Published online before print October 14, 2002, doi: 10.1161/01.CIR.0000036600.39600.66
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(Circulation. 2002;106:2491.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Feedback Inhibition of Catecholamine Release by Two Different 
2-Adrenoceptor Subtypes Prevents Progression of Heart Failure
From the Institut für Pharmakologie und Toxikologie (M.B., R.J., K.H., C.A., M.J.L., L.H.), Medizinische Universitätsklinik (F.W.), and Physikalisches Institut (F.W.), Universität Würzburg, Germany, and Department of Cardiovascular Medicine (S.N.), University of Oxford, UK.
Correspondence to Lutz Hein, MD, Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. E-mail hein{at}toxi.uni-wuerzburg.de
Background— Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which 
2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking 2-adrenoceptor subtypes (2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of 2-adrenoceptors in human patients with chronic heart failure.
Methods and Results— Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in 2A-KO (52%) and 2C-KO (47%) mice compared with wild-type and 2B-deficient (86%) animals. Excess mortality in 2A- and 2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the 2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography.
Conclusions— Our results indicate an essential function of 2A- and 2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic 2-adrenoceptor variants as well as new 2-receptor subtype–selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.
Key Words: receptors, adrenergic, alpha • genetics • heart failure • catecholamines
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