Article

Hydralazine and Organic Nitrates Restore Impaired Excitation-Contraction Coupling by Reducing Calcium Leak Associated with Nitroso-Redox Imbalance

Miller School of Medicine, University of Miami, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2013; 288(9). DOI: 10.1074/jbc.M112.412130
Source: PubMed

ABSTRACT Although the combined use of hydralazine and isosorbide dinitrate confers important clinical benefits in patients with heart
failure, the underlying mechanism of action is still controversial. We used two models of nitroso-redox imbalance, neuronal
NO synthase-deficient (NOS1−/−) mice and spontaneously hypertensive heart failure rats, to test the hypothesis that hydralazine (HYD) alone or in combination
with nitroglycerin (NTG) or isosorbide dinitrate restores Ca2+ cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased
pacing frequency was depressed in NOS1−/− compared with wild type myocytes. Both sarcomere length shortening and intracellular Ca2+ transient (Δ[Ca2+]i) responses in NOS1−/− cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced
Δ[Ca2+]i across the range of pacing frequencies and increased myofilament Ca2+ sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from the heart failure
rat model. HYD alone or in combination with NTG reduced sarcoplasmic reticulum (SR) leak, improved SR Ca2+ reuptake, and restored SR Ca2+ content. HYD and NTG at low concentrations (1 μm), scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, NTG inhibited xanthine oxidoreductase
activity and scavenged NADPH oxidase-dependent superoxide more efficiently than HYD. Together, these results revealed that
by reducing SR Ca2+ leak, HYD improves Ca2+ cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac
excitation-contraction coupling.

Download full-text

Full-text

Available from: Raul A Dulce, Aug 28, 2015
0 Followers
 · 
241 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide is a key signaling molecule in the heart and is produced endogenously by three isoforms of nitric oxide synthase, neuronal NOS (NOS1), endothelial NOS (NOS3), and inducible NOS (NOS2). Nitric oxide signals via cGMP-dependent or independent pathways to modulate downstream proteins via specific post translational modifications (i.e. cGMP-dependent protein kinase phosphorylation, S-nitrosylation, etc.). Dysfunction of NOS (i.e. altered expression, location, coupling, activity, etc.) exists in various cardiac disease conditions, such as heart failure, contributing to the contractile dysfunction, adverse remodeling, and hypertrophy. This review will focus on the signaling pathways of each NOS isoform during health and disease, and discuss current and potential therapeutic approaches targeting nitric oxide signaling to treat heart disease.
    Pharmacology [?] Therapeutics 01/2013; S0163-7258(3). DOI:10.1016/j.pharmthera.2013.12.013 · 7.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The origins of the hydralazine/isosorbide dinitrate (H+ISDN) combination therapy are rooted in the first large-scale clinical trial in heart failure: V-HeFT I. Initially utilized for the balanced vasodilatory properties of each drug, we now know there is "more to the story." In fact, the maintenance of the nitroso-redox balance may be the true mechanism of benefit. Since the publication of V-HeFT I 30 years ago, H+ISDN has been the subject of much discussion and debate. Regardless of the many controversies surrounding H+ISDN, one thing is clear: therapy is underutilized and many patients who could benefit never receive the drugs. Ongoing physician and patient education are mandatory to improve the rates of H+ISDN use.
    Heart Failure Clinics 01/2014; DOI:10.1016/j.hfc.2014.07.001 · 1.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Significance: Heart failure (HF) results from poor heart function and is the leading cause of death in Western society. Abnormalities of Ca2+ handling at the level of the ventricular myocyte are largely responsible for much of the poor heart function. Recent Advances: While studies have unraveled numerous mechanisms for the abnormal Ca2+ handling, investigations over the past decade have indicated that much of the contractile dysfunction and adverse remodeling that occurs in HF involves oxidative stress. Critical Issues: Regrettably, anti-oxidant therapy has been an immense disappoint in clinical trials. Thus, redox signaling is being reassessed to elucidate why antioxidants failed to treat HF. Future Directions: A recently identified aspect of redox signaling (specifically the superoxide anion radical) is its interaction with nitric oxide, known as the nitroso-redox balance. There is a large nitroso-redox imbalance with HF and we suggest that correcting this imbalance may be able to restore myocyte contraction and improve heart function.
    Antioxidants & Redox Signaling 05/2014; 21(14). DOI:10.1089/ars.2014.5873 · 7.67 Impact Factor
Show more