Abstract 3592: Hydralazine and Nitroglycerin Restore Impaired Excitation-Contraction Coupling Associated with Nitroso-Redox Disequilibrium
Background: Experimental and clinical studies support the concept that the balance between the production of reactive oxygen and nitrogen species is disrupted in heart failure, explaining clinical responsiveness to combination regimens such as hydralazine and isosorbide dinitrate. As precise mechanism(s) of action for this regimen is unclear, we hypothesized that these agents correct impaired cardiac excitation-contraction (EC) coupling associated with nitric oxide (NO) /redox disequilibrium.
Methods and Results: We measured sarcomere length (SL) shortening and Ca2+ transients ([Ca2+]i) in isolated cardiac myocytes from C57BL/6 wild type (WT) and neuronal nitric oxide synthase deficient (NOS1−/ −) mice during force-frequency stimulation (1– 8 Hz). Suppressed SL and [Ca 2+]i responses in NOS1−/− cardiomyocytes were augmented by either hydralazine, nitroglycerin, or diethylenetriamine/nitric oxide adduct. Sarcoplasmic reticulum Ca2+ stores, also impaired in NOS1−/ − cardiomyocytes, were similarly restored by these agents. Neither agent affected FFR or EC coupling parameters in WT. We also measured the effect of hydralazine and nitroglycerin on the NADPH oxidase (NOX) and xanthine oxidoreductase(XOR) dependent superoxide and peroxynitrite production by chemiluminescence method. Hydralazine inhibited NOX activity and quenched both superoxide and peroxynitrite production, whereas nitroglycerin inhibited XOR enzyme activity and preferentially quenched superoxide.
Conclusion: Hydralazine and NO donors normalize cardiac EC coupling impaired by NO/redox disequilibrium through decreasing the amount of ROS produced by XOR and NOX. These data offer new insights into the redox-based mechanisms underlying the actions of hydralazine and isosorbide dinitrate.