46(5):1072-6.
Theodorakis NG, Wang YN, Wu JM, et al. Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. Am J Physiol Gastrointest Liver Physiol 2009;297(4):G792-9.
Loureiro-Silva MR, Cadelina GW, Groszmann RJ. Deficit in nitric oxide production in cirrhotic rat livers is located in the sinusoidal and postsinusoidal areas. Am. J. Physiol. Gastrointest Liver Physiol 2003;284(4):G567-74.
Cahill PA, Redmond EM, Hodges R, et al. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J Hepatol 1996;25(3):370-8.
Hartleb M, Michielsen P, Dziurkowska-Marek A. The role of nitric oxide in portal hypertensive systemic and portal vascular pathophysiology. Acta Gastroenterol Belg 1997;60(3):222-32.
Xu L, Carter EP, Ohara M, et al. Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Am J Physiol 2000;279(6):F1110-5.
McKnight GM, Smith LM, Drummond RS, et al. Chemical synthesis of nitric oxide in the stomac from dietary nitrate in humans. Gut 1997;40(2):211-4.
Iijima K, Henry E, Moriya A, et al. Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 2002;122(5):1248-57.
Pannala AS, Mani AR, Spencer PE, et al. The effect of dietry nitrate on salivary, plasma and urinary nitrate metabolism in human. Free Radic Biol Med 2003;34(5):576-84.
Sogni P, Garnier P, Gadano A, et al. Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with severe cirrhosis. J Hepatol 1995;23(4):471-3.
Campillo B, Bories PN, benvenuti C, et al. Serum and urinary nitrate levels in liver cirrhosis: endotoxemia, renal function and hyperdynamic circulation. J Hepatol 1996;25(5):707-14.
Guarner C, Soriano G, Tomas A, et al. Increased nitric oxide levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993;18(5):1139-43.
Dehpour AR, Mani AR, Alikhani Z, et al. Enhancement of aspirin-induced gastric damage by cholestasis in rats. Fundam Clin Pharmacol 1998;12(4):442-5.
Yoshida Y, Sprecher RL, Schneyer CA, et al. Role of β- receptors in sympathetic regulation of electrolytes in rat sub maxillary saliva. Proc Soc Exp Biol Med 1967;126(3):912-6.
Abdollahi M, Dehpour A, Shafayee F. L-arginine/nitric oxide pathway and interaction with lead acetate on rat submandibular gland function. Pharmacol Toxicol 2000;87(5):198-203.
Medina JF, Martinez-anso E, Va´ Zquez JJ, et al. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 1997;25(1):12-7.
Alper SL. Molecular physiology and genetics of Na+- independent SLC4 anion exchangers. J Exp Biol 2009;212(Pt 11):1672-83.
Stewart AK, Chernova MN, Shmukler BE, et al. Regulation of AE2-mediated Cl-Transport by Intracellular or by Extracellular pH Requires Highly Conserved Amino Acid Residues of the AE2 NH2-terminal Cytoplasmic Domain. J. Gen. Physiol 2002;120(5):707-22.
Alper SL, Chernova MN, Stewart AK. Regulation of Na+- Independent Cl-/HCO-3 Exchangers by pH. JOP J Pancreas 2001;2(4 Suppl):171-5.
Alper SL. Molecular physiology of SLC4 anion exchangers. Exp Physiol 2006;91(1):153-61.
|Issue||Vol 53, No 11 (2015)|
|Cirrhosis Nitric oxide Nitrite Nitrate Rat Saliva|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|