Background—Impaired myocardial β-adrenergic receptor (βAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial β-adrenergic receptor kinase (βARK1) activity because levels of this βAR-desensitizing G protein–coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for βAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize βARs to study the dynamic relationship between βAR activation and myocardial levels of βARK1.

Methods and Results—Long-term in vivo stimulation of βARs results in the impairment of cardiac βAR signaling and increases the level of expression (mRNA and protein) and activity of βARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term β-blocker treatment, including the use of carvedilol, improves myocardial βAR signaling and reduces βARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to βAR signaling.

Conclusions—This report demonstrates, for the first time, that βAR stimulation can significantly increase the expression of βARK1, whereas β-blockade decreases expression. This reciprocal regulation of βARK1 documents a novel mechanism of ligand-induced βAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of β-blockers, such as carvedilol, in the treatment of heart failure.