sodium-nitrite and Heart-Failure

Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.. Determine whether inhaled nitrite improves hemodynamics in HFpEF.. In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise before and after treatment with inhaled sodium nitrite (90 mg) or placebo. The primary end point was the pulmonary capillary wedge pressure during exercise. Before study drug administration, HFpEF subjects displayed an increase in pulmonary capillary wedge pressure with exercise from 20±6 to 34±7 mm Hg (P<0.0001). After study drug administration, exercise pulmonary capillary wedge pressure was substantially improved by nitrite as compared with placebo (baseline-adjusted mean 25±5 versus 31±6 mm Hg; analysis of covariance P=0.022). Inhaled nitrite reduced resting pulmonary capillary wedge pressure (-4±3 versus -1±2 mm Hg; P=0.002), improved pulmonary artery compliance (+1.5±1.1 versus +0.6±0.9 mL/mm Hg), and decreased mean pulmonary artery pressures at rest (-7±4 versus -3±4 mm Hg; P=0.007) and with exercise (-10±6 versus -5±6 mm Hg; P=0.05). Nitrite reduced right atrial pressures, with no effect on cardiac output or stroke volume.. Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF.. This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078).

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Double-Blind Method; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Rest; Sodium Nitrite; Stroke Volume

Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH.. Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide.. Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF.. Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients.. ClinicalTrials.gov NCT01431313 FUNDING. This work was supported in part by the NIH grants P01HL103455 (to MAS and MTG), R01HL098032 (to MTG), and R01HL096973 (to MTG), and Mast Therapeutics, Inc.

Topics: Administration, Inhalation; Adult; Aged; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Prospective Studies; Sodium Nitrite; Stroke Volume

Nitrite exhibits hypoxia-dependent vasodilator properties, selectively dilating capacitance vessels in healthy subjects. Unlike organic nitrates, it seems not to be subject to the development of tolerance. Currently, therapeutic options for decompensated heart failure (HF) are limited. We hypothesized that by preferentially dilating systemic capacitance and pulmonary resistance vessels although only marginally dilating resistance vessels, sodium nitrite (NaNO2) infusion would increase cardiac output but reduce systemic arterial blood pressure only modestly. We therefore undertook a first-in-human HF proof of concept/safety study, evaluating the hemodynamic effects of short-term NaNO2 infusion.. Twenty-five patients with severe chronic HF were recruited. Eight received short-term (5 minutes) intravenous NaNO2 at 10 μg/kg/min and 17 received 50 μg/kg/min with measurement of cardiac hemodynamics. During infusion of 50 μg/kg/min, left ventricular stroke volume increased (from 43.22±21.5 to 51.84±23.6 mL; P=0.003), with marked falls in pulmonary vascular resistance (by 29%; P=0.03) and right atrial pressure (by 40%; P=0.007), but with only modest falls in mean arterial blood pressure (by 4 mm Hg; P=0.004). The increase in stroke volume correlated with the increase in estimated trans-septal gradient (=pulmonary capillary wedge pressure-right atrial pressure; r=0.67; P=0.003), suggesting relief of diastolic ventricular interaction as a contributory mechanism. Directionally similar effects were observed for the above hemodynamic parameters with 10 μg/kg/min; this was significant only for stroke volume, not for other parameters.. This first-in-human HF efficacy/safety study demonstrates an attractive profile during short-term systemic NaNO2 infusion that may be beneficial in decompensated HF and warrants further evaluation with longer infusion regimens.

Topics: Adult; Arterial Pressure; Cardiac Output; Chronic Disease; Coronary Circulation; Drug Administration Schedule; England; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Pulmonary Circulation; Recovery of Function; Severity of Illness Index; Sodium Nitrite; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

