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Responsiveness to inhaled NO in isolated–perfused lungs from endotoxin-challenged rats is dependent on endogenous nitrite/nitrate synthesis

Published online by Cambridge University Press:  01 April 2007

CH. Bopp ,
R. Gust ,
F. Taut ,
A. Gries ,
E. Martin  and
A. Klein
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Summary

Background and objectives

In isolated–perfused lungs of lipopolysaccharide (LPS)-challenged rats, vasodilatation to inhaled nitric oxide (NO) is impaired. Inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) prevented hyporesponsiveness to inhaled NO. Here, we investigated whether NOS2-mediated nitrite/nitrate synthesis modulates responsiveness to inhaled NO.

Methods

Sprague–Dawley rats received intraperitoneally 0.5 mg kg−1 LPS. Four hours later, LPS-treated rats received 3, 10 or 30 mg kg−1 AG or 0.01, 0.1 or 1 mg kg−1S-methylisothiourea (SMT) by intraperitoneal injection. Sixteen to eighteen hours later, lungs were isolated and perfused, and pulmonary artery pressure (PAP) was elevated by 6–8 mmHg using the thromboxane analogue U46619. The decrease of PAP in response to inhaled NO and nitrate/nitrite levels in serum and perfusate was measured.

Results

In rats treated with LPS alone or 0.01 or 0.1 mg kg−1 SMT, 40 ppm NO decreased PAP less than in rats treated with AG and 1 mg kg−1 SMT (−1.8 mmHg (95% confidence interval: −1.5 to −2.1) vs. −6.0 mmHg (−5.7 to −6.3), P < 0.01). Improved NO responsiveness was associated with lower serum and perfusate nitrite/nitrate levels than in rats with hyporesponsiveness to inhaled NO (102 μmol (82–122) vs. 282 μmol (261–303) and 8.1 μmol (6.9–9.3) vs. 19.8 μmol (17.2–22.4), respectively, P < 0.01).

Conclusions

These observations demonstrate that in isolated–perfused lungs of LPS-treated rats, NOS2 inhibition improved responsiveness to inhaled NO. Here, responsiveness to inhaled NO is dependent on the ability of NOS2 inhibitors to reduce nitrite and nitrate levels in serum and released in the lung.

Keywords

RESPIRATORY DISTRESS SYNDROMEADULTNITRIC OXIDENITRIC OXIDE SYNTHASE TYPE 2ENDOTOXINSRATLIPOPOLYSACCHARIDES
Type
Research Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 4 , April 2007 , pp. 362 - 369
Copyright
Copyright © European Society of Anaesthesiology 2006

