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  • Oral presentation
  • Open Access

Chronic beta-adrenergic blockade prevents volume overload-induced re-localization and oxidation of soluble guanylyl cyclase

  • 1,
  • 2,
  • 1, 3 and
  • 1, 4Email author
BMC Pharmacology and Toxicology201314 (Suppl 1) :O22

  • Published:


  • Metoprolol
  • Mitral Regurgitation
  • Soluble Guanylyl Cyclase
  • VASP Phosphorylation
  • Metoprolol Succinate


While β-adrenergic blockade is a cornerstone of heart failure therapy, its therapeutic role in chronic mitral regurgitation remains questionable. Animal studies and a small clinical trial have demonstrated cardiac functional improvement with β1-adrenoceptor blocker metoprolol in chronic mitral regurgitation [1, 2]. How β1AR-blockade halts functional decline of the volume-overloaded, eccentric hypertrophied heart is not well understood; anti-oxidant effects of β-blockade (βB) may play a role. We recently demonstrated that volume-overload cardiac stress induces re-localization and microdomain-specific oxidation of the nitric oxide receptor soluble guanylyl cyclase (sGC) in the failing heart [3, 4]. Given that nitric oxide-cyclic guanosine monophosphate (NO-cGMP) modulates cardiac contractility and protects against cardiac hypertrophy, we hypothesized that β1AR-blockade prevents oxidation of sGC and promotes myocardial NO-cGMP signaling in a microdomain-specific fashion.

Materials and methods

Volume-overload (VO) was established by chordal rupture-induced mitral regurgitation (MR) in mongrel dogs. Some dogs were treated with metoprolol succinate (100mg orally once daily; MR+ βB). Expression, localization, cyclase activity, and redox state of myocardial sGC were assessed in Control, MR, and MR+βB dogs.


sGCα1 and -β1 subunits were detected within and outside of caveolae-enriched lipid rafts (Cav3+LR). In MR, total sGCα1 expression fell to nearly 50% of Control and re-localized away from Cav3+LR to non-lipid raft microdomains (NLR). While overall sGCβ1 expression was also less in MR+βB, caveolae-localization of sGCβ1 was preserved. Overall NO-responsiveness of sGC remained intact in MR hearts, irrespective of βB therapy. However, a potentiated response to heme/NO-independent sGC activator BAY 60-2770 suggested that a subset of sGC was heme-oxidized in MR but not in Control or MR+βB. Moreover, differential responses to BAY 60-2770 and NO were noted in Cav3+LR and NLR microdomains. In Control hearts, responses to BAY 60-2770 and NO were similar within respective microdomains, suggesting a predominantly reduced form of sGC in both Cav3+LR and NLR of Controls. In contrast, BAY 60-2770 response of NLR-localized sGC was potentiated in MR but not in MR+βB hearts, suggesting that βB therapy prevented oxidation of NLR-localized sGC. Moreover, BAY 60-2770 responses of Cav3+LR-localized sGC were not potentiated in any hearts, suggesting an anti-oxidation protection associated with caveolae-localization. These changes in caveolae-localization and redox state of sGC were also reflected by microdomain distribution of VASP phosphorylation.


β1AR blocker mediated cardioprotection in the volume-overloaded heart is associated with enhanced microdomain specific myocardial NO-cGMP signaling, both within and outside of caveolae. Such prevention of volume overload-induced spatial and redox dysregulation of myocardial sGC suggests novel strategies to enhancing cardioprotective NO-cGMP signaling.

Authors’ Affiliations

Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
Division of Cardiovascular Disease, Department of Medicine, University of Alabama Birmingham School of Medicine, Birmingham, AL 35233, USA
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
Section of Cardiology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA


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© Liu et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.