Journal of the Chinese Medical Association
Volume 69, Issue 8 , Pages 343-350, August 2006

High-dose Norepinephrine Induces Disruption of Myocardial Extracellular Matrix and Left Ventricular Dilatation and Dysfunction in a Novel Feline Model

  • Yung-Tsung Chiu

      Affiliations

    • Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Ching-Chang Cheng

      Affiliations

    • Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Nai-Nu Lin

      Affiliations

    • Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Yi-Wen Hung

      Affiliations

    • Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Ying-Tsung Chen

      Affiliations

    • Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Shih-Lan Hsu

      Affiliations

    • Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Ching-Shiang Chi

      Affiliations

    • Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • ,
  • Yun-Ching Fu

      Affiliations

    • Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
    • Department of Pediatrics, National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
    • Corresponding Author InformationCorrespondence to: Dr Yun-Ching Fu, Department of Pediatrics, Taichung Veterans General Hospital, 160, Section 3, Chung-Kang Road, Taichung 407, Taiwan, R.O.C.

Received 29 September 2005; accepted 19 June 2006.

Article Outline

Background

Intravenous norepinephrine (NE) at a dose of 1-6 μg/kg/minute can induce increased extracellular matrix (ECM) and hypertrophic cardiomyopathy. This study aimed to investigate the effects of a higher dose of NE on cardiac remodeling.

Methods

After intraperitoneal urethane-chloralose anesthesia, 7 cats (3.03 ± 0.58 kg) received intravenous infusion of NE 30 (ig/kg/minute for 3 hours. Aortic blood pressure and heart rate (HR) were measured by polygraphy at 0, 5,15, 30, 60, 90, 120, and 180 minutes. Left ventricular size and ejection fraction (EF) were measured by M-mode echocardio-graphy before and after NE administration. Histopathology was performed by hematoxylin-eosin, silver impregnation, and Sirius red staining. Activity of matrix metalloproteinases (MMP) in the left ventricle was measured by zymography.

Results

Mean blood pressure (mmHg) increased from 139 ± 20 to 198 ± 19,187 ± 23, and 166 ± 16 at 15, 30, and 60 minutes, respectively, during NE infusion. HR (beats/minute) decreased from 214 ± 10 to 158 ± 28 at 15 minutes and then recovered gradually. The left ventricles showed significant dilatation (end-diastolic diameter: from 1.20 ± 0.18 to 1.58 ± 0.23cm, p = 0.003; end-systolic diameter: from 0.62 ± 0.23 to 1.35 ± 0.29cm, p = 0.002) and hypokinesia (EF: from 86.2 ± 5.2 to 33.1 ± 16.5%, p< 0.001). Histopathology revealed that left ventricular myocytes were elongated, wavy, and fragmented, while collagen fibers were overstretched, straightened, and disrupted. MMP-9 activity was significantly elevated (p = 0.003 vs. control), while MMP-2 activity was unchanged.

Conclusion

High-dose NE increases MMP-9 activity and causes ECM disruption, left ventricular dilatation and dysfunction.

Key Words:  extracellular matrix , heart failure , matrix metalloproteinases , norepinephrine

No full text is available. To read the body of this article, please view the PDF online.

 

