The Pulmonary Effect of Nitric Oxide Synthase Inhibition Following Endotoxemia in a Swine Model (original) (raw)
AJP: Heart and Circulatory Physiology, 2005
Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific ( NG-nitro-l-arginine methyl ester, l-NAME) and NOS2-specific [l- N6-(1-iminoethyl)lysine, l-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without l-NAME or l-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in...
Nitric oxide measurements during endotoxemia
Clinical chemistry, 2001
Excessive continuous NO release from inducible NO synthase over prolonged periods under pathological conditions, such as endotoxemia, contributes significantly to circulatory failure, hypotension, and septic shock. This NO production during endotoxemia is accompanied by superoxide release, which contributes to the fast decay of NO. Therefore, the amount of NO that diffuses to target sites may be much lower than the total amount released under pathological conditions. We performed in vivo and ex vivo measurements of NO (electrochemical) and ex vivo in situ measurements of superoxide, peroxynitrite (chemiluminescence), and nitrite and nitrate (ultraviolet-visible spectroscopy). We determined the effect of lipopolysaccharide administration (20 mg/kg) on diffusible NO, total NO (diffusible plus consumed in chemical reactions), and superoxide and peroxynitrite release in the pulmonary arteries of rats. An increase in diffusible NO generated by constitutive NO synthase was observed immedi...
Inhaled nitric oxide prevents left ventricular impairment during endotoxemia
Journal of Applied Physiology, 1998
Inhaled nitric oxide prevents left ventricular impairment during endotoxemia. J. Appl. Physiol. 85(6): 2018-2024.-We evaluated the effect of longterm inhalation of nitric oxide (NO) on cardiac contractility after endotoxemia by using the end-systolic elastance of the left ventricle (LV) as a load-independent contractility index. Chronic instrumentation in 12 pigs included implantation of two pairs of endocardial dimension transducers to measure LV volume and a micromanometer to measure LV pressure. One week later, the animals were divided into a control group (n ϭ 6) or a NO group (n ϭ 6). All animals received intravenous Escherichia coli endotoxin (10 µg · kg Ϫ1 ·h Ϫ1 ) and equivalent lactated Ringer solution. NO inhalation (20 parts/ million) was begun 30 min after the initiation of endotoxemia and was continued for 24 h. In both groups, tachycardia, pulmonary hypertension, and systemic hyperdynamic changes were noted. The end-systolic elastance in the control group was significantly decreased beyond 7 h. NO inhalation maintained the end-systolic elastance at baseline levels and prevented its impairment. These findings indicate that NO exerts a protective effect on LV contractility in this model of endotoxemia.
Inhaled Nitric Oxide Reduces Lung Fluid Filtration after Endotoxin in Awake Sheep
American Journal of Respiratory and Critical Care Medicine, 1998
We studied the effect on lung fluid filtration of 37.6 ppm inhaled nitric oxide (NO) imposed for 1 h 2.5 h after endotoxin in seven awake sheep, with seven control subjects. The effects of NO on the longitudinal distribution of pulmonary vascular resistance (PVR) before and after endotoxin were specifically addressed in six sheep. Following endotoxin, sheep developed respiratory distress; Pa O 2 , the alveolar-arterial oxygen tension difference ( A aP O 2 ) and venous admixture ( S / T ) changed significantly, as did the pulmonary artery pressure (Ppa), PVR, and lung lymph flow ( L ). Inhaled NO reduced Ppa and PVR by 50%; L decreased from 7.8 Ϯ 0.34 ml/15 min to 4.7 Ϯ 0.80 ml/15 min (mean Ϯ SEM), and lymph protein clearance from 4.9 Ϯ 0.18 ml/15 min to 3.6 Ϯ 0.75 ml/15 min. Lymph/plasma protein concentration ratio (L/P) increased from 0.63 Ϯ 0.016 to 0.72 Ϯ 0.006, concomitant with the decrease in L . The L/P Ϫ L relationships shifted from left, at baseline, to the right during endotoxemia, as did the permeability surface product (PS) isolines. The rightward shift was significantly less in the NO group. Inhaled NO significantly improved Pa O 2 , A aP O 2 , and S / T , reduced the increase in pulmonary microwedge pressure back to baseline and decreased upstream and downstream PVR at 3.0 through 4.0 h. We conclude that, in sheep, inhaled NO reduces lung fluid filtration by decreasing microvascular pressure and apparently also by declining the enhanced microvascular permeability during the late phase of endotoxemia. Bjertnaes LJ, Koizumi T, Newman JH. Inhaled nitric oxide reduces lung fluid filtration after endotoxin in awake sheep.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2005
Nitric oxide (NO), depending on the amount, time and source of generation may exert both, protective and deleterious actions during endotoxic acute lung injury (ALI). Evaluation of the expression and localization of NOS isoforms in the lung of lipopolysaccharide (LPS)-treated rats may contribute to understanding the role of NO in pathogenesis of ALI. Tissue samples (lung, heart, liver, kidney and spleen) as well as peripheral blood polymorphonuclear cells (PMNs) were collected from control male Wistar rats and LPS - treated animals, 15, 30, 60, 120 and 180 min after LPS injection (2 mg kg(-1) min(-1) for 10 minutes, i.v.). Levels of NOS-2 and NOS-3 mRNA and protein in tissues and PMNs were estimated by RT-PCR, Northern blotting and Western blotting. Additionally, myeloperoxidase (MPO) activity in tissue samples was assayed. NOS-3 mRNA as well as protein were detected in lungs of control animals; pulmonary NOS-3 expression was not influenced by LPS. The induction of NOS-2 mRNA in rat...
