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Selective phosphodiesterase type 5 inhibition improves responsiveness to inhaled nitric oxide in endotoxin-challenged rats

Introduction

Inhaled nitric oxide (NO) improves arterial oxygenation and decreases pulmonary artery pressure (PAP) in ARDS. However, up to 60% of septic patients with ARDS show no or only minimal response to inhaled NO. NO induces relaxation of smooth muscle cells via the second messenger 3',5'-cyclic monophosphate (cGMP) which is metabolized by phosphodiesterase (PDE) type 5. Zaprinast and sildenafil are inhibitors of PDE type 5 and have been shown to decrease PAP in sheep with thromboxane analog U46619-induced pulmonary hypertension [1,2]. Because pulmonary PDE activity is increased in rats exposed to endotoxin [3], we hypothesised that inhibition of PDE type 5 with zaprinast or sildenafil improves responsiveness to inhaled NO in isolated-perfused lungs from rats challenged with endotoxin.

Methods

Adult Sprague-Dawley rats (400-450 g BW) were injected intraperitoneally with 0.5 mg/kg E. coli 0111:B4 endotoxin. Sixteen to 20 hours later, lungs were isolated, ventilated and perfused in situ. Lungs were perfused using a modified Hank's balanced salt solution containing 5% dextran, 5% bovine albumine, 30 µM indomethacin, and 580 µM L-NAME to inhibit endogenous nitric oxide synthesis. Then, U46619 was employed to increase PAP by 5 to 8 mmHg. After a stable elevated PAP was reached, 4 or 10 ppm NO with or without zaprinast (50 µg) or sildenafil (10 ng) was administered for 3 min and the decrease of PAP was measured.

Results

Table 1 Results:

Conclusion

These data demonstrate that specific inhibition of PDE type 5 improves responsiveness to inhaled nitric oxide in lungs obtained from endotoxin-challenged rats. In our model, decreased responsiveness to inhaled nitric oxide is at least in part attributable to increased pulmonary PDE type 5 activity.

References

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Zils, U., Holzmann, A., Gebhardt, M. et al. Selective phosphodiesterase type 5 inhibition improves responsiveness to inhaled nitric oxide in endotoxin-challenged rats. Crit Care 5, P035 (2001). https://doi.org/10.1186/cc1103

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Keywords

  • Nitric Oxide
  • Pulmonary Hypertension
  • Phosphodiesterase
  • U46619
  • Pulmonary Artery Pressure