Skip to main content
SpringerLink
Log in

The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to β-adrenoceptor activation, and excitation–contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to β-adrenoceptor activation, both of which appeared to result from altered ECC. β-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed β-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered β-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and β-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

[Ca2+]O :

Extracellular Ca2+ concentration

ECC:

Excitation–contraction coupling

KH:

Krebs–Henseleit physiological salt solution

PVS:

Portal vein stenosis

UDCA:

Ursodeoxycholic acid

dT/dt:

Maximum rate of force development

−dT/dt:

Maximum rate of relaxation

References

  1. Moller, S., & Henriksen, J. H. (2002). Cirrhotic cardiomyopathy: A pathophysiological review of circulatory dysfunction in liver disease. Heart, 87, 9–15.

    Article  CAS  PubMed  Google Scholar 

  2. Battarbee, H. D., & Zavecz, J. H. (1992). Cardiac performance in the portal vein-stenosed rat. American Journal of Physiology–Gastrointestinal and Liver Physiology, 263, G181–G185.

    CAS  Google Scholar 

  3. Bernardi, M., Rubboli, A., Trevisani, F., Cancellieri, C., Ligabue, A., Baraldini, M., et al. (1991). Reduced cardiovascular responsiveness to exercise-induced sympathoadrenergic stimulation in patients with cirrhosis. Journal of Hepatology, 12, 207–216.

    Article  CAS  PubMed  Google Scholar 

  4. Binah, O., Bomzon, A., Blendis, L. M., Mordohovich, D., & Better, O. S. (1985). Obstructive jaundice blunts myocardial contractile response to isoprenaline in the dog: A clue to the susceptibility of jaundiced patients to shock? Clinical Science, 69, 647–653.

    CAS  PubMed  Google Scholar 

  5. Bomzon, A., Rosenberg, M., Gali, D., Binah, O., Mordechowitz, D., Better, O. S., et al. (1986). Systemic hypotension and decreased pressor response in the dog with chronic bile duct ligation (CBDL). Hepatology, 6, 595–600.

    Article  PubMed  Google Scholar 

  6. Grose, R. D., Nolan, J., Dillon, J. F., Errington, M., Hannan, W. J., Bouchier, I. A. D., et al. (1995). Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis. Journal of Hepatology, 22, 326–332.

    Article  CAS  PubMed  Google Scholar 

  7. Ingles, A. C., Hernandez, I., Garcia-Estan, J., Quesada, T., & Carbonell, L. F. (1991). Limited cardiac preload reserve in conscious cirrhotic rats. American Journal of Physiology, 260, H1912–H1917.

    CAS  PubMed  Google Scholar 

  8. Inserte, J., Perello, A., Agullo, L., Ruiz-Meana, M., Schluter, K. D., Escalona, N., et al. (2003). Left ventricular hypertrophy in rats with biliary cirrhosis. Hepatology, 38, 589–598.

    Article  CAS  PubMed  Google Scholar 

  9. Lee, S. S., & Bomzon, A. (1990). The heart in liver disease. In A. Bomzon & L. M. Blendis (Eds.), Cardiovascular complications of liver disease (pp. 81–102). Boca Raton, FL: CRC.

    Google Scholar 

  10. Merli, M., Valeriano, V., Funaro, S., Attili, A. F., Masini, A., Efrati, C., et al. (2002). Modifications of cardiac function in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt (TIPS). American Journal of Gastroenterology, 97, 142–148.

    Article  PubMed  Google Scholar 

  11. Wong, F., Liu, P., Lilly, L., Bomzon, A., & Blendis, L. (1999). Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis. Clinical Science (London), 97, 259–267.

    Article  CAS  Google Scholar 

  12. Zavecz, J. H., Battarbee, H. D., Bueno, O. F., O’Donnell, J. M., Roerig, S. C., & Maloney, R. E. (2000). Cardiac excitation-contraction coupling in the portal hypertensive rat. American Journal of Physiology–Gastrointestinal and Liver Physiology, 279, G28–G39.

    CAS  PubMed  Google Scholar 

  13. Genecin, P., Polio, J., Colombato, L. A., Ferraioli, G., Reuben, A., & Groszmann, R. J. (1990). Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats. American Journal of Physiology–Gastrointestinal and Liver Physiology, 259, G21–G25.

    CAS  Google Scholar 

  14. Binah, O., Rubinstein, I., Bomzon, A., & Better, O. S. (1987). Effects of bile acids on ventricular muscle contraction and electrophysiological properties: Studies in rat papillary muscle and isolated ventricular myocytes. Naunyn-Schmiedeberg’s Archives of Pharmacology, 335, 160–165.

    CAS  PubMed  Google Scholar 

  15. Bogin, E., Better, O., & Harari, I. (1983). The effect of jaundiced sera and bile salts on cultured beating heart cells. Experientia, 39, 1307–1308.

