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

Gonzalez, DR (Gonzalez, Daniel R.). Univ Talca, Fac Ciencias Salud, Dept Ciencias Basicas Biomed, Talca 3460000, ChileAlthough 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 (Delta[Ca2+](i)) responses in NOS1(-/-) cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced Delta[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 mu M), 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

Hydralazine and nitroglycerine restore impaired excitation-contraction coupling associated with nitroso-redox disequilibrium

Johns Hopkins Univ, Baltimore, MD 21218 USAUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Effect of Chronic Arsenic Exposure from Drinking Waters on the QT Interval and Transmural Dispersion of Repolarization

This study investigated the effects of chronic arsenic exposure on QT- and QTc-interval prolongation, QTc dispersion (QTcd) and transmural dispersion of repolarization (TDR). We compared cardiac parameters from 40 male subjects chronically exposed to arsenic (group A) with those of 40 male subjects not exposed to arsenic (group B). Although subjects in both groups had non-corrected QT intervals within normal limits, subjects in group A had significantly longer QTc and QTcd intervals compared with group B. A total of 70 % of group A compared with 10 % of group B had QTcd values> 50 ms. The mean TDR value was also significantly higher in group A compared with group B. Although non-corrected QT intervals were within normal limits, those subjects chronically exposed to arsenic had a slight QT prolongation and a higher prevalence of subtle repolarization abnormalities, which might be clinically relevant

Effect of chronic arsenic exposure from drinking waters on the QT interval and transmural dispersion of repolarization

This study investigated the effects of chronic arsenic exposure on QT- and QTc-interval prolongation, QTc dispersion (QTcd) and transmural dispersion of repolarization (TDR). We compared cardiac parameters from 40 male subjects chronically exposed to arsenic (group A) with those of 40 male subjects not exposed to arsenic (group B). Although subjects in both groups had non-corrected QT intervals within normal limits, subjects in group A had significantly longer QTc and QTcd intervals compared with group B. A total of 70% of group A compared with 10% of group B had QTcd values > 50 ms. The mean TDR value was also significantly higher in group A compared with group B. Although non-corrected QT intervals were within normal limits, those subjects chronically exposed to arsenic had a slight QT prolongation and a higher prevalence of subtle repolarization abnormalities, which might be clinically relevant

Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity

Disruption of the leptin signaling pathway within the heart causes left ventricular hypertrophy (LVH). Because human obesity is a syndrome of leptin resistance, which is not amenable to leptin treatment, the identification of parallel signal transduction pathways is of potential therapeutic value. Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity. We hypothesized that CNTF receptors are present on cardiomyocytes and their activation reverses LVH in both leptin-deficient ob/ob and leptin-resistant db/db mice. The localization of CNTF receptors (CNTFRα) to the sarcolemma in C57BL/6, ob/ob and db/db was confirmed in situ with immunohistochemistry, and immunoblotting (60 and 40 kDa) on isolated myocytes. ob/ob mice were randomly assigned to receive s.c. recombinant CNTF (CNTF(Ax15); 0.1 mg·kg(−1) per day; n = 11) calorie-restriction (n = 9), or feeding ad libitum (n = 11). db/db mice were allocated to three similar groups (n = 8, 7, and 8, respectively) plus a leptin group (1 mg·kg(−1) per day; n = 7). Echocardiography showed that CNTF(Ax15) reduced cardiac hypertrophy [posterior wall thickness decreased by 29 ± 8% (P < 0.01) in ob/ob and by 21 ± 3% in db/db mice (P < 0.01)], which was consistent with the reduction of myocyte width. Western blotting showed that leptin and CNTF(Ax15) activated Stat3 and ERK1/2 pathway in cultured adult mice cardiomyocytes and cardiac tissue from in ob/ob and db/db mice. Together, these findings support the role of a previously undescribed signaling pathway in obesity-associated cardiac hypertrophy and have therapeutic implications for patients with obesity-related cardiovascular disease and other causes of LVH