Inhaled Nitrite Reverses Hemolysis-Induced  Pulmonary Vasoconstriction in Newborn Lambs Without Blood Participation

Blood, Arlin B.; Schroeder, Hobe; Terry, Michael H.; Merrill-Henry, Jeanette; Bragg, Shannon; Vrancken, Kurt; Liu, Taiming; Herring, Jason; Sowers, Lawrence C.; Wilson, Sean; Power, Gordon G.

doi:10.1161/circulationaha.110.001073

Cited by 34 publications

(37 citation statements)

References 48 publications

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“…7 Further evidence showing that it is not hemoglobinderived nitric oxide generation via deoxyhemoglobin nitrite reductase activity, but rather tissue NO 2 Ϫ reductase activity, is the finding that inhaled nitrite, but not infused nitrite, reverses hemolysis-induced pulmonary vasoconstriction, likely by hemoglobin autocapture of vascularly generated nitric oxide. 45 Fourth, we did not measure pulmonary artery pressure or vascular resistance and cannot exclude that nitrite-mediated reductions of pulmonary vascular resistance and pressure may have contributed to lessen the injury. However, with respect to the in vivo pulmonary vasodilator response to nitrite, our protective dose in VILI is 12-fold lower than the half maximal dose for pulmonary vasodilation in normal rat lungs (2.5 vs. 30 mol/kg).…”

Section: Discussionmentioning

confidence: 99%

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Pickerodt

Emery²,

Zarndt

et al. 2012

Anesthesiology

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Background Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. Methods Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n=10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n=14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 μmol/kg IV; n=6-8); group 6: HVT+NaNO2+nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n=6); group 7: HVT+NaNO2+nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n=7); and group 8: HVT+NaNO2+xanthine oxidoreductase inhibitor allopurinol (n=6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. Results Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 μmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. Conclusions Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.

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Section: Discussionmentioning

confidence: 99%

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Pickerodt

Emery²,

Zarndt

et al. 2012

Anesthesiology

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“…Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application. 14 …”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

2012

Circulation

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The following articles are being highlighted as part of Circulation's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the articles related to pulmonary hypertension that were published in Circulation and the Circulation subspecialty journals in . (Circulation. 2012125:e645-e652.) Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide GenerationSummary: Pulmonary arterial hypertension is a disease of the small pulmonary arteries that is characterized by progressive pulmonary vascular remodeling, vasoconstriction, and thrombosis. These changes lead to increased pulmonary vascular pressures and cause right heart failure, which leads to death. In general, therapies have not been effective in reversing the pathophysiological changes associated with pulmonary arterial hypertension. Our investigations define inhaled nebulized sodium nitrite as a potential therapy for pulmonary arterial hypertension. These data demonstrate that sodium nitrite can prevent or reverse pulmonary arterial hypertension in multiple experimental animal models of this disease process. Furthermore, these data show that nitrite is enzymatically converted to vasoactive nitric oxide in lung tissue and pulmonary artery smooth muscle cells via xanthine oxidoreductase. These findings help to define a therapy that may be useful in the treatment of patients with this insidious disease that to this point has lacked effective pharmacological therapies.Conclusion: These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. 1 Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary HypertensionSummary: As a result of ventricular interdependence, analysis of concomitant intrinsic left ventricular (LV) diseases (ie, myocardial fibrosis) in patients with significant pulmonary hypertension (PH) is challenging. The farther a region is from the right ventricle (eg, the lateral wall), the less the impact will be that the PH has on LV strain. Furthermore, parameters based on circumferential fibers appear to propagate farther from the right ventricle than longitudinal parameters, likely reflecting continuity of the circumferential fibers from the septum to the lateral wall. Accordingly, a finding of abnormal LV lateral wall longitudinal strain in patients with PH might identify true LV dysfunction that is independent of PH. We further demonstrated that LV torsion correlated negatively with estimated pulmonary artery systolic pressure and with septal flattening. Abnormally reduced LV torsion in PH could represent an advanced stage of PH and geometric alteration. Interestingly, although torsion was reduced, untwisting velocity was s...

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“…In preclinical models, inhaled nitrite did not lead to rebound hypertension once nitrite inhalation was stopped, which is a frequently observed complication associated with acute termination of inhaled NO gas (42). Putative mechanisms of nitrite action involve activation of pulmonary vascular smooth muscle soluble guanylate cyclase (sGC) and the canonical NO signaling cascade (10). Moreover, nitrite therapy also protects against pulmonary and vascular smooth muscle remodeling after injury and improves lung function after transplantation (4,88,111,139).…”

Section: No and Nitrite Therapeutics For Airway And Pulmonary Vasculamentioning

confidence: 99%

Working with nitric oxide and hydrogen sulfide in biological systems

Yuan

Patel

Kevil

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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(H 2S) are gasotransmitter molecules important in numerous physiological and pathological processes. Although these molecules were first known as environmental toxicants, it is now evident that that they are intricately involved in diverse cellular functions with impact on numerous physiological and pathogenic processes. NO and H 2S share some common characteristics but also have unique chemical properties that suggest potential complementary interactions between the two in affecting cellular biochemistry and metabolism. Central among these is the interactions between NO, H 2S, and thiols that constitute new ways to regulate protein function, signaling, and cellular responses. In this review, we discuss fundamental biochemical principals, molecular functions, measurement methods, and the pathophysiological relevance of NO and H 2S. thiol; oxidation; redox; pulmonary; cardiovascular HISTORICALLY CONSIDERED ONLY as industrial pollutants, nitric oxide (NO) and hydrogen sulfide (H 2 S) are now appreciated as two key physiologically produced signaling molecules that control multiple cellular functions. Appreciation that dysfunction in how these solvated gases affect these functions, through either deficient formation or downstream reactivity, has opened up new therapeutic avenues for a host of diseases in all major organ systems including the lung. Our understanding of NO homeostasis mechanisms are relatively advanced compared with H 2 S, primarily because of the latter's discovery as a biologically relevant entity being postdated by a decade or more compared with NO. Although they are chemically distinct, there are intriguing parallel mechanisms/concepts in NO and H 2 S biology that include overlapping functions, technical challenges in how each of these gases are measured in biological milieu, appreciation of the mechanisms and factors that modulate how metabolism of each of these is regulated, and therapeutic potential for either inhibiting or repleting NO or H 2 S. In this article, and within the framework outlined above, we provide a general overview of NO and H 2 S biology. Nitric Oxide Formation: Enzymatic and Nonenzymatic SourcesEnzymatic sources. Nitric oxide is synthesized by one of three different isoforms of nitric oxide synthase (NOS) that differ in enzymatic activity, in how they are regulated (transcriptional, translational, and posttranslational mechanisms), and in how they are expressed/compartmentalized in tissues as well as the subcellular level. These are called NOS I, II, and III, corresponding to the inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) isoforms, typically with high, mid, and low activities, respectively. In the systemic and pulmonary vasculature, eNOS plays a key role in controlling blood flow and maintaining an antithrombotic and anti-inflammatory luminal surface. On the other hand, iNOS is induced by inflammatory stimuli in leukocytes, airway epithelial cells, and alveolar macrophages to mediate pathogen killing. However, production of NO at higher concentrations in ...

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Inhaled Nitrite Reverses Hemolysis-Induced Pulmonary Vasoconstriction in Newborn Lambs Without Blood Participation

Cited by 34 publications

References 48 publications

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

Working with nitric oxide and hydrogen sulfide in biological systems

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