    Article  CAS  PubMed  Google Scholar 

  16. Ferreira, M., Coxito, P. M., Sardao, V. A., Palmeira, C. M., & Oliveira, P. J. (2005). Bile acids are toxic for isolated cardiac mitochondria: A possible cause for hepatic-derived cardiomyopathies? Cardiovascular Toxicology, 5, 63–73.

    Article  CAS  PubMed  Google Scholar 

  17. Paauw, J. D., Vanwyk, L., & Davis, A. T. (1996). Assay for taurine conjugates of bile acids in serum by reversed-phase high-performance liquid chromatography. Journal of Chromatography B—Biomedical Applications, 685, 171–175.

    Article  CAS  Google Scholar 

  18. Poupon, R. E., Lindor, K. D., CauchDudek, K., Dickson, E. R., Poupon, R., & Heathcote, E. J. (1997). Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology, 113, 884–890.

    Article  CAS  PubMed  Google Scholar 

  19. Bateson, M. C. (1997). Bile acid research and applications. Lancet, 349, 5–6.

    Article  CAS  PubMed  Google Scholar 

  20. Duerksen, D. R., Vanaerde, J. E., Gramlich, L., Meddings, J. B., Chan, G., Thomson, A. B. R., et al. (1996). Intravenous ursodeoxycholic acid reduces cholestasis in parenterally fed newborn piglets. Gastroenterology, 111, 1111–1117.

    Article  CAS  PubMed  Google Scholar 

  21. Heumann, D. M., Pandak, W. M., Hylemon, P. B., & Vlahcevic, Z. R. (1991). Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: In vitro studies in rat hepatocytes and human erythrocytes. Hepatology, 14, 920–926.

    Article  Google Scholar 

  22. Rodrigues, C. M. P., Kren, B. T., Steer, C. J., & Setchell, K. D. R. (1995). Tauroursodeoxycholate increases rat liver ursodeoxycholate levels and limits lithocholate formation better than ursodeoxycholate. Gastroenterology, 109, 564–572.

    Article  CAS  PubMed  Google Scholar 

  23. Baruch, Y., Assy, N., Weisbruch, F., Reisner, S. A., Rinkevich, D., Enat, R., et al. (1999). A pilot study on the hemodynamic effect of short-term ursodeoxycholic acid therapy in patients with stable liver cirrhosis. American Journal of Gastroenterology, 94, 3000–3004.

    Article  CAS  PubMed  Google Scholar 

  24. Battarbee, H. D., Zavecz, J. H., Grisham, M. D., Chandler, L. J., Mercer, J., Bueno, O., et al. (1999). Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat. American Journal of Physiology Liver, 276, G363–G372.

    CAS  Google Scholar 

  25. Zavecz, J. H., Battarbee, H. D., & O’Donnell, J. M. (1995). Cardiac beta-adrenoceptor-effector coupling in portal vein-stenosed rats. American Journal of Physiology, 268, G410–G415.

    CAS  PubMed  Google Scholar 

  26. Limas, C. J., Guiha, N. H., Lekagul, O., & Cohn, J. N. (1974). Impaired left ventricular function in alcoholic cirrhosis with ascites. Ineffectiveness of ouabain. Circulation, 49, 754–760.

    CAS  PubMed  Google Scholar 

  27. Rüegg, J. C. (1986). Calcium in muscle activation. A comparative approach. New York: Springer.

    Google Scholar 

  28. Allen, D. G., & Kurihara, S. (1980). Calcium transients in mammalian ventricular muscle. European Heart Journal, 1(Suppl A), 5–15.

    Google Scholar 

  29. Kitazawa, T. (1984). Effect of extracellular calcium on contractile activation in guinea-pig ventricular muscle. Journal of Physiology, 355, 635–659.

    CAS  PubMed  Google Scholar 

  30. Kinugasa, T., Uchida, K., Kadowaki, M., Takase, H., Nomura, Y., & Saito, Y. (1981). Effect of bile duct ligation on bile acid metabolism in rats. Journal of Lipid Research, 22, 201–207.

    CAS  PubMed  Google Scholar 

  31. DeLean, A., Hancock, A. A., & Lefkowitz, R. J. (1982). Validation and statistical analysis of a computer modeling method for quantitative analysis of radioligand binding data for mixtures of pharmacological receptor subtypes. Molecular Pharmacology, 21, 5–16.

    CAS  Google Scholar 

  32. Simonds, W. F., Goldsmith, P. K., Codina, J., Unson, C. G., & Spiegel, A. M. (1989). Gi2 mediates α2-adrenergic inhibition of adenylyl cyclase in platelet membranes: In situ identification with Gα C -terminal antibodies. Proceedings of the National Academy of Sciences of the United States of America, 86, 7809–7813.

