The Pulmonary Effect of Nitric Oxide Synthase Inhibition Following Endotoxemia in a Swine Model (original) (raw)
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European Journal of Pharmacology, 1993
Nitric oxade (10 ppm) inhaled by pigs before or during endotoxln shock induced by an infusion of E coh lipopolysacchande Nitric oxade inhalation selectively attenuated pulmonary hypertension during endotoxln infusion without influencing mean arterml blood pressure and cardtac output Upon cessation of nitric oxade inhalation, pulmonary artery pressure rapidly increased to levels seen m endotoxm-treated controls The oxygenation and pH of arterial blood were significantly higher m the ammals receiving mtnc oxide A marked increase m arterial plasma noradrenahne and neuropept~de Y was seen m endotorantreated control pigs whde m the mtnc oxide-treated pigs this increase was markedly reduced The increase In arterial plasma endothehn-1 was not influenced by mtric orade inhalation Infusion of L-arglnme (substrate for mtnc oxide synthesis) also attenuated the pulmonary hypertension but was not selectwe for the pulmonary vasculature L-Nltro-arglnme (a nitric oxide synthesis inhibitor) lnltmted a rapid but brief elevahon of arterial blood pressure and of pulmonary artery pressure as well as a reduction m cardiac output Nitric oxade inhalation selectively reduces pulmonary hypertension in porcine endotoxln shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic actwatlon Nitric oxide (NO), Endotoxan shock, Pulmonary hypertension, Adult respiratory distress syndrome (ARDS), Endothehn, Noradrenahne, Neuropeptlde Y
Journal of Pediatric Surgery, 1996
The inducible isoform of nitric oxide synthase (iNOS) is expressed in various organs, including the lung, during systemic endotoxemia. Overproduction of nitric oxide (NO} by iNOS contributes significantly to the vascular failure and end-organ damage in endotoxemia. Using selective pharmacological inhibitors of iNOS, the purpose of this study was to define the role of iNOS in a rat model of endotoxin-induced pulmonary transvascular flux (TVF). Lung TVF was assessed by a method of Evans Blue permeability index (PI). Bacterial lipopo!ysaccharide (LPS) (15 mg/kg intraperitoneally [IP]) significantly increased pulmonary iNOS activity and serum levels of nitrite/nitrate (NO2/NO3). This was accompanied by a significant elevation of the PI 6 hours after injection. Selective iNOS inhibition with either S-methyl isothiourea (SMT; 5 mg/kg IP) or aminoguanidine (AG; 20 mg/kg IP), administered 2 hours after LPS injection, significantly prevented the increase in PI associated with LPS injection. Similarly, inhibition of the induction of iNOS with dexamethasone (10 mg/kg IP), given 3 hours before LPS, also inhibited the increase in PI. All three treatments significantly prevented the increase in both lung iNOS activity and serum NO2/NO3 associated with endotoxemia. In conclusion, the overproduction of NO generated by iNOS during systemic endotoxemia causes a vascular leak in the lung. Thus, it is speculated that selective inhibition of iNOS may be beneficial in preventing the development of acute respiratory failure in sepsis.
Journal of pediatric surgery, 1996
The inducible isoform of nitric oxide synthase (iNOS) is expressed in various organs, including the lung, during systemic endotoxemia. Overproduction of nitric oxide (NO} by iNOS contributes significantly to the vascular failure and end-organ damage in endotoxemia. Using selective pharmacological inhibitors of iNOS, the purpose of this study was to define the role of iNOS in a rat model of endotoxin-induced pulmonary transvascular flux (TVF). Lung TVF was assessed by a method of Evans Blue permeability index (PI). Bacterial lipopo!ysaccharide (LPS) (15 mg/kg intraperitoneally [IP]) significantly increased pulmonary iNOS activity and serum levels of nitrite/nitrate (NO2/NO3). This was accompanied by a significant elevation of the PI 6 hours after injection. Selective iNOS inhibition with either S-methyl isothiourea (SMT; 5 mg/kg IP) or aminoguanidine (AG; 20 mg/kg IP), administered 2 hours after LPS injection, significantly prevented the increase in PI associated with LPS injection. Similarly, inhibition of the induction of iNOS with dexamethasone (10 mg/kg IP), given 3 hours before LPS, also inhibited the increase in PI. All three treatments significantly prevented the increase in both lung iNOS activity and serum NO2/NO3 associated with endotoxemia. In conclusion, the overproduction of NO generated by iNOS during systemic endotoxemia causes a vascular leak in the lung. Thus, it is speculated that selective inhibition of iNOS may be beneficial in preventing the development of acute respiratory failure in sepsis.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002
In a porcine model of endotoxic shock, we evaluated the circulatory and respiratory effects of NO synthase (NOS) blockade.Twentyanaesthetised pigs were divided into three groups and studied for 240 min after induction of endotoxic shock with lipopolysaccharides of Escherichia coli (LPS). After180 min of endotoxic shock, one group (n = 6) received aminoguanidine, another group (n = 6) received N G-nitro-L-arginine methyl ester (L-NAME) and a third group (n = 8) received only LPS. A sham group (n = 3) was also studied.LPS decreased systemic arterialpressure and cardiac output (CO) andincreased mean pulmonary arterial pressure (MPAP), pulmonary vascular resistance (PVR) and heart rate. Significant changes were also observed in compliance (À18.4%) and resistance (+33.6%) of the respiratory system. Aminoguanidine did not modify LPS-dependent effects, while, after L-NAME, a significant increase in MPAP, PVR and SVR and a decrease in CO were observed. In conclusion, aminoguanidine doesnot playa significant cardiocirculatoryand pulmonary role in the short-term dysfunction of endotoxic shock, while L-NAME has a detrimental effect on haemodynamics, suggesting a protective role of constitutive NO production at vascular level during the early stages of endotoxaemia.
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...