Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism |
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| Institution: | 1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil;2. Vascular Medicine Branch, National Heart, Lung and Blood Institute, and Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA;1. Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University – UNESP, Botucatu, Sao Paulo, Brazil;2. Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Ribeirao Preto, Sao Paulo, Brazil;1. Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil;2. São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil;3. University of São Paulo (USP), Faculty of Pharmaceutical Sciences of Ribeirão Preto, Department of Physics and Chemistry, Ribeirão Preto, São Paulo 14040-903, Brazil;4. University of São Paulo (USP), College of Nursing of Ribeirão Preto, Department of Psychiatry Nursing and Human Sciences, Ribeirão Preto, São Paulo 14040-902, Brazil;1. Division of Women''s Health, King''s College London, Women''s Health Academic Centre, UK;2. Department of Obstetrics & Gynaecology, School of Medicine, University of Nottingham, UK;3. Laboratory of Nephrology – IPB, School of Medicine, PUCRS, Brazil;4. Division of Diabetes and Nutritional Sciences, Diabetes Research Group, King''s College London, UK;1. Department of Anesthesiology, Baylor College of Medicine, Texas Children’s Fetal Center, Texas Children’s Hospital, Houston, TX;2. Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Children’s Fetal Center, Texas Children’s Hospital, Houston, TX;3. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children’s Fetal Center, Texas Children’s Hospital, Houston, TX;4. Department of Anesthesiology, Texas Children’s Pavilion for Women, Texas Children’s Hospital, Houston, TX |
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| Abstract: | Acute pulmonary thomboembolism (APT)-induced pulmonary hypertension can be counteracted by activating the nitric oxide (NO)-cGMP pathway. Recent studies have demonstrated that the naturally occurring anion nitrite (NO2-) is a bioactive storage reservoir for NO, and is reduced to NO under conditions of hypoxia and acidosis. We hypothesized that nitrite infused intravenously could attenuate the hemodynamic changes associated with APT. APT was induced with autologous blood clots injected into the right atrium in mongrel dogs. After APT (or saline), the dogs received an intravenous nitrite (or saline) infusion (6.75 μmol/kg over 15 min and then 0.28 μmol/kg/min) and hemodynamic evaluations were carried out for 2 h. Plasma nitrite concentrations were measured using ozone-based reductive chemiluminescence methodologies. APT decreased cardiac index (CI) and increased pulmonary vascular resistance index (PVRI); these effects were improved during infusions of sodium nitrite. Accordingly, nitrite infusion increased cardiac index by 28%, reduced the PVRI by 48%, and the systemic vascular resistance index (SVRI) by 21% in embolized dogs, suggesting a greater effect on the ischemic embolized vascular system than the systemic circulation following embolization. Interestingly, in nonembolized control dogs the same nitrite infusion decreased MAP and CI (all P < 0.05). The nitrite infusion increased plasma nitrite concentrations by approximately 2 μM, and produced dose-dependent effects on PVRI, MAP, and SVRI. Remarkably, blood levels of nitrite as low as 500 nM decreased PVRI and SVRI in this model, suggesting a potential role of nitrite in physiological blood flow regulation. These results suggest that a low-dose nitrite infusion produces beneficial hemodynamic effects in a dog model of APT. These findings suggest a new therapeutic application for nitrite and support emerging evidence for a surprisingly potent and potentially physiological vasoactivity of nitrite. |
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