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Br J Pharmacol. 2012 Aug;166(8):2430-40. doi: 10.1111/j.1476-5381.2012.01972.x.

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

Author information

1
Cardiology Division, Fondazione Salvatore Maugeri, IRCCS, Telese Terme (BN), Italy. giuseppe.rengo@unina.it

Abstract

BACKGROUND AND PURPOSE:

Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of β-adrenoceptor antagonist (β-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. β-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-α(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing α(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if β-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 α(2) adrenoceptors 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 α(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related α(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression.

CONCLUSION AND IMPLICATIONS:

Blockade of β-adrenoceptors normalized the adrenal α(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by β-blockers.

PMID:
22519418
PMCID:
PMC3448904
DOI:
10.1111/j.1476-5381.2012.01972.x
[Indexed for MEDLINE]
Free PMC Article
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