There is no effective medical treatment for heart failure with preserved ejection fraction (HFpEF). Increases in pulmonary capillary wedge pressure (PCWP) develop in patients with HFpEF during exercise coupled with impaired nitric oxide (NO) signaling. Nitrite can be reduced to bioactive NO in vivo, particularly under conditions of tissue hypoxia, as with exercise.. This study sought to determine whether acute nitrite administration improves exercise hemodynamics and cardiac reserve in HFpEF.. In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (N = 28) underwent invasive cardiac catheterization with simultaneous expired gas analysis at rest and during exercise, before and 15 min after treatment with either sodium nitrite or matching placebo.. Before the study drug infusion, HFpEF subjects displayed an increase in PCWP with exercise from 16 ± 5 mm Hg to 30 ± 7 mm Hg (p < 0.0001). After study drug infusion, the primary endpoint of exercise PCWP was substantially improved by nitrite compared with placebo (adjusted mean: 19 ± 5 mm Hg vs. 28 ± 6 mm Hg; p = 0.0003). Nitrite-enhanced cardiac output reserve improved with exercise (+0.5 ± 0.7 l/min vs. -0.4 ± 0.7 l/min; p = 0.002) and normalized the increase in cardiac output relative to oxygen consumption. Nitrite improved pulmonary artery pressure-flow relationships in HFpEF and increased left ventricular stroke work with exercise versus placebo, indicating an improvement in ventricular performance with stress.. Acute sodium nitrite infusion favorably attenuates hemodynamic derangements of cardiac failure that develop during exercise in individuals with HFpEF. Prospective trials testing long-term nitrite therapy in this population are warranted. (Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606).

Topics: Aged; Cardiac Catheterization; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Heart Failure; Heart Ventricles; Humans; Male; Prospective Studies; Sodium Nitrite; Stroke Volume; Ventricular Function, Left

Nitrite (NO₂⁻) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO₂⁻ in healthy volunteers and patients with stable congestive heart failure (CHF).. The acute haemodynamic effects of brachial artery infusion of NO₂⁻ (0.31 to 7.8 μmol·min⁻¹) was assessed in normal subjects (n = 20) and CHF patients (n = 21).. NO₂⁻ infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO₂⁻ infusion rates which induced no changes in normal subjects (ANOVA: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO₂⁻ infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO₂⁻ infusion. Venous plasma NO₂⁻ concentrations were lower in CHF patients at baseline, and rose substantially less with NO₂⁻ infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO₂⁻ infusion. Prolonged NO₂⁻ exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro.. The findings of arterial hyper-responsiveness to infused NO₂⁻ in CHF patients, with evidence of accelerated transvascular NO₂⁻ clearance (presumably with concomitant NO release) suggests that NO₂⁻ effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO₂⁻ as a therapeutic modality in CHF.

Topics: Aged; Brachial Artery; Cohort Studies; Drug Tolerance; Female; Forearm; Heart Failure; Hemodynamics; Humans; In Vitro Techniques; Infusions, Intra-Arterial; Male; Metabolic Clearance Rate; Middle Aged; Nitric Oxide; Nitroglycerin; Oxidative Stress; Regional Blood Flow; Saphenous Vein; Sodium Nitrite; Vasodilation; Vasodilator Agents; Vasomotor System

Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

Topics: Animals; Disease Models, Animal; Drinking Water; Heart Failure; Hydralazine; Male; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Sodium Nitrite; Stroke Volume

The severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance, which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, and thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with heart failure with preserved ejection fraction who were administered inhaled sodium nitrite to better understand the acute effects on afterload.. Fourteen patients with PH associated with heart failure with preserved ejection fraction underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both before and after nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (inversely related to proximal pulmonary artery compliance) and total work performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output. There was a mild decrease in pulmonary steady-state resistance after the administration of inhaled sodium nitrite, but this effect was not significant.. PVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance via a decrease in characteristic impedance, more so than pulmonary steady-state resistance. This effect was associated with improved RV efficiency and total work.

