Circulation, Vol 85, 790-804, Copyright © 1992 by American Heart Association
DL Mann, RL Kent, B Parsons and G Cooper 4th
BACKGROUND. To delineate the mechanism(s) of catecholamine-mediated cardiac
toxicity, we exposed cultures of adult cardiac muscle cells, or
cardiocytes, to a broad range of norepinephrine concentrations. METHODS AND
RESULTS. Norepinephrine stimulation resulted in a concentration- dependent
decrease in cardiocyte viability, as demonstrated by a significant decrease
in viable rod-shaped cells and a significant release of creatine kinase
from cells in norepinephrine-treated cultures. Norepinephrine-mediated cell
toxicity was attenuated significantly by beta-adrenoceptor blockade and
mimicked by selective stimulation of the beta-adrenoceptor, whereas the
effects mediated by the alpha-adrenoceptor were relatively less apparent.
When norepinephrine stimulation was examined in terms of cardiocyte
anabolic activity, there was a concentration-dependent decrease in the
incorporation of [3H]phenylalanine and [3H]uridine into cytoplasmic protein
and nuclear RNA, respectively. The decrease in cytoplasmic labeling was
largely attenuated by beta-adrenoceptor blockade and mimicked by selective
stimulation of the beta-adrenoceptor, but alpha- adrenoceptor stimulation
resulted in relatively minor decreases in cytoplasmic labeling. The
norepinephrine-induced toxic effect appeared to be the result of cyclic
AMP-mediated calcium overload of the cell, as suggested by studies in which
pharmacological strategies that increased intracellular cyclic AMP led to
decreased cell viability, as well as studies that showed that influx of
extracellular calcium through the verapamil-sensitive calcium channel was
necessary for the induction of cell lethality. Additional time-course
studies showed that norepinephrine caused a rapid, fourfold increase in
intracellular cyclic AMP, followed by a 3.2-fold increase in intracellular
calcium [( Ca2+]i). CONCLUSIONS. These results constitute the initial
demonstration at the cellular level that adrenergic stimulation leads to
cyclic AMP-mediated calcium overload of the cell, with a resultant decrease
in synthetic activity and/or viability.
ARTICLES
Adrenergic effects on the biology of the adult mammalian cardiocyte
Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston.
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N. Satoh, T. Sato, M. Shimada, K. Yamada, and Y. Kitada Lusitropic Effect of MCC-135 Is Associated with Improvement of Sarcoplasmic Reticulum Function in Ventricular Muscles of Rats with Diabetic Cardiomyopathy J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1161 - 1166. [Abstract] [Full Text] [PDF]
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 H. E. Dincer, N. Gangopadhyay, R. Wang, and B. D. Uhal Norepinephrine induces alveolar epithelial apoptosis mediated by {alpha}-, {beta}-, and angiotensin receptor activation Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L624 - L630. [Abstract] [Full Text] [PDF]
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 M. Loubani and M. Galinanes {{alpha}}1-Adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: Effect of the dose and time of administration J. Thorac. Cardiovasc. Surg., July 1, 2001; 122(1): 103 - 112. [Abstract] [Full Text] [PDF]
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 D. M. Kaye, L. Johnston, G. Vaddadi, H. Brunner-LaRocca, G. L. Jennings, and M. D. Esler Mechanisms of Carvedilol Action in Human Congestive Heart Failure Hypertension, May 1, 2001; 37(5): 1216 - 1221. [Abstract] [Full Text] [PDF]
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M. Gomberg-Maitland, D. A. Baran, and V. Fuster Treatment of Congestive Heart Failure: Guidelines for the Primary Care Physician and the Heart Failure Specialist Arch Intern Med, February 12, 2001; 161(3): 342 - 352. [Abstract] [Full Text] [PDF]
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M. Flesch, S. Ettelbruck, S. Rosenkranz, C. Maack, B. Cremers, K.-D. Schluter, O. Zolk, and M. Bohm Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in {beta}-adrenoceptor density and systolic function in rat cardiac myocytes Cardiovasc Res, February 1, 2001; 49(2): 371 - 380. [Abstract] [Full Text] [PDF]
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Y. Ishibashi, J. C. Rembert, B. A. Carabello, S. Nemoto, M. Hamawaki, M. R. Zile, J. C. Greenfield Jr., and G. Cooper IV Normal myocardial function in severe right ventricular volume overload hypertrophy Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H11 - H16. [Abstract] [Full Text] [PDF]