Back to Article Outline

References 

  1. D'Armiento J . Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction . Trends Cardiovasc Med . 2002;12:97–101
  2. Kim HE , Dalal SS , Young E , Legato MJ , Weisfeldt ML , D'Armiento J . Disruption of the myocardial extracellular matrix leads to cardiac dysfunction . J Clin Invest . 2000;106:857–866
  3. Spinale FG . Matrix metalloproteinases: regulation and dysregu-lation in the failing heart . Circ Res . 2002;90:520–530
  4. Chiu YT, Liu SK, Liu M, Chen SP, Lin YH, Mao SJ, et al. Characterization and quantitation of extracellular collagen matrix in myocardium of pigs with spontaneously occurring hypertrophic cardiomyopathy . Cardiovasc Pathol . 1999;8:169–175
  5. Thomas CV , Coker ML , Zellner JL , Handy JR , Crumbley AJ , Spinale FG . Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy . Circulation . 1998;97:1708–1715
  6. Schwartzkopff B , Fassbach M , Pelzer B , Brehm M , Strauer BE . Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy . Eur J Heart Fail . 2002;4:439–444
  7. Yokoseki O , Yazaki Y , Suzuki J , Imamura H , Takenaka H , Isobe M . Association of matrix metalloproteinase expression and left ventricular function in idiopathic dilated cardiomyo-pathy . Jpn Circ J . 2000;64:352–357
  8. Briest W , Holzl A , Rassler B , Deten A , Baba HA , Zimmer HG . Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts . Cardiovasc Res . 2003;57:379–387
  9. Barth W , Deten A , Bauer M , Reinohs M , Leicht M , Zimmer HG . Differential remodeling of the left and right heart after norepi-nephrine treatment in rats: studies on cytokines and collagen . J Mol Cell Cardiol . 2000;32:273–284
  10. Irlbeck M , Muhling O , Iwai T , Zimmer HG . Different response of the rat left and right heart to norepinephrine . Cardiovasc Res . 1996;31:157–162
  11. Spinale FG , Coker ML , Bond BR , Zellner JL . Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target . Cardiovasc Res . 2000;46:225–238
  12. Mann DL , Spinale FG . Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds . Circulation . 1998;98:1699–1702
  13. Nagase H , Woessner JF . Matrix metalloproteinases . J Biol Chem . 1999;274:21491–21494
  14. Li YY , Feldman AM . Matrix metalloproteinases in the progression of heart failure: potential therapeutic implications . Drugs . 2001;61:1239–1252
  15. Rouet-Benzineb P, Buhler JM, Dreyfus P, Delcourt A, Dorent R, Perennec J, et al  Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation . Eur J Heart Fail . 1999;1:337–352
  16. Nishikawa N, Yamamoto K, Sakata Y, Mano T, Yoshida J, Miwa T, et al  Differential activation of matrix metal-loproteinases in heart failure with and without ventricular dilatation . Cardiovasc Res . 2003;57:766–774
  17. Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, et al  Downregulation of matrix metallopro-teinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices . Circulation . 2001;104:1147–1152
  18. Rona G . Catecholamine cardiotoxicity . J Mol Cell Cardiol . 1985;17:291–306
  19. Jiang JP , Downing SE . Catecholamine cardiomyopathy: review and analysis of pathogenetic mechanisms . Yale J Biol Med . 1990;63:581–591
  20. Samuels MA . Neurally induced cardiac damage: definition of the problem . Neurol Clin . 1993;11:273–292
  21. Connor RC . Heart damage associated with intracranial lesions . Br Med J . 1968;3:29–31
  22. Sato K , Masuda T , Izumi T . Subarachnoid hemorrhage and myocardial damage: clinical and experimental studies . Jpn Heart J . 1999;40:683–701
  23. Masuda T, Sato K, Yamamoto S, Matsuyama N, Shimohama T, Matsunaga A, et al  Sympathetic nervous activity and myocardial damage immediately after subarachnoid hemorrhage in a unique animal model . Stroke . 2002;33:1671–1676
  24. Pollick C , Cujec B , Parker S , Tator C . Left ventricular wall motion abnormalities in subarachnoid hemorrhage: an echo-cardiographic study . J Am Coll Cardiol . 1988;12:600–605
  25. Fu YC, Chi CS, Jan SL, Wang TM, Chen PY, Chang Y, et al  Pulmonary edema of enterovirus 71 encephalomyelitis is associated with left ventricular failure: implications for treatment . Pediatr Pulmonol . 2003;35:263–268
  26. Fu YC, Chi CS, Chiu YT, Hsu SL, Hwang B, Jan SL, et al  Cardiac complications of enterovirus rhombencephalitis . Arch Dis Child . 2004;89:368–373
  27. Khullar M , Datta BN , Wahi PL , Chakravarti RN . Catecholamine-induced experimental cardiomyopathy: a histopathological, his-tochemical and ultrastructural study . Indian Heart J . 1989;41:307–313
  28. Powers FM , Pifarre R , Thomas JX . Ventricular dysfunction in norepinephrine-induced cardiomyopathy . Circ Shock . 1994;43:122–129
  29. Briest W, Holzl A, Rassler B, Deten A, Leicht M, Baba HA, et al. Cardiac remodeling after long term norepineph-rine treatment in rats . Cardiovasc Res . 2001;52:265–273
  30. Gong CL , Chiu YT , Lin NN , Lin SZ , Cheng FC , Kuo JS . Inhibitory actions of serotonin on glutamate release in dorsal medulla suppress systemic arterial pressure of cats . Neurosci Lett . 2004;355:73–76
  31. Albrechtsson U , Eskilsson J , Lomsky M , Stubbe I , Svensson SE , Tylen U . Comparison of left ventricular ejection fraction assessed by radionuclide angiocardiography, echocardiography and contrast angiocardiography . Acta Med Scand . 1982;211:147–152
  32. Romanic AM , Burns-Kurtis CL , Gout B , Berrebi-Bertrand I , Ohlstein EH . Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit . Life Sci . 2001;68:799–814
  33. Lopez-De Leon A , Rojkind M . A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections . J Histochem Cytochem . 1985;33:737–743
  34. Liu SK, Chiu YT, Shyu JJ, Factor SM, Chu R, Lin JH, et al  Hypertrophic cardiomyopathy in pigs: quantitative pathologic features in 55 cases . Cardiovasc Pathol . 1994;3:261–268
  35. Baroldi G . Myocardial cell death, including ischemic heart disease and its complications . In:  Silver MD ,  Gotlieb AI ,  Schoen FJ editor. Cardiovascular Pathology . 3rd edition. Philadelphia: Churchill Livingstone; 2001;p. 202–206

PII: S1726-4901(09)70271-0

doi:10.1016/S1726-4901(09)70271-0

Journal of the Chinese Medical Association
Volume 69, Issue 8 , Pages 343-350, August 2006

Article Tools