title: Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiology Division, Fondazione Salvatore Maugeri, IRCCS, Telese Terme (BN), Italy. giuseppe.rengo@unina.it
authors.forename: G
authors.initials: G
authors.lastname: Rengo
authors.forename: A
authors.initials: A
authors.lastname: Lymperopoulos
authors.forename: C
authors.initials: C
authors.lastname: Zincarelli
authors.forename: Gd
authors.initials: G
authors.lastname: Femminella
authors.forename: D
authors.initials: D
authors.lastname: Liccardo
authors.forename: G
authors.initials: G
authors.lastname: Pagano
authors.forename: C
authors.initials: C
authors.lastname: de Lucia
authors.forename: A
authors.initials: A
authors.lastname: Cannavo
authors.forename: P
authors.initials: P
authors.lastname: Gargiulo
authors.forename: N
authors.initials: N
authors.lastname: Ferrara
authors.forename: P
authors.initials: P
authors.lastname: Perrone Filardi
authors.forename: Wj
authors.initials: W
authors.lastname: Koch
authors.forename: D
authors.initials: D
authors.lastname: Leosco
mesh_terms: D000311:Adrenal Glands / Q000166:cytology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017298:Bisoprolol / Q000008:administration & dosage / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D018341:Receptors, Adrenergic, alpha-2; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D017298:Bisoprolol