Critical Care Medicine, 2005
N itric oxide (NO) inhalation has gained great interest in critical care medicine over the past decade (1) because of its "selective" pulmonary vasodilatory properties, its apparent safety, and the easy delivery as a gas by the inhalational route (2). When administered into the airways, NO diffuses into the pulmonary vascular smooth muscle cells, where it increases cyclic guanosine monophosphate (cGMP) concentrations, causing se-lective pulmonary vasodilation (3). Two major indications for NO inhalation are commonly accepted, based on its pulmonary vessel vasodilator properties. The first is rapid improvement of ventilation/ perfusion mismatch and subsequent oxygenation in acute lung injury in adults (4, 5) and, more important, in children . The other indication of pulmonary vessel vasodilation is to improve compromised right ventricular function, especially in the presence of pulmonary hypertension (7). In addition to its direct effect on the pulmonary vasculature, many other effects have been documented suggesting anti-inflammatory (8), anti-platelet aggregation (9, 10), and cytoprotective actions (6).
Effect of inhaled nitric oxide on pulmonary function after sepsis in a swine model
PubMed, 1994
Background: Inhaled nitric oxide (NO) has been shown to improve sepsis induced pulmonary dysfunction. This study evaluated the mechanism by which inhaled NO improves pulmonary function in a porcine sepsis model. Methods: After an infusion of Escherichia coli lipopolysaccharide (LPS, 200 micrograms/kg), animals were resuscitated with saline solution (1 ml/kg/min) and observed for 3 hours while mechanically ventilated (fraction of inspired oxygen, 0.6; tidal volume, 12 ml/kg; positive end-expiratory pressure, 5 cm H2O). Group 1 (LPS, n = 6) received no additional treatment. Group 2 (NO, n = 6) received inhaled NO (40 ppm) for the last 2 hours. Group 3 (control, n = 5) received only saline solution without LPS. Cardiopulmonary variables and blood gases were measured serially. Multiple inert gas elimination technique was performed at 3 hours. Wet to dry lung weight ratio was measured after necropsy. Results: Lipopolysaccharide resulted in pulmonary arterial hypertension, pulmonary edema, and hypoxemia. Multiple inert gas elimination technique analysis indicated a significant increase in blood flow to true shunt and high ventilation perfusion distribution (VA/Q) areas with an increased dispersion of VA/Q distribution. All of these changes were significantly attenuated by NO. Conclusions: Inhaled NO significantly improved LPS induced VA/Q mismatching by decreasing both true shunt and high VA/Q areas, by decreasing pulmonary edema, and by redistributing blood flow from true shunt to ventilated areas.
Renal Effects of Nitric Oxide in Endotoxemia
American Journal of Respiratory and Critical Care Medicine, 2001
Nitric oxide (NO) is postulated to play a key role in the pathophysiology of renal failure in sepsis. Whether the renal effects of increased NO are beneficial or harmful remains unclear. In a porcine model of lipopolysaccharide (LPS)-induced shock, we evaluated the effect of LPS on glomerular filtration rate (GFR) and renal blood flow (RBF). We then administered the nonselective nitric oxide synthase (NOS) inhibitor N G-L-arginine methyl ester (L-NAME), and compared its effects on GFR and RBF with those of S-methylisothiourea (SMT), a selective NOS inhibitor, and those of saline. We postulated that SMT, by maintaining constitutive NO, would be more beneficial than either L-NAME or saline. LPS infusion decreased mean arterial pressure (MAP), and increased cardiac output, RBF, and medullary NO content. The increased RBF was diverted to the medulla. There was no evidence of renal dysfunction in the saline-resuscitated group. Both NOS inhibitors increased MAP but decreased RBF, but only L-NAME reduced GFR and increased sodium excretion and renal oxygen extraction. We conclude that NO in endotoxemia is beneficial because it maintains RBF and GFR. Additionally, selective NOS inhibition did not offer any advantages over saline resuscitation.
Journal of applied physiology (Bethesda, Md. : 1985), 2014
Inhaled nitric oxide (INO) improves ventilation-perfusion matching and alleviates pulmonary hypertension in patients with acute respiratory distress syndrome. However, outcome has not yet been shown to improve, and non-response is common. A better understanding of the mechanisms by which INO acts, may guide in improving treatment with INO in patients with severe respiratory failure. We hypothesized that INO may act not only by vasodilation in ventilated lung regions, but also by causing vasoconstriction via endothelin (ET-1) in atelectatic, non-ventilated lung regions. This was studied in 30 anesthetized, mechanically ventilated piglets. The fall in oxygenation and rise in pulmonary artery pressure during a sepsis-like condition (infusion of endotoxin) were blunted by INO 40ppm. Endotoxin infusion increased serum ET-1, and INO almost doubled the ratio between mRNA expression of endothelin receptor A (mediating vasoconstriction) and B (mediating vasodilation and clearance of ET-1) (E...