Blockade of [beta]-adrenoceptors restores the GRK2-mediated adrenal [alpha]2-adrenoceptor-catecholamine production axis in heart failure

BACKGROUND AND PURPOSE Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of [beta]-adrenoceptor antagonist ([beta]-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. [beta]-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-[alpha]2adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing [alpha]2-adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if [beta]-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels. EXPERIMENTAL APPROACH Four weeks after myocardial infarction-induced HF, adult rats were randomized to 10-week treatment with vehicle (HF/C) or bisoprolol (HF/B). Cardiac function and dimensions were measured. In heart and adrenal gland, GRK2 levels were assessed by RT-PCR and Western blotting and adrenoceptors studied with radioligand binding. Catecholamines and [alpha]2adrenoceptors in adrenal medulla chromaffin cell cultures were also measured. KEY RESULTS Bisoprolol treatment ameliorated HF-related adverse cardiac remodelling and reduced plasma catecholamine levels, compared with HF/C rats. Bisoprolol also attenuated adrenal GRK2 overexpression as observed in HF/C rats and increased [alpha]2adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related [alpha]2adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression. CONCLUSION AND IMPLICATIONS Blockade of [beta]-adrenoceptors normalized the adrenal [alpha]2adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by [beta]-blockers. [PUBLICATION ABSTRACT]