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Protective effect of intermedin on myocardial cell in a rat model of severe acute pancreatitis


Severe acute pancreatitis (SAP) is a common disease with a poor prognosis. Heart failure is one cause of SAP patient death. Intermedin (IMD) is a potent endogenous cardio-protective substance. Administration of exogenous IMD showed beneficial effects in cardiovascular diseases. The aim of this study was to investigate the myocardial damage in SAP and to determine the therapeutic potential of IMD for SAP. Using an SAP rat model, we examined endogenous IMD expression following SAP induction, and determined the effect of IMD on myocardial function, histological morphology, apoptosis-related gene expression, and prognosis. Our results indicated that the cardiac function and histological structure were significantly disrupted in SAP rats. Infusion of exogenous IMD significantly preserved cardiac function and ameliorated myocardial damage. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) revealed that myocardial apoptosis was extensively present in SAP rats, and IMD infusion led to increased expression of the prosurvival factor Bcl-2, but decreased pro-apoptotic factors Bax and caspase-3. In addition, IMD infusion also reversed the change of IMD receptor systems in SAP rat heart tissue. Furthermore, we found that IMD infusion greatly decreased mortality of SAP rats. In conclusion, administration of SAP produced therapeutic effects in SAP through modulating apoptotic and pro-survival gene expression, inhibiting myocardial apoptosis, preserving cardiac function, and a useful therapeutic agent for SAP, and provides us an insight for a clinical trial of IMD for treating human severe acute pancreatitis.





calcitonin gene-related peptide


calcitonin receptor-like receptor




multiple organ dysfunction syndrome


receptor-activity-modifying protein


severe acute pancreatitis


terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling


  1. 1.

    Waldthaler, A. Schutte, K. and Malfertheiner, P. Causes and mechanisms in acute pancreatitis. Dig. Dis. 28 (2010) 364–372.

  2. 2.

    Harper, S.J. and Cheslyn-Curtis, S. Acute pancreatitis. Ann. Clin. Biochem. 48 (2011) 23–37.

  3. 3.

    McKay, C.J. and Imrie, C.W. The continuing challenge of early mortality in acute pancreatitis. Brit. J. Surg. 91 (2004) 1243–1244.

  4. 4.

    Gravante, G., Garcea, G., Ong, S.L., Metcalfe, M.S., Berry, D.P., Lloyd, D.M. and Dennison, A.R. Prediction of mortality in acute pancreatitis: a systematic review of the published evidence. Pancreatology 9 (2009) 601–614.

  5. 5.

    Isenmann, R., Rau, B. and Beger, H.G. Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis. Brit. J. Surg. 86 (1999) 1020–1024.

  6. 6.

    Takeda, K., Matsuno, S., Sunamura, M. and Kobari, M. Surgical aspects and management of acute necrotizing pancreatitis: recent results of a cooperative national survey in Japan. Pancreas 16 (1998) 316–322.

  7. 7.

    Pandol, S.J., Saluja, A.K., Imrie, C.W. and Banks, P.A. Acute pancreatitis: bench to the bedside. Gastroenterology 132 (2007) 1127–1151.

  8. 8.

    Darvas, K., Futo, J., Okros, I., Gondos, T., Csomos, A. and Kupcsulik, P. [Principles of intensive care in severe acute pancreatitis in 2008]. Orv. Hetil. 149 (2008) 2211–2220.

  9. 9.

    Yegneswaran, B., Kostis, J.B. and Pitchumoni, C.S. Cardiovascular manifestations of acute pancreatitis. J. Crit. Care 26 (2011) 225.e11–8.

  10. 10.

    Chang, C.L., Roh, J. and Hsu, S.Y. Intermedin, a novel calcitonin family peptide that exists in teleosts as well as in mammals: a comparison with other calcitonin/intermedin family peptides in vertebrates. Peptides 25 (2004) 1633–1642.

  11. 11.

    Takei, Y., Hyodo, S., Katafuchi, T. and Minamino, N. Novel fish-derived adrenomedullin in mammals: structure and possible function. Peptides 25 (2004) 1643–1656.

  12. 12.

    Takei, Y., Inoue, K., Ogoshi, M., Kawahara, T., Bannai, H. and Miyano, S. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett. 556 (2004) 53–58.

  13. 13.

    Roh, J., Chang, C.L., Bhalla, A., Klein, C. and Hsu, S.Y. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J. Biol. Chem. 279 (2004) 7264–7274.

  14. 14.