    Article  CAS  PubMed  Google Scholar 

  33. Spiegel, A. M. (Ed.). (1990). Antibodies as probes of the structure and function of heterotrimeric GTP-binding proteins. Washington, DC: American Society of Microbiology.

    Google Scholar 

  34. Bassani, R. A., & Bers, D. M. (1994). Na-Ca exchange is required for rest-decay but not for rest potentiation of twitches in rabbit and rat ventricular myocytes. Journal of Molecular and Cellular Cardiology, 26, 1335–1347.

    Article  CAS  PubMed  Google Scholar 

  35. Combes, B., Carithers, R. L., Maddrey, J., Munoz, W. C., Garcia-Tsao, S., Bonner, G., et al. (1999). Biliary bile acids in primary biliary cirrhosis: Effect of ursodeoxycholic acid. Hepatology, 29, 1649–1654.

    Article  CAS  PubMed  Google Scholar 

  36. Larghi, A., Crosignani, A., Battezzati, P. M., DeValle, G., Allocca, M., Invernizzi, P., et al. (1997). Ursodeoxycholic and tauro-ursodeoxycholic acids for the treatment of primary biliary cirrhosis: A pilot crossover study. Alimentary Pharmacology & Therapeutics, 11, 409–414.

    Article  CAS  Google Scholar 

  37. Lindor, K. D., Therneau, T. M., Jorgensen, R. A., Malinchoc, M., & Dickson, E. R. (1996). Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology, 110, 1515–1518.

    Article  CAS  PubMed  Google Scholar 

  38. Lumlertgol, D., Boonyaprapa, S., Bunnacheck, D., Thanachaikun, N., Praisontarangkul, O. A., Phornphutkul, K., et al. (1991). The jaundiced heart: Evidence for blunted response to positive inotropic stimulation. Renal Failure, 13, 15–22.

    Article  Google Scholar 

  39. Ohkubo, H., Okuda, K., Iida, S., Ohnishi, K., Ikawa, S., & Makino, I. (1984). Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology, 86, 514–520.

    CAS  PubMed  Google Scholar 

  40. Poupon, R. E., Bonnand, A. M., Chretien, Y., Poupon, R., & Group, T. U.-P. S. (1999). Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Hepatology, 29, 1668–1671.

    Article  CAS  PubMed  Google Scholar 

  41. Kaab, S., Nuss, H. B., Chiamvimonvat, N., O’Rourke, B., Pak, P. H., Kass, D. A., et al. (1996). Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circulation Research, 78, 262–273.

    CAS  PubMed  Google Scholar 

  42. Ma, Z., & Lee, S. S. (1996). Cirrhotic cardiomyopathy: Getting to the heart of the matter. Hepatology, 24, 451–459.

    Article  CAS  PubMed  Google Scholar 

  43. Ward, C. A., Liu, H., & Lee, S. S. (2001). Altered cellular calcium regulatory systems in a rat model of cirrhotic cardiomyopathy. Gastroenterology, 121, 1209–1218.

    Article  CAS  PubMed  Google Scholar 

  44. Ma, Z., Miyamoto, A., & Lee, S. S. (1996). Role of altered β-adrenoceptor signal transduction in the pathogenesis of cirrhotic cardiomyopathy in rats. Gastroenterology, 110, 1191–1198.

    Article  CAS  PubMed  Google Scholar 

  45. Bassani, R. A., & Bers, D. M. (1995). Rate of diastolic Ca release from the sarcoplasmic reticulum of intact rabbit and rat ventricular myocytes. Biophysical Journal, 68, 2015–2022.

    Article  CAS  PubMed  Google Scholar 

  46. Gazawi, H., Ljubuncic, P., Cogan, U., Hochgraff, E., Ben-Shachar, D., & Bomzon, A. (2000). The effects of bile acids on β-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes. Biochemical Pharmacology, 59, 1623–1628.

    Article  CAS  PubMed  Google Scholar 

  47. Ma, Z., Meddings, J. B., & Lee, S. S. (1995). Cardiac plasma membrane physical properties and β-adrenergic receptor function are unaltered in portal-hypertensive rats. Hepatology, 22, 188–193.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Ron Maloney for technical assistance and Dr. Tammy Dugas for critically reading the manuscript. This work was supported by a grant from the Louisiana Affiliate of the American Heart Association.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA, 71130-3932, USA

    James H. Zavecz

  2. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    Harold D. Battarbee

Authors
  1. James H. Zavecz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harold D. Battarbee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James H. Zavecz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zavecz, J.H., Battarbee, H.D. The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy. Cardiovasc Toxicol 10, 117–129 (2010). https://doi.org/10.1007/s12012-010-9069-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-010-9069-8

Keywords

Search

Navigation