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References

1.Rossaint, R, Falke, KJ, Lopez, F et al. . Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328 (6): 399–405.CrossRefGoogle ScholarPubMed
2.Bigatello, LM, Hurford, WE, Kacmarek, RM et al. . Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome – effects on pulmonary hemodynamics and oxygenation. Anesthesiology 1994; 80: 761–770.CrossRefGoogle ScholarPubMed
3.Krafft, P, Fridrich, P, Fitzgerald, RD et al. . Effectiveness of nitric oxide inhalation in septic ARDS. Chest 1996; 109: 486–493.CrossRefGoogle ScholarPubMed
4.Holzmann, A, Bloch, KD, Sanchez, LS et al. . Hyporesponsiveness to inhaled nitric oxide in isolated, perfused lungs from endotoxin-challenged rats. Am J Physiol 1996; 271: L981–L986.Google ScholarPubMed
5.Nakayama, DK, Geller, DA, Lowenstein, CL et al. . Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. Am J Respir Cell Mol Biol 1992; 7: 471–476.CrossRefGoogle ScholarPubMed
6.Geller, DA, Nussler, AK, Silvio, MD et al. . Cytokines, endotoxin and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA 1993; 90: 522–526.CrossRefGoogle ScholarPubMed
7.Liu, SF, Crawley, DE, Rohde, JA et al. . Role of nitric oxide and guanosine 3′-5′-cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea-pig pulmonary arteries. Br J Pharmacol 1992; 107 (3): 861–866.CrossRefGoogle ScholarPubMed
8.Holzmann, A, Manktelow, C, Taut, FJH et al. . Inhibition of nitric oxide synthase prevents hyporesponsiveness to inhaled nitric oxide in lungs from endotoxin-challenged rats. Anesthesilogy 1999; 91: 215–221.CrossRefGoogle ScholarPubMed
9.Szabo, C, Ferrer-Sueta, G, Zingarelli, B et al. . Mercaptoethylguanidine and guanidine inhibitors of nitric oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage. J Biol Chem 1997; 272: 9030–9036.CrossRefGoogle ScholarPubMed
10.Giardino, I, Fard, AK, Hatchell, DL et al. . Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation and oxidant-induced apoptosis. Diabetes 1998; 47: 1114–1120.CrossRefGoogle ScholarPubMed
11.Oudkerk Pool, M, Bouma, G, Visser, JJ et al. . Serum nitrate levels in ulcerative colitis and Crohn’s disease. Scand J Gastroenterol 1995; 30: 784–788.CrossRefGoogle ScholarPubMed
12.Dellinger, RP, Zimmerman, JL, Taylor, RW et al. . Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome. Crit Care Med 1999; 26: 15–23.CrossRefGoogle Scholar
13.MacNaul, KL, Hutchinson, NI. Differential expression of iNOS and cNOS mRNA in human vascular smooth muscle cells and endothelial cells under normal and inflammatory conditions. Biochem Biophys Res Commun 1993; 196: 1330–1334.CrossRefGoogle ScholarPubMed
14.Wong, HR, Carcillo, JA, Burckart, G et al. . Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome. Crit Care Med 1995; 23 (5): 835–842.CrossRefGoogle ScholarPubMed
15.Gutierrez, HH, Pitt, BR, Schwarz, M et al. . Pulmonary alveolar epithelial inducible NO synthase gene expression: regulation by inflammatory mediators. Am J Physiol 1995; 268: L501–L508.Google ScholarPubMed
16.Arkowitz, MS, Wispe, JR, Garcia, VF et al. . Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia. J Pediatr Surg 1996; 31: 1009–1015.CrossRefGoogle Scholar
17.Doursout, MF, Hartley, CJ, Chelly, JE. Comparison of cardial and regional hemodynamic responses to N-methyl-l-arginine and aminoguanidine infusions in conscious pigs. J Cardiovasc Pharmacol 2001; 37: 349–358.CrossRefGoogle Scholar
18.Griffiths, MJD, Messent, M, MacAllister, RJ et al. . Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br J Pharmacol 1993; 110: 963–968.CrossRefGoogle ScholarPubMed
19.Arkowitz, MS, Wispe, JR, Garcia, VF et al. . Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular during acute enotoxemia. J Pediatr Surg 1996; 31: 1009–1015.CrossRefGoogle Scholar
20.Hayashi, Y, Abe, M, Murai, A et al. . Comparison of effects of nitric oxide synthase (NOS) inhibitors on plasma nitrite/nitrate levels and tissue NOS activity in septic organs. Microbiol Immunol 2005; 49: 139–147.CrossRefGoogle ScholarPubMed
21.Weimann, J, Bloch, KD, Takata, M et al. . Congenital NOS2 deficiency protects mice from LPS-induced hyporesponsiveness to inhaled nitric oxide. Anesthesiology 1999; 91: 1744–1753.CrossRefGoogle ScholarPubMed
22.Combs, X, Mazmanian, M, Gourlain, H et al. . Effect of 48 hours of nitric oxide inhalation on pulmonary vasoreactivity in rats. Am J Resp Crit Care Med 1997; 156: 473–477.CrossRefGoogle Scholar
23.Frank, DU, Horstman, DJ, Morris, GN et al. . Regulation of the endogenous NO pathway by prolonged inhaled NO in rats. J Appl Physiol 1998; 85: 1070–1078.CrossRefGoogle ScholarPubMed
24.Roos, CM, Frank, DU, Xue, C et al. . Chronic inhaled nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats. J Appl Physiol 1996; 80: 252–260.CrossRefGoogle ScholarPubMed
25.Radi, R, Beckman, JS, Bush, KM et al. . Peroxynitrite oxidation of sulfhydryls – the cytotoxic potential of superoxide and nitric oxide. J Biol Chem 1991; 266 (7): 4244–4250.CrossRefGoogle ScholarPubMed
26.Giardino, I, Fard, AK, Hatchell, DL et al. . Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation and oxidant-induced apoptosis. Diabetes 1998; 47: 1114–1120.CrossRefGoogle ScholarPubMed
27.Wolff, DJ, Gauld, DS, Neulander, MJ et al. . Inactivation of nitric oxide synthase by substituted aminoguanidines and aminoisothioureas. J Pharmacol Exp Ther 1997; 283: 265.Google ScholarPubMed
28.Jang, D, Szabo, C, Murrell, GA. S-substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage. Eur J Pharmacol 1996; 312: 341–347.CrossRefGoogle ScholarPubMed
29.Wolfard, A, Kaszaki, J, Szabo, C et al. . Effects of selective nitric oxide synthase inhibition in hyperdynamic endotoxemia in dogs. Eur Surg Res 1999; 31: 314–323.CrossRefGoogle ScholarPubMed
30.Rosselet, A, Feihl, F, Markert, M et al. . Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Resp Crit Care Med 1998; 157: 162–170.CrossRefGoogle ScholarPubMed
31.Numata, M, Suzuki, S, Miyazawa, N et al. . Inhibition of inducible nitric oxide synthase prevents LPS-induced acute lung injury in dogs. J Immunol 1998; 160: 3031–3037.CrossRefGoogle ScholarPubMed
32.Sartorio, CL, Pinto, VD, de Sallas Cutini, GJ et al. . Effects of inducible nitric oxide synthase inhibition on the rat tail vascular bed reactivity three days after myocardium infarction. J Cardiovasc Pharmacol 2005; 45: 321–326.CrossRefGoogle ScholarPubMed
33.Lee, CC, Lin, NT, Hsu, YH et al. . Inducible nitric oxide synthase inhibition potentiates multiple organ dysfunction by endotoxin in conscious rats. J Cardiovasc Pharmacol 2005; 45: 396–403.CrossRefGoogle ScholarPubMed