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Blockade of ?-adrenoceptors restores the GRK2-mediated adrenal ?(2) -adrenoceptor-catecholamine production axis in heart failure.


ABSTRACT: Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of ?-adrenoceptor antagonist (?-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. ?-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-?(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing ?(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if ?-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels.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 ?(2) adrenoceptors in adrenal medulla chromaffin cell cultures were also measured.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 ?(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related ?(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression.Blockade of ?-adrenoceptors normalized the adrenal ?(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by ?-blockers.

SUBMITTER: Rengo G 

PROVIDER: S-EPMC3448904 | BioStudies | 2012-01-01T00:00:00Z

REPOSITORIES: biostudies

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