Critical Care

, 5:P035 | Cite as

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

  • U Zils
  • A Holzmann
  • MM Gebhardt
  • H Schmidt
  • E Martin
Meeting abstract
  • 983 Downloads

Keywords

Nitric Oxide Pulmonary Hypertension Phosphodiesterase U46619 Pulmonary Artery Pressure 

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:

 

NO 4 ppm

NO 10 ppm

Decrease of PAP (mmHg)

-0.7 ± 0.1 (n = 6)

-1.0 ± 0.1- (n = 6)

Zaprinast (50 µg)

-1.9 ± 1.8* (n = 14)

-2.9 ± 1.3* (n = 4)

Sildenafil (10 ng)

-1.8 ± 1.1* (n = 6)

-2.4 ± 0.5* (n = 5)

-P < 0.05 vs NO ppm and *P < 0.05 vs NO 4 ppm and NO 10 ppm, respectively; ANOVA.

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

  1. 1.
    Weimann , et al.: Anesthesiology 2000, 92: 1702-1712. 10.1097/00000542-200006000-00030CrossRefGoogle Scholar
  2. 2.
    Ichinose , et al.: Anesthesiology 1998, 88: 410-416. 10.1097/00000542-199802000-00020CrossRefGoogle Scholar
  3. 3.
    Holzmann A, et al.: Am J Physiol 1996, 271: L981-L986.Google Scholar

Copyright information

© The Author(s) 2001

Authors and Affiliations

  • U Zils
    • 1
  • A Holzmann
    • 1
  • MM Gebhardt
    • 2
  • H Schmidt
    • 1
  • E Martin
    • 1
  1. 1.Department of AnaesthesiologieRuprecht-Karls-UniversitätHeidelbergGermany
  2. 2.Department of Experimental SurgeryRuprecht-Karls-UniversitätHeidelbergGermany

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