Minocycline attenuates cirrhotic cardiomyopathy and portal hypertension in a rat model: Possible involvement of nitric oxide pathway

Document Type: Original Article


1 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Toxicology–Pharmacology, Faculty of Pharmacy, Pharmaceutical Science Branch, Islamic Azad University (IAUPS), Tehran, Iran

3 Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

4 Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran

5 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

6 Department of Pharmacology, School of Medicine, International Campous, Tehran University of Medical Sciences, Tehran, Iran


Objective(s): An increase in nitric oxide (NO) production has been reported in cirrhotic cardiomyopathy and, portal hypertension. Since minocycline has been shown to inhibit NO overproduction, we aimed to examine its role in a rat model of CCl4-induced cirrhotic cardiovascular complications.
Materials and Methods: Portal pressure and inotropic responsiveness of isolated papillary muscles to isoproterenol were measured in cirrhotic rats, following minocycline (50 mg/kg/day for 8 weeks) treatment. Moreover, isolated papillary muscles were incubated with nonselective and selective nitric oxide synthase (NOS) inhibitors, N (ω)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG) respectively, in an organ bath. Ventricular expression and localization of inducible NOS (iNOS), tumor necrosis factor-alpha (TNF-α) and serum nitrite concentration were evaluated.
Results: We found a decreased portal hypertension in minocycline-treated cirrhotic rats. Cirrhosis decreased contractility in response to isoproterenol stimulation, which was significantly attenuated by minocycline. Incubation with either L-NAME or AG reversed the impaired contractility in cirrhotic rats. Furthermore, minocycline decreased iNOS expression and localization in cardiomyocytes. A drop in serum nitrite and cardiac TNF-α level were also observed in cirrhotic rat that were treated by minocycline.
Conclusion: The results suggest that minocycline may improve impaired cardiac contractility and hyperdynamic state in cirrhotic rats, and this effect could be mediated by NO-dependent mechanism.


1. Zardi EM, Abbate A, Zardi DM, Dobrina A, Margiotta D, Van Tassel BW, et al. Cirrhotic cardiomyopathy. J Am Coll Cardiol 2010; 56:539-549.

2. SHORR E, ZWEIFACH BW, FURCHGOTT RF, BAEZ S. Hepatorenal factors in circulatory homeostasis IV. Tissue origins of the vasotropic principles, VEM and VDM, which appear during evolution of hemorrhagic and tourniquet shock.Circulation 1951; 3:42-79.

3. Gould L, Shariff M, Zahir M, Di Lieto M. Cardiac hemodynamics in alcoholic patients with chronic liver disease and a presystolic gallop. J Clin Invest 1969; 48:860.

4.Møller S, Henriksen JH. Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease. Heart 2002; 87:9-15.

5.Donovan CL, Marcovitz PA, Punch JD, Bach DS, Brown KA, Lucey MR, et al. Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation1996; 61:1180-1188.

6.van Obbergh L, Vallieres Y, Blaise G. Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related. J Hepatol 1996; 24:747-752.

7. Kumar A, Paladugu B, Mensing J, Kumar A, Parrillo JE. Nitric oxide-dependent and-independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility. Am J Physiol Regul Integr Comp Physiol  2007; 292: 1900-1906.

8. Liu H, Ma Z, Lee SS. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct–ligated rats. Gastroenterology 2000; 118:937-944.

9. 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; 411:135-141.

10. Ebrahimi F, Tavakoli S, Hajrasouliha AR, Shafaroodi H, Sadeghipour H, Riazi K, et al. Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats. Eur JPharmacol 2005; 523:93-100.

11. Battarbee HD, Zavecz JH, Grisham MB, Maloney RE, Chandler LJ, Mercer JW, et al. Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat. Am J PhysiolGastrointest Liver Physiol 1999; 276: 363-372.

12. Aronson A. Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc 1980; 176:1061-1068.

13. Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol 2010; 299: 539-548.

14. Scarabelli TM, Stephanou A, Pasini E, Gitti G, Townsend P, Lawrence K, et al. Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO. J Am Coll Cardiol2004; 43:865-874.

15. Matsuki S, Iuchi Y, Ikeda Y, Sasagawa I, Tomita Y, Fujii J. Suppression of cytochrome c release and apoptosis in testes with heat stress by minocycline. Biochem Biophys Res Commun 2003; 312:843-849.

16. Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK. Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res2009; 1286:174-184.

17. Bahrami F, L Morris D, H Pourgholami M. Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem 2012; 12:44-52.

18. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med2000; 6:797-801.

19. Saravi SSS, Mousavi SE, Saravi SSS, Dehpour AR. Minocycline Attenuates Depressive‐Like Behaviour Induced by Rat Model of Testicular Torsion: Involvement of Nitric Oxide Pathway. Basic Clin PharmacolToxicol 2015; 118:249-258.

20. Tao R, Kim SH, Honbo N, Karliner JS, Alano CC. Minocycline protects cardiac myocytes against simulated ischemia-reperfusion injury by inhibiting poly (ADP-ribose) polymerase-1. J Cardiovasc Pharmacol  2010; 56:659.

21. Romero-Perez D, Fricovsky E, Yamasaki KG, Griffin M, Barraza-Hidalgo M, Dillmann W, et al. Cardiac uptake of minocycline and mechanisms for in vivo cardioprotection. J Am Coll Cardiol 2008; 52:1086-1094.

22. Hu X, Zhou X, He B, Xu C, Wu L, Cui B, et al. Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Eur J Pharmacol 2010; 638:84-89.

23. Silveira MG, Torok NJ, Gossard AA, Keach JC, Jorgensen RA, Petz JL, et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am JGastroenterol2009; 104:83-88.

24. Pérez-Vargas J, Zarco N, Vergara P, Shibayama M, Segovia J, Tsutsumi V, et al. l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor. Hum Exp Toxicol  2016; 35:135-146.

25. Bortoluzzi A, Ceolotto G, Gola E, Sticca A, Bova S, Morando F, et al. Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology 2013; 57:266-276.

26. Jazaeri F, Tavangar SM, Ghazi‐Khansari M, Khorramizadeh MR, Mani AR, Dehpour AR. Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats. Liver Int2013; 33:368-374.

27. Ma Z, Miyamoto A, Lee SS. Role of altered beta-adrenoceptor signal transduction in the pathogenesis of cirrhotic cardiomyopathy in rats. Gastroenterology  1996; 110:1191-1198.

28. Ackerman Z, Karmeli F, Amir G, Rachmilewitz D. Renal vasoactive mediator generation in portal hypertensive and bile duct ligated rats. J Hepatol 1996; 24:478-486.

29. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric oxide  2001; 5:62-71.

30. Vos TA, Gouw A, Klok PA, Havinga R, van Goor H, Huitema S, et al. Differential effects of nitric oxide synthase inhibitors on endotoxin-induced liver damage in rats. Gastroenterology 1997; 113:1323-1333.

31. Smith TW, Balligand J-L, Kaye DM, Wiviott SD, Simmons WW, Han X, et al. The role of the NO pathway in the control of cardiac function. J Card Fail 1996; 2:S141-S147.

32. Eu JP, Xu L, Stamler JS, Meissner G. Regulation of ryanodine receptors by reactive nitrogen species. Biochem Pharmacol 1999; 57:1079-1084.

33. Zahradníková A, Minarovic I, Venema RC, Meszaros L. Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide. Cell Calcium 1997; 22:447-453.

34. Kim MY, Baik SK. Pathophysiology of portal hypertension, what's new? Korean J Gastroenterol 2010; 56:129-134.

35. Perri RE, Langer DA, Chatterjee S, Gibbons SJ, Gadgil J, Cao S, et al. Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation. Am J PhysiolGastrointest Liver Physiol2006; 290: 535-542.

36. Napoli J, Bishop GA, McCaughanGW. Increased intrahepatic messenger RNA expression of interleukins 2, 6, and 8 in human cirrhosis. Gastroenterology 1994; 107:789-798.

37. Tilg H, Wilmer A, Vogel W, Herold M, Nölchen B, Judmaier G, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology 1992; 103:264-274.

38. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257:387-389.

39. Haywood GA, Tsao PS, Heiko E, Mann MJ, Keeling PJ, Trindade PT, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996; 93:1087-1094.

40. De Belder A, Why H, Richardson P, Bucknall C, Martin J, Radomski M, et al. Nitric oxide synthase activities in human myocardium.Lancet 1993; 341:84-85.