(Circulation. 2000;101:1634.)
© 2000 American Heart Association, Inc.
Editorial |
Catecholamines, Cardiac ß-Adrenergic Receptors, and Heart Failure
From the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry (R.J.L.), Department of Medicine (H.A.R.), and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Robert J. Lefkowitz, HHMI, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail lefko001@receptor-biol.duke.edu
Key Words: Editorials • catecholamines • receptors, adrenergic, beta • heart failure
It is now generally accepted that chronically elevated stimulation of the cardiac ß-adrenergic system is toxic to the heart and that such stimulation may contribute to the pathogenesis of congestive heart failure of various causes. Administration of either ß-adrenergic agonists or phosphodiesterase inhibitors has been shown to decrease survival of patients with chronic heart failure, even though they produce immediate and long-term hemodynamic benefits.1 Moreover, in human heart failure, as well as in several animal models, elevated circulating catecholamines lead, via various compensatory mechanisms, to decreased levels and functional activity of cardiac ß1-adrenergic receptors (ß1ARs) and thus to marked desensitization of the heart to inotropic ß-adrenergic stimulation.2
These biochemical and physiological changes appear to be mediated by elevated levels of the enzyme ßAR kinase1 (ßARK-1, GRK2) in the heart that are invariably associated with dampened responsiveness to catecholamine stimulation.3 ßARK is one of a family of enzymes (G protein–coupled receptor kinases) that phosphorylate ßARs and other G protein–coupled receptors after they have been stimulated, thus leading to their desensitization.4 Currently, it is widely believed that these mechanisms protect the heart from the toxic effects of inotropic ß-adrenergic support. The recent success of ß-blockers in treating chronic heart failure is generally explained by their ability to block the noxious effects of chronic endogenous sympathetic stimulation of the failing heart. In contrast, infusion of ß-adrenergic agonists is used solely for short-term and palliative inotropic support.
Given these findings, it is not surprising that there has been little
recent interest in
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