    Mizunuma T, K.S. and Kishino Y. Effects of injecting excess arginine on rat pancreas. J. Nutr. 114 (1984) 467–471.

  15. 15.

    Hegyi, P., Rakonczay, Z., Jr., Sari, R., Gog, C., Lonovics, J., Takacs, T. and Czako, L. L-arginine-induced experimental pancreatitis. World J. Gastroenterol. 10 (2004) 2003–2009.

  16. 16.

    Ren, Y.S., Yang, J.H., Zhang, J., Pan, C.S., Yang, J., Zhao, J., Pang, Y.Z., Tang, C.S. and Qi, Y.F. Intermedin 1–53 in central nervous system elevates arterial blood pressure in rats. Peptides 27 (2006) 74–79.

  17. 17.

    Bell, D. and McDermott, B.J. Intermedin (adrenomedullin-2): a novel counterregulatory peptide in the cardiovascular and renal systems. Br. J. Pharmacol. 153Suppl 1 (2008) S247–262.

  18. 18.

    Zhao, Y., Bell, D., Smith, L.R., Zhao, L., Devine, A.B., McHenry, E.M. Nicholls, D.P., and McDermott, B.J. Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension. J. Pharmacol. Exp. Ther. 316 (2006) 1269–1281.

  19. 19.

    Cobelens, P.M., van Putte, B.P., Kavelaars, A., Heijnen, C.J. and Kesecioglu, J. Inflammatory consequences of lung ischemia-reperfusion injury and lowpressure ventilation. J. Surg. Res. 153 (2009) 295–301.

  20. 20.

    Yang, K.M., Pyo, J.O., Kim, G.Y., Yu, R., Han, I.S., Ju, S.A., Kim, W.H. and Kim, B.S. Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines. Cell. Mol. Biol. Lett. 14 (2009) 497–510.

  21. 21.

    Nagae, T., Mukoyama, M., Sugawara, A., Mori, K., Yahata, K., Kasahara, M., Suganami, T., Makino, H., Fujinaga, Y., Yoshioka, T., Tanaka, I. and Nakao, K. Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy. Biochem. Biophys. Res. Commun. 270 (2000) 89–93.

  22. 22.

    Jia, Y.X., Yang, J.H., Pan, C.S., Geng, B., Zhang, J., Xiao, Y., Zhao, J., Gerns, H., Yang, J., Chang, J.K., Wen, J.K., Tang, C.S. and Qi, Y.F. Intermedin 1–53 protects the heart against isoproterenol-induced ischemic injury in rats. Eur. J. Pharmacol. 549 (2006) 117–123.

  23. 23.

    Gottlieb, R.A., Burleson, K.O., Kloner, R.A., Babior, B.M. and Engler, R.L. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J. Clin. Invest. 94 (1994) 1621–1628.

  24. 24.

    Sargent, S. Pathophysiology, diagnosis and management of acute pancreatitis. Br. J. Nurs. 15 (2006) 999–1005.

  25. 25.

    Yang, J.H., Jia, Y.X., Pan, C.S., Zhao, J., Ouyang, M., Yang, J., Chang, J.K., Tang, C.S. and Qi, Y.F. Effects of intermedin(1–53) on cardiac function and ischemia/reperfusion injury in isolated rat hearts. Biochem. Biophys. Res. Commun. 327 (2005) 713–719.

  26. 26.

    Holleyman, C.R. and Larson, D.F. Apoptosis in the ischemic reperfused myocardium. Perfusion 16 (2001) 491–502.

  27. 27.

    Pan, C.S., Yang, J.H., Cai, D.Y., Zhao, J., Gerns, H., Yang, J., Chang, J.K., Tang, C.S. and Qi, Y.F. Cardiovascular effects of newly discovered peptide intermedin/adrenomedullin 2. Peptides 26 (2005) 1640–1646.

  28. 28.

    Grossini, E., Molinari, C., Mary, D.A., Uberti, F., Caimmi, P.P. and Vacca, G. Intracoronary intermedin 1–47 augments cardiac perfusion and function in anesthetized pigs: role of calcitonin receptors and beta-adrenoreceptor-mediated nitric oxide release. J. Appl. Physiol. 107 (2009) 1037–1050.

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Correspondence to Zhi Zeng.

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Du, X., Cao, Y., Xue, P. et al. Protective effect of intermedin on myocardial cell in a rat model of severe acute pancreatitis. Cell Mol Biol Lett 16, 462–476 (2011).

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Key words

  • Severe acute pancreatitis
  • Myocardial damage
  • Apoptosis
  • Intermedin treatment