Inhibition of lung phosphodiesterase improves responsiveness to inhaled nitric oxide in isolated-perfused lungs from rats challenged with endotoxin

Objectives:To investigate the ability of phosphodiesterase (PDE) selective inhibitors to improve responsiveness to inhaled nitric oxide (NO) in isolat ed-perfused lungs of rats pretreated with endotoxin/lipopolysaccharide (LPS ). Design and setting: Prospective, controlled animal study in the animal rese arch facility of a university hospital. Interventions: Sixteen hours after adult Sprague-Dawley rats were injected intraperitoneally with 0.4 mg/ kg E. coli 0111:B4 LPS administration, lungs were isolated and perfused, and the thromboxane mimetic U46619 was employe d to increase the mean pulmonary artery pressure by 5-7 mmHg. The lungs wer e then ventilated with or without 0.4 ppm NO, and erythro-9-(2-hydroxy-3-no nyl) adenine (EHNA; PDE type 2 inhibitor), milrinone (PDE type 3 inhibitor) , or zaprinast (inhibitor of PDE types 5 and 9) were added to the perfusate . Measurements and results: In the presence of EHNA (12.5, 25, 50 muM) the va sodilator response to inhaled NO was not greater than in its absence (0.25 +/- 0.25, 0.5 +/- 0.25, 0.75 +/- 0.25 mmHg vs. 0.25 +/- 0.25, 0.5 +/- 0.25, 0.75 +/- 0.25 mmHg, re spectively). In the presence of milrinone (125, 250 , 500 nM), the vasodilator response to inhaled NO was also not improved. In contrast, zaprinast (3.7, 7.4, 14.8 muM) augmented the pulmonary vasodilat ory effect of inhaled NO in lungs from LPS-pretreated rats from 0.25 +/- 0. 25, 0.5 +/- 0.25, 0.75 +/- 0.25 mmHg to 0.75 +/- 0.25, 1.5 +/- 0.5, 1.75 +/ - 0.75 mmHg, respectively (p < 0.05). Conclusions: Our results demonstrate that inhibition of pulmonary PDE enzym e activity with zaprinast increases vasodilator responsiveness to inhaled N O in lungs obtained from rats 16 h after LPS challenge.