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Endotoxin-induced pulmonary hyporesponsiveness to inhaled nitric oxide is improved by nitric oxide synthase 2 inhibition

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Introduction

In isolated-perfused lungs of endotoxin-challenged rats, inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) improved responsiveness to inhaled nitric oxide (NO) [1]. In dogs treated with lipopolysaccharide (LPS), S-methylisothiourea (SMT) and AG prevented worsening of hemodynamics and gas exchange [2]. In this study, inhibition of NOS2 by SMT and AG modulates responsiveness to inhaled NO in lungs of endotoxin (LPS)-challenged rats in a dose-dependent manner.

Methods

Sprague-Dawley rats (400-450 gm BW) were injected i.p. with 0.5 mg/kg E. coli 0111:B4 LPS (n=42) or were controls (n=9). Four hours later, LPS-treated rats were injected i.p. with 3, 10, and 30 mg/kg AG or 0.01, 0.1, 1 and 10 mg/kg SMT. 18 h later, lungs were isolated-perfused in situ using Hank's solution. Pulmonary artery pressure (PAP) was elevated by 6-8 mmHg using the thromboxane analogue U46619. Decrease of PAP in response to inhaled NO (0.4, 4, and 40 ppm NO in random order) was measured. Serum and lung perfusate nitrate/nitrite levels were measured with the Griess-reaction.

Results

See Table.

Conclusions

AG is more effective in improving NO responsiveness than SMT. Responsiveness to inhaled NO appears to be dependent on the degree of NOS2 inhibition in lungs of LPS-challenged rats, because improvement of NO responsiveness correlated with nitrate/nitrite levels in serum and lung perfusate.

Table 1

References

  1. 1.

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Bopp, C., Holzmann, A., Schmidt, H. et al. Endotoxin-induced pulmonary hyporesponsiveness to inhaled nitric oxide is improved by nitric oxide synthase 2 inhibition. Crit Care 4, P52 (2000). https://doi.org/10.1186/cc772

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Keywords

  • Nitric Oxide
  • Full Text
  • Thromboxane
  • U46619
  • Pulmonary Artery Pressure