Efficacy of inhaled nitric oxide in oleic acid-induced acute lung injury.

OBJECTIVE: To assess the efficacy of inhaled nitric oxide in improving pulmonary hypertension and gas exchange following oleic acid-induced acute lung injury. DESIGN: Prospective, pharmacologic study. SETTING: Surgical research laboratory at the University of Pittsburgh, Pittsburgh, PA. SUBJECTS: Instrumented, intubated pigs weighing 16 to 27 kg. INTERVENTIONS: Intravenous oleic acid and inhaled nitric oxide. MEASUREMENTS AND MAIN RESULTS: All pigs treated with intravenous oleic acid (0.11 mL/kg) developed a severe lung injury with pulmonary hypertension, accompanied by impaired oxygenation, intrapulmonary shunting, and increased extravascular lung water (p < .05 compared with baseline). Following nitric oxide inhalation, although pulmonary hypertension decreased in a dose-dependent fashion, no amelioration in pulmonary gas exchange was observed, as reflected by PaO2 and intrapulmonary shunt. Plasma nitrite and nitrate concentrations, the stable end products of nitric oxide metabolism, did not increase following nitric oxide exposure in this model of severe lung injury. CONCLUSIONS: The effect of inhaled nitric oxide, restricted to relieving pulmonary vasoconstriction in this model of lung injury, may have limited benefit in improving pulmonary gas exchange when diffusion is impaired by severe lung injury and inflammatory thickening of the alveolar-capillary barrier. Nitric oxide inhalation may have better results when used at an earlier, less severe stage of acute lung injury.

Nitric oxide does not contribute to sodium retention and peripheral vasodilation induced by partial portal vein ligation in rats.

The role of nitric oxide (NO) synthesis in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) was investigated. Hemodynamic studies in PVL rats with sodium retention and in sham-operated controls were conducted on the day when PVL rats developed transient and maximal sodium retention. Measurements were obtained before and during two consecutive periods after NO synthesis inhibition with NG-monomethyl-L-arginine (L-NMMA). Under baseline conditions, PVL rats with sodium retention were hypotensive, with equivalent decreases in total peripheral resistance and glomerular filtration rate in comparison to the control group. After L-NMMA, peripheral resistance and arterial pressure increased by similar extent in both groups. As compared with controls, PVL rats with sodium retention remained hypotensive and vasodilated. Furthermore, L-NMMA-induced natriuresis was attenuated in the PVL group. Additionally, serum and urinary levels of nitrate and nitrite did not vary before surgery and at the time of sodium retention. These results suggest that in PVL rats (1) vasodilation is not NO mediated; (2) vasodilation is not a sufficient explanation for sodium retention, and (3) a sodium-retaining factor acting on the renal tubules is responsible for sodium retention.

Hemodynamic effects and metabolic fate of inhaled nitric oxide in hypoxic piglets.

We describe the hemodynamic effects and metabolic fate of inhaled NO gas in 12 anesthetized piglets. Pulmonary and systemic hemodynamic responses to incremental [NO] (5-80 ppm) were tested during ventilation with high- [0.30 inspired O2 fraction (FIO2)] and low-O2 (0.10 FIO2) mixtures. In six animals, inhalation of 40 ppm NO was maintained over 6 h to test effects of prolonged exposure (0.30 FIO2). In the other six animals, pulmonary hypertension was induced by hypoxic ventilation (0.10 FIO2) and responses to NO were tested. Inhaled low [NO] partially reversed pulmonary hypertension induced by alveolar hypoxia; mean pulmonary arterial pressure decreased from 31.4 +/- 2.3 mmHg during hypoxia to 18.2 +/- 1.2 mmHg during 5 ppm NO. Mean pulmonary arterial pressure at 0.10 FIO2 did not fall further at higher [NO] (10-40 ppm) and never reached control levels. Pulmonary vascular resistance increased with institution of hypoxic ventilation and fell with subsequent administration of NO, ultimately reaching control levels. Inhaled NO did not affect systemic vascular resistance. Plasma levels of NO2- + NO3- and methemoglobin (MetHb) levels increased with increasing [NO]. Over 6 h of NO administration during high-O2 ventilation, MetHb equilibrated at subtoxic levels while NO2- + NO3- increased. Nitrosylhemoglobin, analyzed by electron paramagnetic resonance spectrophotometry was not detected in blood at any time. At the relatively low concentrations (5-80 ppm) that are effective in relieving experimental pulmonary hypertension induced by alveolar hypoxia, inhaled NO gas causes accumulation of NO2- + NO3- in plasma and a small increase in MetHb but no detectable nitrosylhemoglobin.

Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome.

