Skip to main content
Log in

Effect of melatonin on altered expression of vasoregulatory genes during hepatic ischemia/reperfusion

  • Article
  • Drug efficacy and safety
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The production of reactive oxygen species during hepatic ischemia/reperfusion (I/R) can help create disturbances in microcirculation. This study examined the effect of melatonin, a pineal secretory product and a potent antioxidant, on the expression of vascular stress genes during hepatic I/R. Rats were subjected to 60 min of hepatic warm ischemia followed by 5 h reperfusion. Melatonin (10 mg/kg) was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. The serum alanine aminotransferase and hepatic malondial-dehyde levels increased markedly after I/R. These increases were significantly inhibited by melatonin. The levels of endothelin-1 (ET-1) and its receptor, ETB mRNA, were elevated by I/R but attenuated by melatonin. The mRNA levels of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and heme oxygenase-1 were significantly higher after I/ R. Melatonin augmented the increase in the eNOS mRNA level, whereas it reduced the increase in the iNOS mRNA level. The expression of tumor necrosis factor-α was increased markedly by I/R. This increase was also attenuated by melatonin. These results suggest that melatonin ameliorates the imbalanced expression of the vascular stress genes during hepatic I/R through its antioxidant property.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Atalla, S. L., Toledo-Pereyra, L. H., Mackenzie, G. H., and Cederna, J. P., Influence of oxygen-derived free radical scavengers on ischemic livers.Transplantation, 40, 584–590 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Bautista, A. P., Schuler, A., Spolarics, Z., and Spitzer, J. J., Tumor necrosis factor-alpha stimulates Superoxide anion generation by perfused rat liver and Kupffer cells.Am. J. Physiol., 261, G891-G895 (1991).

    PubMed  CAS  Google Scholar 

  • Bromont, C., Marie, C., and Bralet, J., Increased lipid peroxida- tion in vulnerable brain regions after transient forebrain ischemia in rats.Stroke, 20, 918–924 (1989).

    PubMed  CAS  Google Scholar 

  • Buege, T. A. and Aust, S. D., Microsomal lipid peroxidation.Methods Enzymol., 52, 302–310 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Chomczynski, P. and Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.Anal. Biochem., 162, 156–159 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Chun, K., Zhang J., Biewer, J. E., Ferguson, D., and Clemens, M. G., Microcirculatory failure determines lethal hepatocyte injury in ischemia/reperfused rat livers.Shock, 1, 3–9 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Clemens, M. G., Bauer, M., Gingalewski, C., Miescher, E., and Zhang, J. X., Hepatic intercellular communication in shock and inflammation.Shock, 2, 1–9 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Dobsak, P., Siegelova, J., Eicher, J. C., Jancik, J., Svacinova, H., Vasku, J., Kuchtickova, S., Horky, M., and Wolf, J. E., Melatonin protects against ischemia-reperfusion injury and inhibits apoptosis in isolated working rat heart.Pathophysiology, 9, 179–187 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Ferrari, R., Oxygen-free radicals at myocardial level: effects of ischaemia and reperfusion.Adv. Exp. Med. Biol., 366, 99–111 (1994).

    PubMed  CAS  Google Scholar 

  • Horie, Y., Wolf, Ft., Russell, J., Shanley, T. P., and Granger, D. N., Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice.Hepatology, 26, 1499–1505 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Jin, M. B., Zhu, Y., Zhang, S., Ishizaki, N., Tanaka, H., Subbotin, V. M., Lee, R. G. Starzl, T. E., and Todo, S., Attenuation of ischemic liver injury by a non-selective endothelin receptor antagonist.Transplant. Proc., 29, 1335 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Lopez, O. S., Hernandez, P. O., Navarro, A. J., Perez, L. G. Rodriguez, P. M., Lamas, S., and Rodriguez, P. D., Role of reactive oxygen species in the signalling cascade of cyclosporine A-mediated up-regulation of eNOS in vascular endothelial cells.Br. J. Pharmacol., 124, 447–454 (1998).

    Article  Google Scholar 

  • Maines, M. D., Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications.FASEB J., 2, 2557–2568 (1988).

