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Cardiovascular Pharmacology

Role of norepinephrine in development of short-term myocardial hibernation



To investigate the role of norepinephrine in the development of short-term myocardial hibernation.


Hearts were removed from rats and set up as isometrically beating or short-term hibernation models. The hearts were perfused with modified Krebs-Henseleit buffer under a controlled perfusion pressure. The myocardial ultrastructure was examined, and the content of ATP, phosphocreatine, and glycogen in myocardium, the extent of myocyte apoptosis, and the amount of Bcl-2 and Bax products were determined after 120-min ischemia assessed by TUNEL and immunocytochemistry.


There was no significant difference between the reserpinized hearts and the NS control group with respect to heart function, myocardial ultrastructure, ATP, phosphocreatine, or glycogen content, myocyte apoptosis, or amount of Bax or Bcl-2 products. However, relative to the normal saline group, in the norepinephrine-treated hearts, heart function, and myocardial ultrastructure deteriorated significantly, apoptosis and amount of Bax product increased significantly, and the ATP, phosphocreatine, and glycogen content decreased significantly, as did the amount of Bcl-2 product.


Myocardial norepinephrine does not contribute to the development of short-term hibernation, but that exogenous NE can induce progressive decreases in coronary flow and cardiac performance, which might result from the increases in apoptosis and necrosis. Norepinephrine may be an important factor in the deterioration of myocardial structure and function during hibernation, and that antiadrenergic treatment may be helpful for the development and sustainment of short-term myocardial hibernation.


  1. 1

    Rahimtoola SH . A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 1985; 72 ( Suppl V): 123–35.

  2. 2

    Arend FLS, Jeroen JB, Don P . Clinical assessment of myocardial hibernation. Heart 2005; 91: 111–7.

  3. 3

    Heusch G, Schulz R, Rahimtoola SH . Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 2005; 288: H984–99.

  4. 4

    Westaby S . Coronary revascularization in ischemic cardiomyopathy. Surg Clin North Am 2004; 84: 179–99.

  5. 5

    Southworth R, Garlick PB . Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart? Am J Physiol Circ Physiol 2003, 285: H316–H324.

  6. 6

    Rump AFE, Klaus W . Evidence for noradrenaline cardiotoxicity mediated by superoxide anion radicals in isolated rabbit hearts. Naunyn Schmiedebergs Arch Pharmacol 1994; 349: 295–300.

  7. 7

    Sperlagh B, Kittel A, Lajtha A, Vizi ES . ATP acts as fast neurotransmitter in rat habenula: neurochemical and enzyme cytochemical evidence. Neuroscience 1995; 66: 915–20.

  8. 8

    Kordas KS, Sperlagh B, Tihanyi T, Topa L, Steward MC, Varga G, et al. ATP and ATPase secretion by exocrine pancreas in rat, guinea pig, and human. Pancreas 2004; 29: 53–60.

  9. 9

    Zhang YW, Long C, Ding LL . Determination of phosphocreatine in muscular tissues by high performance liquid chromatography. Chin J Chromatogr 2001; 19: 251–2.

  10. 10

    Bergmeyer HU . Methods of enzymatic analysis. 3rd ed. Vol III. New York: Wiley; 1984. p 126–32.

  11. 11

    Ross J Jr . Myocardial perfusion-contraction matching Implications for coronary heart disease and hibernation. Circulation 1991; 83: 1076–83.

  12. 12

    Berry GJ, Masek M . The pathology of hibernating myocardium. Nucl Med Commun 2002; 23: 303–9.

  13. 13

    Shen YT, Vatner SF . Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs. Hibernation versus stunning. Circ Res 1995; 76: 479–88.

  14. 14

    Heusch G . Hibernating myocardium. Physiol Rev 1998; 78: 1055–85.

  15. 15

    Heusch G, Rose J, Skyschally A, Post H, Schulz R . Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart: inotropic responses to postextrasystolic potentiation and intracoronary calcium. Circulation 1996; 93: 1556–66.

  16. 16

    Schulz R, Rose J, Martin C, Heusch G . Development of short-term myocardial hibernation: its limitation by the severity of ischemia and inotropic stimulation. Circulation 1993; 88: 684–95.

  17. 17

    Waldenstrom AP, Hjalmarson AH, Thornell L . A possible role of noradrenaline in the development of myocardial infarction. Am Heart J 1978; 95: 43–51.

  18. 18

    Rump AFE, Schierholz J, Klaus W . Studies on the cardiotoxicity of noradrenaline in isolated rabbit hearts. Arzneim-Forsch Drug Res 2002; 52: 543–51.

  19. 19

    Oltvai ZN, Korsmeyer SJ . Checkpoints of dueling dimers foil death wishes. Cell 1994; 79: 189–92.

  20. 20

    Ponicke K, Heinroth-Hoffmann I, Brodde OE . Role of beta 1- and beta 2-adrenoceptors in hypertrophic and apoptotic effects of noradrenaline and adrenaline in adult rat ventricular cardiomyocytes. Naunyn Schmiedebergs Arch Pharmacol 2003; 367: 592–9.

  21. 21

    Fu YC, Chi CS, Yin SC, Hwang B, Chiu YT, Hsu SL . Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species–TNF alpha-caspase signaling pathway. Cardiovasc Res 2004; 62: 558–67.

  22. 22

    Singh K, Xiao L, Remondino A, Sawyer DB, Colucci WS . Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 2001; 189: 257–65.

  23. 23

    Depre C, Taegtmeyer H . Metabolic aspects of programmed cell survival and cell death in the heart. Cardiovasc Res 2000; 45: 538–48.

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Correspondence to Zuo-lin Fu.

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About this article


  • norepinephrine
  • dobutamine
  • myocardial ischemia
  • myocardial reperfusion
  • myocardial stunning
  • myocardium
  • left ventricular function
  • lactic acid
  • coronary circulation

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