(Circulation. 1999;99:2702-2707.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Enhanced Contractility and Decreased ß-Adrenergic Receptor Kinase-1 in Mice Lacking Endogenous Norepinephrine and Epinephrine
From the Department of Medicine (M.-C.C., H.A.R.), University of North Carolina at Chapel Hill; University of California San Diego School of Medicine (M.R.), LaJolla, Calif; Department of Surgery (W.J.K.), Duke University, Durham, NC; and Department of Biochemistry and Howard Hughes Medical Institute (S.A.T., R.D.P.), University of Washington, Seattle, Wash.
Correspondence to Howard A. Rockman, MD, Department of Medicine, CB#7075, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7075. E-mail hrockman{at}med.unc.edu
Background—Elevated circulating norepinephrine (NE) has been implicated in causing the profound ß-adrenergic receptor (ßAR) downregulation and receptor uncoupling that are characteristic of end-stage human dilated cardiomyopathy, a process mediated in part by increased levels of ß-adrenergic receptor kinase (ßARK1). To explore whether chronic sustained NE stimulation is a primary stimulus that promotes deterioration in cardiac signaling, we characterized a gene-targeted mouse in which activation of the sympathetic nervous system cannot lead to an elevation in plasma NE and epinephrine.
Methods and Results—Gene-targeted mice that lack dopamine ß-hydroxylase (dbh-/-), the enzyme needed to convert dopamine to NE, were created by homologous recombination. In vivo contractile response to the ß1AR agonist dobutamine, measured by a high-fidelity left ventricular micromanometer, was enhanced in mice lacking the dbh gene. In unloaded adult myocytes isolated from dbh-/- mice, basal contractility was significantly increased compared with control cells. Furthermore, the increase in ßAR responsiveness and enhanced cellular contractility were associated with a significant reduction in activity and protein level of ßARK1 and increased high-affinity agonist binding without changes in ßAR density or G-protein levels.
Conclusions—Mice that lack the ability to generate NE or epinephrine show increased contractility associated primarily with a decrease in the level of ßARK1 protein and kinase activity. This animal model will be valuable in testing whether NE is required for the pathogenesis of heart failure through mating strategies that cross the dbh-/- mouse into genetically engineered models of heart failure.
Key Words: contractility • catecholamines • heart failure • receptors, adrenergic, beta
This article has been cited by other articles:
 |
|
 |
|
  O. Oldenburg, A. Schmidt, B. Lamp, T. Bitter, B. G. Muntean, C. Langer, and D. Horstkotte Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration Eur J Heart Fail, June 1, 2008; 10(6): 581 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Ebert and D. G. Taylor Catecholamines and development of cardiac pacemaking: An intrinsically intimate relationship Cardiovasc Res, December 1, 2006; 72(3): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Penela, C. Murga, C. Ribas, A. S. Tutor, S. Peregrin, and F. Mayor Jr. Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease Cardiovasc Res, January 1, 2006; 69(1): 46 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang, S. Cotecchia, S. A. Thomas, A. Tanoue, G. Tsujimoto, and J. E. Faber Gene deletion of dopamine {beta}-hydroxylase and {alpha}1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2106 - H2114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Swoap, D. Weinshenker, R. D. Palmiter, and G. Garber Dbh(-/-) mice are hypotensive, have altered circadian rhythms, and have abnormal responses to dieting and stress Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R108 - R113. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Vial and R. J. Evans P2X1 Receptor-Deficient Mice Establish the Native P2X Receptor and a P2Y6-Like Receptor in Arteries Mol. Pharmacol., December 1, 2002; 62(6): 1438 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. A. Janssen and J. F. M. Smits Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1545 - R1564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Carson and D. Robertson Genetic Manipulation of Noradrenergic Neurons J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 410 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Esposito, A. Rapacciuolo, S. V. Naga Prasad, H. Takaoka, S. A. Thomas, W. J. Koch, and H. A. Rockman Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress Circulation, January 1, 2002; 105(1): 85 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rapacciuolo, G. Esposito, K. Caron, L. Mao, S. A. Thomas, and H. A. Rockman Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy J. Am. Coll. Cardiol., September 1, 2001; 38(3): 876 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Iaccarino, E. Barbato, E. Cipolleta, A. Esposito, A. Fiorillo, W. J. Koch, and B. Trimarco Cardiac {beta}ARK1 Upregulation Induced by Chronic Salt Deprivation in Rats Hypertension, August 1, 2001; 38(2): 255 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice Cardiovasc Res, June 1, 2001; 50(3): 443 - 453. [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Kim, M. S. Szczypka, and R. D. Palmiter Dopamine-Deficient Mice Are Hypersensitive to Dopamine Receptor Agonists J. Neurosci., June 15, 2000; 20(12): 4405 - 4413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Weinshenker, N. C. Rust, N. S. Miller, and R. D. Palmiter Ethanol-Associated Behaviors of Mice Lacking Norepinephrine J. Neurosci., May 1, 2000; 20(9): 3157 - 3164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. Cho, A. Rapacciuolo, W. J. Koch, Y. Kobayashi, L. R. Jones, and H. A. Rockman Defective beta -Adrenergic Receptor Signaling Precedes the Development of Dilated Cardiomyopathy in Transgenic Mice with Calsequestrin Overexpression J. Biol. Chem., August 6, 1999; 274(32): 22251 - 22256. [Abstract] [Full Text] [PDF]
|
|