    PubMed  CAS  Google Scholar 

  • McCord, J. M., Oxygen-derived free radicals in postischemic tissue injury.N. Engl. J. Med., 17, 159–163 (1985).

    Google Scholar 

  • Muller, T. B., Haraldseth, O., Jones, R. A., Sebastiani, G., Godtliebsen, F., Lindboe, C. F., and Unsgard, G., Combined perfusion and diffusion-weighted magnetic resonance imaging in a rat model of reversible middle cerebral artery occlusion.Stroke, 26, 451–457 (1995).

    PubMed  CAS  Google Scholar 

  • Nevalainen, T. J., Arminger, L. C., and Gavin, J. B., Effects of ischaemia on vasculature.J. Mol. Cell Cardiol., 18, 7–10 (1986).

    Article  PubMed  Google Scholar 

  • Omar, R., Nomikos, I., Piccorelli, G., Savino, J., and Agarwal, N., Prevention of post ischemic lipid peroxidation and liver cell injury by iron chelation.Gut, 30, 510–514 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Otterbein, L. E., Bach, F. H., Alam, J., Soares, M., Tao Lu, H., Wysk, M., Davis, R. J., Flavell, R. A., and Choi, A. M., Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.Nat. Med., 6, 422–428 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Otterbein, L. E. and Choi, A. M., Heme oxygenase: colors of defense against cellular stress.Am. J. Physiol., 279, L1029-L1037 (2000).

    CAS  Google Scholar 

  • Padillo, F. J., Cruz, A., and Navarrete, C., Melatonin prevents oxidative stress and hepatocyte cell death induced by experimental cholestasis.Free Radic. Res., 38, 697–704 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Pannen, B. H., Al-Adili, F., Bauer, M., Clemens, M. G., and Geiger, K. K., Role of endothelins and nitric oxide in hepatic reperfusion injury in the rat.Hepatology, 27, 755–764 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Pannen, B. H., Bauer, M., Zhang, J., Robotham, J. L., and Clemens, M. G., A time-dependent balance between endothelins and nitric oxide regulating portal resistance after endotoxin.Am. J. Physiol., 271, 1953–1961 (1996).

    Google Scholar 

  • Pei, Z. and Cheung, R. T., Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model.J. Pineal Res., 37, 85–91 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Petty, M., Grisar, J. M., Dow, J., and Jong, W. D., Effects of an αtocopherol analogue on myocardial ischemia and reperfusion injury in rats.Eur. J. Pharmacol., 179, 241–242 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Prasad, K., Lee, P., and Kalra, J., Influence of endothelin on cardiovascular function, oxygen free radicals, and blood chemistry.Am. Heart J., 121, 178–187 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez-Reynoso, S., Leal, C., Portilla, E., Olivares, N., and Muniz, J., Effect of exogenous melatonin on hepatic energetic status during ischemia/reperfusion: possible role of tumor necrosis factor-alpha and nitric oxide.J. Surg. Res., 100, 141–149 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Sener, G., Tosun, O., Sehirli, A. O., Kacmaz, A., Arbak, S., Ersoy, Y., and Ayanoglu-Dulger, G., Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion.Life Sci., 72, 2707–2718 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Sonin, N. V., Garcia-Pagan, J. C., Nakanishi, K., Zhang, J. X., and Clemens, M. G., Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia.Shock, 11, 175–179 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Yokoyama, Y., Baveja, R., Kresge, N., Sonin, N., Nakanishi, K., Zhang, J. X., Gitzelmann, C. A., and Clemens, M. G., Endothelin receptor remodeling induces the portal venous hyper-response to endothelin-1 following endotoxin pretreatment.Shock, 17, 36–40 (2002).

    Article  PubMed  Google Scholar 

  • Zhang, W. H., Li, J. Y., and Zhou, Y., Melatonin abates liver ischemia/reperfusion injury by improving the balance between nitric oxide and endothelin.Hepatobiliary Pancreat. Dis. Int., 5, 574–579 (2006).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sun-Mee Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, SW., Choi, SM. & Lee, SM. Effect of melatonin on altered expression of vasoregulatory genes during hepatic ischemia/reperfusion. Arch Pharm Res 30, 1619–1624 (2007). https://doi.org/10.1007/BF02977332

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02977332

Key words

Navigation