Time-Limited Hyporesponsiveness to Inhaled Nitric Oxide and Pulmonary Phosphodiesterase Activity in Endotoxemic Rats

Abstract

In acute lung injury (ALI) pulmonary hyporesponsiveness to inhaled nitric oxide (iNO) still represents an unresolved clinical challenge. In septic ALI-patients the incidence of hyporesponsiveness to iNO is increased; therefore, endotoxemia appears to play a major role. Experimental data suggest that endotoxemia, e.g., induced by lipopolysaccharides (LPS), contribute to the hyporesponsiveness to iNO. Guanosine 3',5'-cyclic monophosphate (cGMP) is metabolized by phosphodiesterases (PDE). The role of PDE in reduced pulmonary vascular response in experimental endotoxemia is still not known. Here, we hypothesized that PDE activity modulates initial pulmonary responsiveness to iNO in ALI following systemic endotoxin exposure. Rats were treated with LPS or used as controls. Lungs were isolated-perfused 0-36 h after LPS injection and the synthetic thromboxane analogue U46619 was added to increase pulmonary artery pressure by 6-8 mmHg (n = 47). Then, the pulmonary vasodilatory response to 3 doses of iNO (0.4, 4 and 40 ppm) was measured. Furthermore, lungs were prepared as described previously, and 2, 10, and 18 h after LPS the change in pulmonary artery pressure in response to two different inhibitors of PDE, one of which is PDE sensitive (8-Br-cGMP) and one is PDE stable (8-pCPT-cGMP), was determined (n = 43). Serum nitrite/nitrate levels started to increase 4 h after LPS, with a maximum at 18 h. In contrast, decreased pulmonary vasoreactivity in response to iNO developed as early as 2 h later and remained depressed up to 18 h. The pulmonary vasoreactivity to the PDE-sensitive 8-Br-cGMP after LPS-stimulation was lower than that in lungs treated with the PDE-stable 8-pCPT-cGMP. In rats pretreated with LPS, hyporesponsiveness of pulmonary vessels to iNO is time-limited and associated with increased serum nitrite/nitrate levels, and appears to be attributed in part to increased pulmonary PDE activity.