Hydralazine and organic nitrates restore impaired excitation-contraction coupling by reducing calcium leak associated with nitroso-redox imbalance

Raul A. Dulce, Omer Yiginer, Daniel R. Gonzalez, Garrett Goss, Ning Feng, Meizi Zheng, Joshua M. Hare

Research output: Contribution to journalArticle

24 Scopus citations

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 Ca 2+ 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[Ca 2+]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 oxidasedependent superoxide more efficiently than HYD. Together, these results revealed that by reducing SR Ca2+ leak, HYD improves Ca2+ cycling and contractility impaired by nitrosoredox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling.

Original languageEnglish (US)
Pages (from-to)6522-6533
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number9
DOIs
StatePublished - Mar 1 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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