Elevated Plasma Hemoglobin Levels Increase Nitric Oxide Consumption in Experimental and Clinical Acute Pulmonary Thromboembolism*

Sertório, Jonas T.; Neto-Neves, Evandro M.; Dias‐Junior, Carlos A.; Sousa-Santos, Ozélia; Kiss, Tamás; Mühl, Diána; Tanus‐Santos, Jose E.

doi:10.1097/ccm.0b013e31827c0b43

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…Preliminary evidence from animal models and humans suggests that acute PE is associated with intravascular haemolysis, related to the severity of PE [3][4][5][6][7][8]. Intravascular haemolysis liberates haemoglobin and diffusible haem, both of which directly bind NO.…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

“…Upon its rupture, the erythrocyte releases tetrameric (a 2 b 2 ) haemoglobin, which can immediately and avidly bind NO, but haemoglobin must first dissociate into ab dimers before haptoglobin can bind and inactivate this NO scavenging effect, an effect that may require a few seconds to occur [11]. In contrast to the millimolar concentrations required to constrict peripheral vasculature, free haemoglobin in the low micromolar concentration range will significantly increase pulmonary vascular resistance by NO scavenging [5,12].…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

“…Therefore, careful selection of operable candidates is paramount. A correlation between the main pulmonary artery (PA) diameter and pulmonary haemodynamic parameters before PEA have been described in CTEPH patients [5]. We evaluated whether preoperative PA diameter indices could predict the occurrence of mortality and clinical worsening after PEA.…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

“…According to the study by HEINRICH et al [5], the widest diameters of the ascending aorta (Ao) and the widest diameter of the main PA perpendicular to its long axis were measured at the level of the bifurcation of the PA. The ratio of the PA and the Ao diameters was calculated [5].…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

“…The ratio of the PA and the Ao diameters was calculated [5]. The PA diameter was indexed by body surface area (BSA).…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

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Severe pulmonary embolism decreases plasma L-arginine

Kline

Watts

Courtney³

et al. 2013

European Respiratory Journal

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Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

“…The ratio of the PA and the Ao diameters was calculated [5]. The PA diameter was indexed by body surface area (BSA).…”

Section: Severe Pulmonary Embolism Decreases Plasma L-argininementioning

confidence: 99%

See 3 more Smart Citations

Severe pulmonary embolism decreases plasma L-arginine

Kline

Watts

Courtney³

et al. 2013

European Respiratory Journal

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Treatment with new organic nitrites in pulmonary hypertension of acute experimental pulmonary embolism

Nilsson

Gustafsson

2019

Pharmacology Res & Perspec

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Acute pulmonary embolism may cause right heart failure due to increased pulmonary vascular resistance and arterial hypoxemia. Effective vasodilator therapy of the pulmonary hypertension is highly needed. Therefore, we investigated the effects of a newly developed effective pulmonary vasodilator, the organic mononitrites of 1,2‐propanediol (PDNO), in a rabbit model of acute pulmonary embolism. In anesthetized and ventilated rabbits, systemic and pulmonary hemodynamics, exhaled nitric oxide (NO), plasma nitrite concentration, and blood gases were monitored. First, dose–response experiments with intravenous and left heart ventricle infusions of PDNO and inorganic nitrite were done in naive animals and in pulmonary hypertension induced by a thromboxane A2 analogue. Second, acute pulmonary embolism was induced and either PDNO or placebo were administered intravenously within 20 minutes and evaluated within 1 hour after pulmonary embolization. PDNO intravenously, in contrast to inorganic nitrite intravenously, increased exhaled NO and counteracted pulmonary hypertension and vasodilated the systemic circulation, dose‐dependently, thereby showing efficient NO donation. Pulmonary embolization induced pulmonary hypertension and gas exchange disturbances. PDNO significantly decreased and normalized pulmonary vascular resistance and the right ventricle rate‐pressure product, without causing tolerance, with no significant side effects on the systemic circulation, nor on blood‐gas values or on methemoglobin formation. In conclusion, PDNO is a NO donor and an efficient vasodilator in the pulmonary circulation. Treatment with this or similar organic nitrites intravenously may be a future option to avoid right heart failure in life‐threatening acute pulmonary embolism.

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Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin

Meschiari

Pinheiro

Guimaraes

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Imbalanced matrix metalloproteinase (MMP) activity promotes cardiovascular alterations that are attenuated by statins. These drugs exert pleiotropic effects independent of cholesterol concentrations, including upregulation of nitric oxide (NO) formation and MMP downregulation. However, statins also increase tissue concentrations of nitrites, which activate new signaling pathways independent of NO. We examined whether atorvastatin attenuates MMP-9 production by human umbilical vein endothelial cells (HUVEC) stimulated with phorbol 12-myristate 13-acetate (PMA) by mechanisms possibly involving increased nitrite, and whether this effect results of NO formation. We also examined whether such an effect is improved by sildenafil, an inhibitor of phosphodiesterase-5 which potentiates NO-induced increases in cyclic GMP. MMP activity and nitrite concentrations were measured by gelatin zymography and ozone-based reductive chemiluminescence, respectively, in the conditioned medium of HUVECs incubated for 24 h with these drugs. Phospho-NFκB p65 concentrations were measured in cell lysate to assess NFκB activation. Atorvastatin attenuated PMA-induced MMP-9 gelatinolytic activity by mechanisms not involving NO, although it increased nitrite concentrations, whereas sildenafil had no effects. Combining both drugs showed no improved responses compared to atorvastatin alone. While sodium nitrite attenuated MMP-9 production by HUVECs, adding hemoglobin (NO scavenger) did not affect the responses to nitrite. Neither atorvastatin nor nitrite inhibited PMA-induced increases in phospho-NFκB p65 concentrations. These findings show that sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects exerted by atorvastatin. With both drugs, the inhibitory effects on MMP-9 production are not dependent on NO formation or on inhibition of NFκB activation. Our findings may help to elucidate important new nitrite-mediated mechanisms by which statins affect imbalanced MMP activity in a variety of cardiovascular disease.

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Elevated Plasma Hemoglobin Levels Increase Nitric Oxide Consumption in Experimental and Clinical Acute Pulmonary Thromboembolism*

Abstract: Our results show consistent evidence indicating a new mechanism involving increased hemoglobin decompartmentalization and augmented nitric oxide consumption, possibly contributing to the hemodynamic derangement of acute pulmonary thromboembolism.

Cited by 17 publications

References 35 publications

Severe pulmonary embolism decreases plasma L-arginine

Severe pulmonary embolism decreases plasma L-arginine

Treatment with new organic nitrites in pulmonary hypertension of acute experimental pulmonary embolism

Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin

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