Topics: Electric Impedance; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Artery; Sodium Nitrite; Stroke Volume; Vascular Resistance; Ventricular Function, Right

Topics: Electric Impedance; Heart Failure; Humans; Hypertension, Pulmonary; Sodium Nitrite; Stroke Volume

In the follow-up of patients in a trial of intracoronary sodium nitrite given during primary percutaneous coronary intervention (PCI) after acute myocardial infarction (AMI), we found a reduction in the incidence of major adverse cardiac events (MACEs). Specifically, MACE rates were 5.2% versus 25.0% with placebo at 3 years ( P = .013). Such MACE reductions should also be associated with economic benefit. Thus, we assessed the cost utility of sodium nitrite therapy versus standard primary PCI only.. We developed a model to simulate costs and quality-adjusted life years (QALYs) over the first 36 months after ST-Segment Elevation Myocardial Infarction (STEMI). Decision tree analysis was used to assess different potential cardiovascular outcomes after STEMI for patients in both treatment groups. Model inputs were derived from the NITRITE-AMI study. Cost of comparative treatments and follow-up in relation to cardiovascular events was calculated from the United Kingdom National Health Service perspective. Higher procedural costs for nitrite treatment were offset by lower costs for repeat revascularization, myocardial infarction, and hospitalization for heart failure compared to primary PCI plus placebo. Nitrite treatment was associated with higher utility values (0.91 ± 0.19 vs 0.82 ± 0.30, P = .041). The calculated incremental cost-effectiveness ratio of £2177 per QALY indicates a cost-effective strategy. Furthermore, positive results were maintained when input parameters varied, indicating the robustness of our model. In fact, based on the difference in utility values, the cost of nitrite could increase by 4-fold (£2006 per vial) and remain cost-effective.. This first analysis of sodium nitrite as a cardioprotective treatment demonstrates cost-effectiveness. Although more comparative analysis and assessment of longer follow-up times are required, our data indicate the considerable potential of nitrite-mediated cardioprotection.

Topics: Clinical Decision-Making; Cost Savings; Cost-Benefit Analysis; Drug Costs; Heart Failure; Hospital Costs; Humans; Models, Economic; Myocardial Infarction; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Progression-Free Survival; Quality-Adjusted Life Years; Retreatment; Sodium Nitrite; ST Elevation Myocardial Infarction; State Medicine; Time Factors; United Kingdom; Vasodilator Agents

Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared with healthy volunteers (HVs) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood.. Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29), and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared with healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP.. We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the 'platelet NO resistance' phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Blood Platelets; Case-Control Studies; Cell Adhesion Molecules; Chronic Disease; Drug Resistance; Female; Heart Failure; Humans; Male; Microfilament Proteins; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Phosphoproteins; Phosphorylation; Random Allocation; Sodium Nitrite; Soluble Guanylyl Cyclase; Stroke Volume; Ventricular Function, Left

Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension.. To evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of metabolic syndrome attributable to double-leptin receptor defect (obese ZSF1) with the combined treatment of vascular endothelial growth factor receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose-lowering effect of nitrite was abolished in SIRT3-deficient human skeletal muscle cells, and in SIRT3 knockout mice fed a high-fat diet, as well. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMP-activated protein kinase. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMP-activated protein kinase.. These studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Enzyme Activation; Heart Failure; Humans; Hyperglycemia; Hypertension, Pulmonary; Male; Metformin; Mice; Mice, 129 Strain; Mice, Knockout; Muscle, Skeletal; Rats; Rats, Zucker; Sirtuin 3; Sodium Nitrite; Stroke Volume

Topics: Exercise Tolerance; Female; Heart Failure; Heart Ventricles; Humans; Male; Sodium Nitrite; Stroke Volume; Ventricular Function, Left

Topics: Exercise Tolerance; Female; Heart Failure; Heart Ventricles; Humans; Male; Sodium Nitrite; Stroke Volume; Ventricular Function, Left

Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross-talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia-reperfusion injury and HF. Nuclear factor-erythroid-2-related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia-induced chronic heart failure (CHF).. Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein-related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia-induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2-treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn-superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S-producing enzymes, and ultimately increased H2S bioavailability in ischemia-induced CHF in mice as compared with vehicle.. Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.

