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: 4.6). 01/2013; 288(9). DOI: 10.1074/jbc.M112.412130
Source: PubMed

ABSTRACT Although the combined use of hydralazine and isosorbide dinitrate has provided surprising beneficial outcomes 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 (SHHF) rats, to test the hypothesis that hydralazine alone or in combination with nitroglycerin or isosorbide dinitrate (ISDN) restores Ca(2+) cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased pacing frequency was depressed in NOS1(-/-) compared to wild type (WT) myocytes. Both sarcomere length shortening and Δ[Ca(2+)](i) responses in NOS1(-/-) cardiomyocytes were augmented by hydralazine in a dose-dependent manner. Nitroglycerin alone did not affect myocyte shortening but reduced Δ[Ca(2+)](i) across the range of pacing frequencies and increased myofilament Ca(2+) sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from SHHF rats. Hydralazine alone or in combination with nitroglycerin reduced SR Ca(2+) leak, improved SR Ca(2+) reuptake and restored SR Ca(2+) content. Both, hydralazine and nitroglycerin at concentrations as low as 1 μM, scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, nitroglycerin inhibited xanthine oxidoreductase activity and scavenged NADPH oxidase-dependent superoxide more efficiently than hydralazine. Therefore, we revealed that by reducing SR Ca(2+) leak, hydralazine improved Ca(2+) cycling and contractility impaired by nitroso-redox imbalance, and nitroglycerin enhanced the contractile efficiency, restoring cardiac excitation-contraction coupling.

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    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.
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