Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α2-adrenoceptor-catecholamine production axis in heart failure

G. Rengo, A. Lymperopoulos, C. Zincarelli, G. D. Femminella, D. Liccardo, G. Pagano, C. De Lucia, A. Cannavo, P. Gargiulo, N. Ferrara, P. Perrone Filardi, W. J. Koch, D. Leosco

Research output: Contribution to journalArticlepeer-review

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)-α2adrenoceptor- catecholamine production axis is up-regulated in the adrenal medulla during HF causing α2-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 α2adrenoceptors 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 α2adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related α2adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression. Conclusion and Implications Blockade of β-adrenoceptors normalized the adrenal α2adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by β-blockers.

Original languageEnglish
Pages (from-to)2430-2440
Number of pages11
JournalBritish Journal of Pharmacology
Volume166
Issue number8
DOIs
Publication statusPublished - Aug 2012

Keywords

  • β-blocker
  • adrenal GRK2
  • catecholamines
  • heart failure
  • sympathetic overactivity

ASJC Scopus subject areas

  • Pharmacology

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