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A. Chesley, M. S. Lundberg, T. Asai, R.-P. Xiao, S. Ohtani, E. G. Lakatta, and M. T. Crow The {beta}2-Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through Gi-Dependent Coupling to Phosphatidylinositol 3'-Kinase Circ. Res., December 8, 2000; 87(12): 1172 - 1179. [Abstract] [Full Text] [PDF]
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 E. Omerovic, E. Bollano, R. Mobini, V. Kujacic, B. Madhu, B. Soussi, M. Fu, A. Hjalmarson, F. Waagstein, and J. Isgaard Growth Hormone Improves Bioenergetics and Decreases Catecholamines in Postinfarct Rat Hearts Endocrinology, December 1, 2000; 141(12): 4592 - 4599. [Abstract] [Full Text] [PDF]
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N.G. Mahon and W.J. Mckenna Genes and acquired disease: beta-adrenoceptor polymorphisms and heart failure Eur. Heart J., November 2, 2000; 21(22): 1810 - 1812. [PDF]
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 L. L. Clark Perioperative Treatment of Congestive Heart Failure Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2000; 4(4): 223 - 235. [Abstract] [PDF]
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H. N. Sabbah, V. G. Sharov, R. C. Gupta, A. Todor, V. Singh, and S. Goldstein Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1698 - 1705. [Abstract] [Full Text] [PDF]
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N. Satoh, T. M. Suter, R. Liao, and W. S. Colucci Chronic {alpha}-Adrenergic Receptor Stimulation Modulates the Contractile Phenotype of Cardiac Myocytes In Vitro Circulation, October 31, 2000; 102(18): 2249 - 2254. [Abstract] [Full Text] [PDF]
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N. Parekh, B. Venkatesh, D. Cross, A. Leditschke, J. Atherton, W. Miles, A. Winning, A. Clague, and C. Rickard Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1328 - 1335. [Abstract] [Full Text] [PDF]
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P. A. Carson, C. M. O'Connor, A. B. Miller, S. Anderson, R. Belkin, G. W. Neuberg, J. H. Wertheimer, D. Frid, A. Cropp, and M. Packer Circadian rhythm and sudden death in heart failure: Results from prospective randomized amlodipine survival trial J. Am. Coll. Cardiol., August 1, 2000; 36(2): 541 - 546. [Abstract] [Full Text] [PDF]
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M. Zaugg, W. Xu, E. Lucchinetti, S. A. Shafiq, N. Z. Jamali, and M. A. Q. Siddiqui {beta}-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes Circulation, July 18, 2000; 102(3): 344 - 350. [Abstract] [Full Text] [PDF]
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C. Piper, J. Bilger, E.-M. Henrichs, H.-P. Schultheiss, D. Horstkotte, and A. Doerner Is myocardial Na+/Ca2+ exchanger transcription a marker for different stages of myocardial dysfunction? Quantitative polymerase chain reaction of the messenger RNA in endomyocardial biopsies of patients with heart failure J. Am. Coll. Cardiol., July 1, 2000; 36(1): 233 - 241. [Abstract] [Full Text] [PDF]
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W. T. Abraham {beta}-Blockers: The New Standard of Therapy for Mild Heart Failure Arch Intern Med, May 8, 2000; 160(9): 1237 - 1247. [Abstract] [Full Text] [PDF]
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D. M. Kaye, G. Vaddadi, S. L. Gruskin, X.-J. Du, and M. D. Esler Reduced Myocardial Nerve Growth Factor Expression in Human and Experimental Heart Failure Circ. Res., April 14, 2000; 86 (7): e80 - e84. [Abstract] [Full Text] [PDF]
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C Berry and A.L Clark Catabolism in chronic heart failure Eur. Heart J., April 1, 2000; 21(7): 521 - 532. [PDF]
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R. J. Hajjar, F. del Monte, T. Matsui, and A. Rosenzweig Prospects for Gene Therapy for Heart Failure Circ. Res., March 31, 2000; 86(6): 616 - 621. [Abstract] [Full Text] [PDF]
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S. Bonet, A. Agusti, J. M. Arnau, X. Vidal, E. Diogene, E. Galve, and J.-R. Laporte {beta}-Adrenergic Blocking Agents in Heart Failure: Benefits of Vasodilating and Nonvasodilating Agents According to Patients' Characteristics: A Meta-analysis of Clinical Trials Arch Intern Med, March 13, 2000; 160(5): 621 - 627. [Abstract] [Full Text] [PDF]
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M. Nagatsu, F. G. Spinale, M. Koide, H. Tagawa, G. DeFreitas, G. Cooper IV, and B. A. Carabello Bradycardia and the Role of {beta}-Blockade in the Amelioration of Left Ventricular Dysfunction Circulation, February 15, 2000; 101(6): 653 - 659. [Abstract] [Full Text] [PDF]
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