Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats

In concentrations of 10-20 ppm, inhaled nitric oxide (NO) decreases pulmonary artery pressure and attenuates vascular remodeling in pulmonary hypertensive rats. Because NO is potentially toxic, it is important to know whether lower concentrations attenuate vascular remodeling produced by different etiologies. Therefore, we determined the effects of prolonged, small-dose inhaled NO administration on hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling. Rats were subjected to normoxia, hypoxia (normobaric 10% oxygen), or hypoxia plus NO in concentrations of 50 ppb, 200 ppb, 2 ppm, 20 ppm, and 100 ppm for 3 wk. A second group of normoxic rats was given MCT (60 mg/kg intraperitoneally) alone or in the presence of 2, 20, and 100 ppm of NO. Subsequently, pulmonary artery smooth muscle thickness and the number of muscular arteries (percentage of total arteries) were determined. Right ventricular hypertrophy was determined by right to left ventricle plus septum weight ratio (RV/LV + S). Pulmonary artery smooth muscle thickness and the percent muscular arteries were increased by hypoxia and MCT. The hypoxic increase in thickness was attenuated by all concentrations of NO, with 100 ppm being greatest, whereas NO had no effect on MCT rats. NO attenuated the increase in percent muscular arteries in hypoxic but not MCT rats. The RV/LV + S was increased by hypoxia and MCT compared with normoxia. Hypoxia-induced RV hypertrophy was decreased by all concentrations of inhaled NO, although attenuation with 50 ppb was less than with 200 ppb, 20 ppm, and 100 ppm. In MCT rats 2 and 100 ppm NO increased RV hypertrophy, whereas 20 ppm had no effect. In conclusion, inhaled NO in concentrations as low as 50 ppb attenuates the pulmonary vascular remodeling and RV hypertrophy secondary to hypoxia. In contrast, concentrations as high as 100 ppm do not attenuate MCT-induced pulmonary remodeling. These results demonstrate that extremely low concentrations of NO may attenuate remodeling but that the effectiveness is dependent on the mechanism inducing pulmonary remodeling. Implications: The authors determined whether inhaled NO, a selective pulmonary vasodilator, attenuates pulmonary vascular remodeling caused by two models of pulmonary hypertension: chronic hypoxia and monocrotaline injection. Analysis of pulmonary vascular morphology suggests that very low concentrations of NO effectively attenuate hypoxic remodeling but that NO is not effective in monocrotaline-induced pulmonary remodeling.