Progressive lung and cardiac changes associated with pulmonary hypertension in the fetal rat

To determine the natural history of lung vascular remodeling and cardiac changes in the rat model of persistent pulmonary hypertension syndrome (PPHN) of the newborn, we studied fetal rats subjected to maternal indomethacin administration initiated on day 19 of gestation and continued for 2, 3, or 4 days. Animals receiving a similar volume of water or alcohol served as controls. Significant pulmonary hypertension was noted in the experimental group, as evidenced by a significantly increased right to left ventricular wall ratio to 1.6 +/- 0.1 in the 4-day treatment group, as compared with 1.2 +/- 0.4 in the control group (P < 0.01). The smooth muscle area for <25 microm external diameter arterial vessels was significantly increased (12.7 +/- 0.6 vs. 10.0 +/- 0.6 microm; P < 0.01) and the adventitial area of all diameters vessels was significantly greater (P < 0.01) following 3 days of indomethacin treatment, as compared with water controls. Associated with these changes, the 4-day treatment group's lung/body weight ratio was 0.021 +/- 0.001, and was significantly less (P < 0.01) than for the control group (0.035 +/- 0.001). This reduction in lung weight was not associated with changes in lung protein content or wet/dry weight ratio, indicating that pulmonary hypertension in the fetal rat induced lung hypoplasia. In conclusion, closure of the ductus arteriosus in the fetal rat results in early-onset right ventricular hypertrophy, followed by pulmonary vascular remodeling and lung hypoplasia. We speculate that lung growth in late gestation is adversely affected by pulmonary hypertension.