Topics: Animals; Antioxidants; Cardiotonic Agents; Coronary Occlusion; Heart Failure; Hydrogen Sulfide; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Oxidative Stress; Signal Transduction; Sodium Nitrite; Stroke Volume

Topics: Animals; Blood Pressure; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Male; Muscle, Skeletal; Nitrates; Radial Artery; Sodium Nitrite; Stroke Volume; Vasodilation

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2 (-) to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2 (-) infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2 (-) infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2 (-) infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1) and CHF + NO2 (-): 0.93 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1), P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2 (-): 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2 (-): 109 ± 7 ml·min(-1)·100 g(-1) ml·min(-1)·100 g(-1), P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2 (-) infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2 (-) infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2 (-)-based therapy may provide an attractive "needs-based" approach for treatment of the vascular dysfunction in CHF.

Topics: Animals; Chronic Disease; Disease Models, Animal; Exercise Tolerance; Heart Failure; Hemodynamics; Hindlimb; Infusions, Intra-Arterial; Male; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Myocardial Infarction; Nitric Oxide; Physical Exertion; Rats, Sprague-Dawley; Regional Blood Flow; Sodium Nitrite; Time Factors

Topics: Exercise Tolerance; Female; Heart Failure; Heart Ventricles; Humans; Male; Sodium Nitrite; Stroke Volume; Ventricular Function, Left

Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.. Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.. These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.

Topics: Aged; Animals; Biological Availability; Cyclic GMP; Cytoprotection; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Middle Aged; Nitric Oxide; Signal Transduction; Sodium Nitrite; Stroke Volume; Ventricular Dysfunction, Left

Although it is known that endothelin (ET-1) is elevated in heart failure (HF), it remains unclear if chronic ET(A/B) receptor antagonism affects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function.. We examined the effects of an ET(A/B) receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7), and vehicle (n=8) in conscious dogs with previously implanted aortic, coronary sinus and left atrial catheters, LV pressure gauge, aortic flow probe, LV dimension crystals and pacers.. Baseline hemodynamics were similar in the two groups. During the development of rapid pacing-induced HF, treatment with the ET(A/B) antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of pacing, LV diastolic function (tau) was improved (P<0.05) in the ET(A/B) antagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ET(A/B) antagonist treatment attenuated the increase in mean left atrial pressure and LV end-diastolic pressure that occurred during heart failure in vehicle-treated animals. However, LV systolic function (LV dP/dt, fractional shortening and Vcfc) neither at rest nor in response to dobutamine was altered by ET(A/B) antagonist treatment. Also, ET(A/B) antagonist treatment did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca(2+) transport in isolated cardiac sarcoplasmic reticulum (SR) was reduced (P<0.02) in the vehicle-treated compared to the ET(A/B) antagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 micromol/mg/min, respectively). The improvement in SR function in the ET(A/B) antagonist-treated dogs was associated with a significant attenuation of the reduction in protein expression of SERCA2a and calsequestrin observed in the vehicle-treated dogs. Coronary arteries isolated from the dogs treated with the ET(A/B) antagonist exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation compared to the vehicle group, while coronary responses to an NO donor were identical in the two groups. Plasma NO levels in the coronary sinus during the late stage of HF were higher (P<0.05) in the ET(A/B) antagonist group (40+/-2 microM) compared to the vehicle group (18+/-2 microM).. We conclude that in conscious dogs during the development of HF induced by rapid pacing, chronic inhibition of ET(A/B) receptors does not affect resting myocardial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in intracellular Ca(2+) regulation by the SR is also attenuated, and endothelium-dependent coronary relaxation is improved, which appears to be related to the preservation of coronary NO levels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Analysis of Variance; Animals; Calcium; Cardiac Pacing, Artificial; Coronary Vessels; Dogs; Endothelin Receptor Antagonists; Heart Failure; In Vitro Techniques; Myocardial Contraction; Nitric Oxide; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Sarcoplasmic Reticulum; Sodium Nitrite; Stroke Volume; Thromboxane A2; Vascular Resistance; Vasoconstriction

Topics: Adult; Aged; Blood Coagulation; Blood Viscosity; Conjunctiva; Drug Evaluation; Drug Therapy, Combination; Heart Failure; Humans; Microcirculation; Middle Aged; Nitrites; Sodium Nitrite; Time Factors

Topics: Cardiovascular Diseases; Heart; Heart Failure; Humans; Nitrites; Sodium Nitrite