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Effect of ursodeoxycholic acid on ischemia/reperfusion injury in isolated rat heart

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  • Pharmacology & Toxicology
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Abstract

In this study, the effects of ursodeoxycholic acid (UDCA) on ischemia/reperfusion injury were investigated on isolated heart perfusion model. Hearts were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, 37°C) on a Langendorff apparatus. After equilibration, isolated hearts were treated with UDCA 20 to 160 μM or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. After global ischemia (30 min), ischemic hearts were reperfused and allowed to recover for 30 min. The physiological (i.e. heart rate, left ventricular developed pressure, coronary flow, double product and time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 21.4 min during ischemia, LVDP was 18.5 mmHg at the endpoint of reperfusion and LDH activity in total reperfusion effluent was 54.0 U/L. Cardioprotective effects of UDCA against ischemia/reperfusion consisted of a reduced TTC (EC25=97.3 μM), reduced LDH release and enhanced recovery of cardiac contractile function during reperfusion. Especially, the treatments of UDCA 80 and 160 μM significantly increased LVDP and reduced LDH release. Our findings suggest that UDCA ameliorates ischemia/reperfusion-induced myocardial damage.

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References Cited

  • Bernstein E. A., Eberli F. R. and Silverman A. M., Beneficial effects of felodifine on myocardial and coronary function during low flow ischemia and reperfusion.Cardiovasc.Drugs Ther., 10, 167–168 (1996).

    Article  CAS  Google Scholar 

  • Beuers, U., Nathanson, M. H. and Boyer, J. L., Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes.Gastroenterology, 104, 604–612 (1993).

    PubMed  CAS  Google Scholar 

  • Braunwald, E. and Kloner, R. A., Myocardial reperfusion: a double edged sword?J. Clin. Invest, 76, 1713–1719 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Ceriana, P., Effect of myocardial ischaemia-reperfusion on granulocyte elastase release.Anaesth. Int. Care, 20, 187–190 (1992).

    CAS  Google Scholar 

  • Chien, K. R., Willerson, J. T. and Buja, L. M., Phospholipid alteration and membrane injury during myocardial ischemia. In:Advances in Myocardiology, edited by Harris, P. and Poole-Wilson. New York: Plenum, vol. 5, 347–352 (1985).

    Google Scholar 

  • Drew, R. and Priestly, B. C., Choleretic and cholestatic effects of infused bile salts in the rat.Experientia, 35, 809–811 (1978).

    Article  Google Scholar 

  • Forman, M. B., Puett, D. W. and Virmani, R., Endothelial and myocardial injury during ischeamia and reperfusion: pathogenesis and therapeutic implica-tions.J. Am. Coll. Cardiol., 13, 450–459 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Gaudel, Y. and Duvelleroy, M. A., Role of oxygen radicals in cardiac injury due to reoxygenation.J. Mol. Cell. Cardiol., 16, 459–470 (1984).

    Article  Google Scholar 

  • Grover, G. J., McCullough, J. R., D'Alonzo, A. J., Sargent, C. A. and Atwal, K. S., Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448.J. Cardiovasc. Pharmacol., 25, 40–50 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Grover, G. J., Sleph, P. G. and Dzwonczyk, S., Pharmacological profile of cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs.J. Cardiovasc. Pharmacol., 16, 853–864 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Güldütuna, S., Zimmer, G., Imhof, M., Bhatt, S., You, T. and Leuschner, M., Molecular aspects of membrane stabilization by ursodeoxycholate.Gastroenterology, 104, 1736–1744 (1993).

    PubMed  Google Scholar 

  • Hara, A., Matsumura, H. and Abiko, Y., Lidocaine attenuates both mechanical and metbolic changes induced by hydrogen peroxide in the rat heart.Am. J. Physiol., 265, 1478–1485 (1993).

    Google Scholar 

  • Hattori, Y., Murakami, Y., Hattori, S., Kuroda, H., Kasai, K. and Shimoda, S., Ursodeoxycholic acid inhibits the induction of nitric oxide synthase.Eur. J. Pharmacol., 300, 147–150 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Hearse, D. J., Humphrey, S. M., Nayler, W. G., Sale, A. and Border, Z., Ultrastructural damage associated with reoxygenation of anoxic myocardium.J. Mol. Cell Cardiol., 7, 315–324 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Hearse, D. J., Manning, A. S., Downey, J. M. and Yellen, D. M., Xanthine oxidase: a critical mediator of myocardial injury during ischaemia and reperfusion?Acta Physiol. Scand., 548, 65–74 (1986).

    CAS  Google Scholar 

  • Hess, M. L. and Manson, N. H., Molecular oxygen: friend and foe-the role of the oxygen free radical system in the calcium paradox and ischemia/reperfusion injury.Mol. Cell Cardiol., 16, 969–989 (1984).

    Article  CAS  Google Scholar 

  • Josephson, R. A., Silverman, H. S. and Lakatta, E. G., Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes.J. Biol. Chem., 266, 2354–2361 (1991).

