title: Hydralazine and organic nitrates restore impaired excitation-contraction coupling by reducing calcium leak associated with nitroso-redox imbalance.
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 Ca(2+) 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[Ca(2+)]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 Ca(2+) 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 Ca(2+) reuptake, and restored SR Ca(2+) 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 Ca(2+) leak, HYD improves Ca(2+) cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling.
authors: Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors: Raul A
authors: RA
authors: Dulce
authors: Omer
authors: O
authors: Yiginer
authors: Daniel R
authors: DR
authors: Gonzalez
authors: Garrett
authors: G
authors: Goss
authors: Ning
authors: N
authors: Feng
authors: Meizi
authors: M
authors: Zheng
authors: Joshua M
authors: JM
authors: Hare
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D056966:Excitation Contraction Coupling / Q000187:drug effects* / Q000235:genetics; D006830:Hydralazine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D009124:Muscle Proteins; D014665:Vasodilator Agents; D006830:Hydralazine; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D005996:Nitroglycerin; D002118:Calcium