Acta Medica Iranica 2017. 55(1):29-34.

The Possible Role of Nitric Oxide and Oxidative Stress in the Enhanced Apoptosis of Cardiac Cells in Cirrhotic Rats
Hamed Shafaroodi, Mehrdad Hashemi, Zahra Nadia Sharif, Leila Moezi, Zeinab Janahmadi, Ahmad Reza Dehpour


 Cirrhosis has been related with hyperdynamic circulation, manifesting as increased cardiac output and decreased systemic vascular resistance. In the present study we examined the cirrhosis outcome on apoptosis of rat hearts. We also tried to explore the role of nitric oxide (NO) and oxidative stress in the probable changed apoptosis of cirrhotic hearts. Twenty eight days after ligation of bile duct, heart tissues were tested for apoptosis. The extent of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been calculated in heart tissues. The cirrhotic hearts exhibited structural defects and greater apoptosis. Chronic treatment of cirrhotic rats with L-NAME, a non-selective inhibitor of NO synthase, inhibited heart structural defects and reduced apoptosis of hearts. We also showed that cirrhotic rat hearts had an enhanced level of MDA and reduced activities of CAT, GSHPx and SOD. When the animals were treated by L-NAME chronically, the MDA level reduced and activities of CAT, GSHPx and SOD augmented in cirrhotic heart. In conclusion, increased apoptosis of cirrhotic hearts probably happen due to NO overproduction and increased oxidative stress in hearts of cirrhotic rats.


Cirrhosis; Heart; Apoptosis; Nitric oxide; Oxidative stress

Full Text:



Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology 1996;24:451-9.

Gaskari SA, Honar H, Lee SS. Therapy insight: Cirrhotic cardiomyopathy. Nat Clin Pract Gastroenterol Hepatol


Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991;337:776-8.

Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993;18:1139-43.

Ebrahimi F, Tavakoli S, Hajrasouliha AR, Sadeghipour H, Dehghani M, Ahmadi SH, et al. Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta- adrenergic stimulation in cirrhotic rats. Fundam Clin Pharmacol 2006;20:461-71.

Tavakoli S, Hajrasouliha AR, Jabehdar-Maralani P, Ebrahimi F, Solhpour A, Sadeghipour H, et al. Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: the roles of nitric oxide and endogenous opioid peptides. J Hepatol 2007;46:432-9.

Hajrasouliha AR, Tavakoli S, Jabehdar-Maralani P, Shafaroodi H, Borhani AA, Houshmand G, et al. Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids. Eur J Pharmacol 2004;499:307-13.

Tanikawa K, Torimura T. Studies on oxidative stress in liver diseases: important future trends in liver research. Med Mol Morphol 2006;39:22-7.

Moustafa AH, Ali EM, Mohamed TM, Abdou HI.Oxidative stress and thyroid hormones in patients with liver diseases. Eur J Intern Med 2009;20:703-8.

Hardwick RN, Fisher CD, Canet MJ, Lake AD, Cherrington NJ. Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos 2010;38:2293-301.

Bolukbas C, Bolukbas FF, Horoz M, Aslan M, Celik H, Erel O. Increased oxidative stress associated with the severity of the liver disease in various forms of hepatitis B virus infection. BMC Infect Dis 2005;5:95.

Nolan JP. The role of intestinal endotoxin in liver injury:a long and evolving history. Hepatology 2010;52:1829-35.

Salazar-Montes A, Ruiz-Corro L, Lopez-Reyes A, Castrejon-Gomez E, Armendariz-Borunda J. Potent antioxidant role of pirfenidone in experimental cirrhosis. Eur J Pharmacol 2008;595:69-77.

Mani AR, Ippolito S, Ollosson R, Moore KP. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 2006;43:847-56.

Moezi L, Rezayat M, Samini M, et al. Potentiation of anandamide effects in mesenteric beds isolated from bile duct-ligated rats: role of nitric oxide. Eur J Pharmacol 2004;486:53-9.

Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 1984;65:305-11.

Moezi L, Gaskari SA, Liu H, Baik SK, Dehpour AR, Lee SS. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br J Pharmacol 2006;149:898-908.

Cai L, Chen S, Evans T, Deng DX, Mukherjee K, Chakrabarti S. Apoptotic germ-cell death and testicular damage in experimental diabetes: prevention by endothelin antagonism. Urol Res 2000;28:342-7.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.

Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest 1953;32:1025-33.

Abelmann WH, Kowalski HJ, Mc NW. The hemodynamic response to exercise in patients with Laennec's cirrhosis. J Clin Invest 1955;34:690-5.

Liu H, Lee SS. Cardiopulmonary dysfunction in cirrhosis.J Gastroenterol Hepatol 1999;14:600-8.

Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med 1989;151:530-5.

van Obbergh L, Vallieres Y, Blaise G. Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related. J Hepatol 1996;24:747-52.

Liu H, Ma Z, Lee SS. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct- ligated rats. Gastroenterology 2000;118:937-44.

Mani AR, Nahavandi A, Moosavi M, Safarinejad R, Dehpour AR. Dual nitric oxide mechanisms of cholestasis-induced bradycardia in the rat. Clin Exp Pharmacol Physiol 2002;29:905-8.

Nahavandi A, Dehpour AR, Mani AR, Homayounfar H, Abdoli A, Abdolhoseini MR. The role of nitric oxide in bradycardia of rats with obstructive cholestasis. Eur J Pharmacol 2001;411:135-41.

Farzaneh-Far R, Moore K. Nitric oxide and the liver.Liver 2001;21:161-74.

Tazi KA, Barriere E, Moreau R, Heller J, Sogni P, Pateron D, et al. Role of shear stress in aortic eNOS up-regulation in rats with biliary cirrhosis. Gastroenterology 2002;122:1869-77.

Lee FY, Wang SS, Tsai YT, Lin HJ, Chu CJ, Wu SL, et al. Aminoguanidine corrects hyperdynamic circulation without ameliorating portal hypertension and portal hypertensive gastropathy in anesthetized portal hypertensive rats. J Hepatol 1997;26:687-93.

Xu L, Carter EP, Ohara M, Martin PY, Rogachev B, Morris K, et al. Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Am J Physiol Renal Physiol 2000;279:F1110-5.

Liu H, Gaskari SA, Lee SS. Cardiac and vascular changes in cirrhosis: pathogenic mechanisms. World J Gastroenterol 2006;12:837-42.

Squadrito GL, Pryor WA. Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 1998;25:392-403.

Pryor WA, Squadrito GL. The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 1995;268:L699-722.

Siqueira C, de Moura MC, Pedro AJ, Rocha P. Elevated nitric oxide and 3',5' cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis. World J Gastroenterol 2008;14:236-42.

Razavi HM, Hamilton JA, Feng Q. Modulation of apoptosis by nitric oxide: implications in myocardial ischemia and heart failure. Pharmacol Ther 2005;106:147-62.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.