OBJECTIVE: To assess the efficacy of inhaled nitric oxide (NO) in reducing pulmonary hypertension in a porcine model of adult respiratory distress syndrome. DESIGN: Nonrandomized, controlled experiment without blinding. SETTING: Surgical research laboratory. PARTICIPANTS: Twelve pigs, matched equally for body weight. INTERVENTION: Acute lung injury was induced by intravenous injection of oleic acid. Animals were then divided into either a control group, for monitoring without any further intervention, or a NO-treatment group, in which NO was administered at concentrations of 10 to 80 ppm, with each step separated by a NO-free interval to assess duration of effect. MAIN OUTCOME MEASURES: Pulmonary artery pressure, systemic blood pressure, PaO2, intrapulmonary shunt fraction, and extravascular lung water. Nitrosylated hemoglobin, arterial methemoglobin, and plasma nitrite and nitrate concentrations. RESULTS: All animals responded to oleic acid injection with rapid development of pulmonary hypertension and deterioration of PaO2 and intrapulmonary shunt fraction. Inhaled NO reversed these changes in a concentration-dependent manner. Cessation of NO administration led to a prompt return of pulmonary hypertension. A small but significant drop in systemic blood pressure was observed only at the highest concentration of NO administered (80 ppm). Extravascular lung water almost doubled following oleic acid injury. This increase was sustained in all animals for the remainder of the experiment. Significant increases in circulating methemoglobin and plasma nitrite and nitrate concentrations were measured during NO inhalation. CONCLUSION: Inhaled NO appears to be a selective pulmonary vasodilator and may prove to be useful in improving gas exchange in adult respiratory distress syndrome.

Avulsion of the internal mammary artery caused by blunt trauma.

Injury to the subclavian artery or its branches is uncommon after blunt trauma. We report a case of blunt thoracic trauma resulting in avulsion of the right internal mammary artery from its origin on the subclavian artery. This presented as an atypical mediastinal hematoma in a patient with multiple injuries.

Nitric oxide production is inhibited in trauma patients.

Elevated levels of nitrates/nitrites, the stable endproducts of nitric oxide (NO), were recently observed in septic patients. In this setting, NO maintains blood flow by vasodilation and inhibition of platelet aggregation. Trauma patients were found to have low plasma levels of nitrates/nitrites, even when they developed sepsis. The current study substantiated that trauma patients have suppressed production of NO; reductions in plasma nitrate/nitrite levels correlated with low urinary excretion of these endproducts. Nitric oxide production was upregulated in trauma patients with clinical infection compared with trauma patients without infection, but was still significantly suppressed compared with nitric oxide production in normal controls. The inability of trauma patients to produce NO may be an important component of the susceptibility of these patients to infection.

Nitric oxide may upregulate in vivo hepatic protein synthesis during endotoxemia.

Nitric oxide (NO) has been implicated as a mediator of hemodynamic and metabolic changes associated with endotoxemia and inflammation. In vitro studies suggest that NO inhibits hepatocyte protein synthesis but the role of NO in the regulation of hepatic protein synthesis in vivo is not known. In this study, rats were given endotoxin or saline after pretreatment with the NO synthase inhibitor NG-nitro-L-arginine or solvent, and plasma levels of nitrite (NO2), nitrate (NO3), and aspartate aminotransferase and hepatic protein synthesis rate in vivo were measured after 4 and 10 hours. The NG-nitro-L-arginine effectively blocked the increase in serum NO2/NO3 seen in endotoxemia and also inhibited the increase in hepatic protein synthesis in endotoxemic rats. The aspartate aminotransferase levels were elevated in endotoxemic rats pretreated with NG-nitro-L-arginine. Results support previous reports of a protective effect of NO on the liver in endotoxemia and suggest that NO may upregulate hepatic protein synthesis in vivo. Further study is needed to clarify the reason for the apparent difference between the effect of NO on hepatic protein synthesis in vivo and in vitro.

Detection of nitric oxide by electron paramagnetic resonance spectroscopy during rejection and graft-versus-host disease after small-bowel transplantation in the rat.

BACKGROUND: Our previous observation that nitric oxide (NO) is synthesized during antigen-specific immune reactions in vitro led us to investigate whether NO is produced during the in vivo immune response to a vascularized organ allograft. METHODS: Orthotopic small-bowel transplantation in the rat was performed by standard microsurgical techniques in the LBNF1 to Lewis (rejection alone), Lewis to LBNF1 (graft-versus-host disease [GVHD] alone), and a syngeneic strain combination with and without immunosuppressive therapy with FK 506. The recipient serum NO2-/NO3- levels (stable end products of NO metabolism) were measured and erythrocytes were evaluated for the presence of nitrosylferrohemoglobin (specific for NO bound to hemoglobin). RESULTS: Animals that acutely rejected small-bowel allografts or suffered from acute GVHD showed significantly elevated serum NO2-/NO3- levels on days 6 and 9, and nitrosylferrohemoglobin electron paramagnetic resonance signals of different intensity were detected on days 3, 6, and 9. FK 506-treated allograft recipients and recipients of syngeneic grafts showed normal serum NO2-/NO3- levels and lacked nitrosylferrohemoglobin signals at all time points. CONCLUSIONS: This study indicates that NO is produced early during the course of small-bowel allograft rejection and GVHD and might therefore serve as a simple marker to detect such immune reactions.

Negative inotropic effects of cytokines on the heart mediated by nitric oxide.

The direct effects of pro-inflammatory cytokines on the contractility of mammalian heart were studied. Tumor necrosis factor alpha, interleukin-6, and interleukin-2 inhibited contractility of isolated hamster papillary muscles in a concentration-dependent, reversible manner. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) blocked these negative inotropic effects. L-Arginine reversed the inhibition by L-NMMA. Removal of the endocardial endothelium did not alter these responses. These findings demonstrate that the direct negative inotropic effect of cytokines is mediated through a myocardial nitric oxide synthase. The regulation of pro-inflammatory cytokines and myocardial nitric oxide synthase may provide new therapeutic strategies for the treatment of cardiac disease.