    PubMed  CAS  Google Scholar 

  • Kokita, N. and Hara, A., Propofol attenuates hydrogen peroxide-induced mechanical and metabolic derangements in the isolated rat heart. Anesthesiology, 84, 117–127 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Lefer, A. M., Aoki, N. and Mulloy, D., Coronary endo-thelium-protective effects of defibrotide in ischaemia and reperfusion.Naunyn Schmiederberg's Arch. Pharmacol., 341, 246–250 (1990).

    CAS  Google Scholar 

  • Lefer, A. M., Johnson, G., Ma, X. L., Tsao, P. S. and Thomas, G. R., Cardioprotective and endothelial protective effects of [Ala-IL8]77 in a rabbit model of myocardial ischaemia and reperfusion.Br. J. Pharmacol., 103, 1153–1159 (1991).

    PubMed  CAS  Google Scholar 

  • Lefer, A. M., Tsao, P. S., Lefer, D. J. and Ma, X. L. Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia.FASEB J., 5, 2029–2034 (1991).

    PubMed  CAS  Google Scholar 

  • Ljubuncic, P., Fuhrman, B., Oiknine, J., Aviram, M. and Bomzon, A., Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages.Gut, 39, 475–478 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi, B. R. Myocardial ischemia, reperfusion and free radical injury.Am. J. Cardiol., 65, 141–231 (1990).

    Article  Google Scholar 

  • Lum, H. L., Barr, D. A., Shaffer, J. R., Cordon, R. J., Ezrin, A. M. and Malik, A. B., Reoxygenation of endothelial cells increases permeability by oxygen-dependent mechanisms.Ore. Res., 70, 991–998 (1992).

    CAS  Google Scholar 

  • Maxwell, L. and Gavin, J. B., The role of post-ischaemic reperfusion in the development of microvascular imcompetence and ultrastructural damage in the myocardium.Basic Res. Cardiol., 86, 544–553 (1991).

    Article  PubMed  CAS  Google Scholar 

  • McCord, J. M., Oxygen-derived free radicals in postishemic tissue injury.N. Engl. J. Med., 312, 159–163 (1985).

    PubMed  CAS  Google Scholar 

  • McFalls, E. O., Duncker, D. J., Krams, R., Ward, H., Gomick, C. and Verdouw, P. D., Endothelium dependent vasodilatation following brief ischaemia and reperfusion in anaesthetised swine.Cardiovasc. Res., 25, 659–665 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Nakaya, H., Tohse, N. and Kanno, M. Electrophysiological derangements induced by lipid peroxidation in cardiac tissue.Am. J. Physiol., 253, 1089–1097 (1987).

    Google Scholar 

  • Ono, T., Nagasue, N., Kohno, H., Uchida, M., Takemoto, Y. Dhar, D. K. and Nakamura, T., Effect of taurourso-deoxycholic acid on bile flow and calcium excretion in ischemia-reperfusion injury of rat liver.J. Hepatology, 23, 582–590 (1995).

    Article  CAS  Google Scholar 

  • Pabla, R. and Curtis, M. J., Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus nonneuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart.J. Mol. Cell Cardiol., 28, 2097–2110 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Ro, J. Y., Cho, T. S. and Hong, S. S., The effects of cholates on smooth muscle strips and cardiac muscle.Kor. J. Pharmacol., 16, 41–50 (1986).

    Google Scholar 

  • Sheridan, F. M., Dauber, I. M., McMurty, I. F., Lesnefsky, E. J. and Horwitz, L. D., Role of leukocytes in coronary vascular endothelial injury due to ischaemia and reperfusion.Cire. Res., 69, 1566–1574 (1991).

    CAS  Google Scholar 

  • Simon, R. J. and Gregory, Y. H., Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options.Int. J. Cardiol., 58, 95–117 (1997).

    Article  Google Scholar 

  • Steenbergen, C., Murphy, E., Watts, J. A. and London, R. E. Correlation between cystosolic free calcium, contracture, ATP and irreversible ischemic injury in perfused rat heart.Ore. Res., 66, 135–146 (1990).

    CAS  Google Scholar 

  • Woodward, B. and Zakaria, M. V. M., Effect of some free radical scavengers on reperfusion induced arrhythmias in the isolated rat heart.J. Mol. Cell Cardiol., 84, 485–493 (1985).

    Article  Google Scholar 

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Authors and Affiliations

  1. R&D Center, Daewoong Pharmaceutical Co. Ltd., Sungnam, Korea

    Young-Hyo Yoo

  2. Department of Pharmacology, College of Pharmacy, Sungkyunkwan University, 440-746, Suwon, Korea

    Woo-Yong Lee, Suk-Hee Han, Tai-Soon Cho & Sun-Mee Lee

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  1. Woo-Yong Lee
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  2. Suk-Hee Han
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  3. Tai-Soon Cho
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  4. Young-Hyo Yoo
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  5. Sun-Mee Lee
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Correspondence to Sun-Mee Lee.

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Lee, WY., Han, SH., Cho, TS. et al. Effect of ursodeoxycholic acid on ischemia/reperfusion injury in isolated rat heart. Arch Pharm Res 22, 479–484 (1999). https://doi.org/10.1007/BF02979156

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  • DOI: https://doi.org/10.1007/BF02979156

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