Abstract 1897 Poster Session I, Saturday, 5/1 (poster 85)

Mechanisms that contribute to high pulmonary vascular resistance (PVR) and abnormal vasoreactivity in persistent pulmonary hypertension of the newborn (PPHN) are uncertain. Acute compression of the ductus arteriosus (DA) rapidly increases pulmonary blood flow (Qp) and decreases PVR in the normal fetal lamb. Acute inhibition of nitric oxide (NO) release blocks fetal pulmonary vasodilation and unmasks a potent myogenic response (MR) during brief DA occlusion. Since past studies have demonstrated decreased NO synthase expression and activity in an experimental model of PPHN due to chronic DA compression, we hypothesized that chronic pulmonary hypertension may attenuate flow-induced vasodilation and enhance the MR in the fetal lung. Therefore, we studied hemodynamic responses during chronic DA compression in chronically prepared late-gestation fetal lambs (128-132 days; term = 147 days). Catheters were inserted in the left pulmonary artery (LPA) for selective drug infusion, and in the main pulmonary artery (PAP), aorta, left atrium and amniotic cavity to measure pressure. An inflatable vascular occluder was placed around the DA, but not inflated until the time of study. Qp was measured in the left lung with an ultrasonic flow transducer. Two days after surgery, animals were randomly assigned to control (n=5) or PPHN (n=5) groups. In the PPHN group, mean PAP was increased 30% by partial DA compression for 4 days. On day 4, the DA compression was released 20 minutes before study. In controls, acute DA compression increased mean PAP by 20 mm Hg and Qp by 2-fold (from 85 + 12 to 160 + 28 ml/min; p<0.05). Despite the same increase in PAP, Qp did not increase during acute DA compression in the PPHN group (86 + 16 (baseline) vs. 75 + 24 ml/min; p=NS). Inhibition of NO production with nitro-L-arginine (L-NA) increased PVR in control but not PPHN lambs. Acute DA compression after L-NA treatment increased PVR in both groups, but the increase in PVR was higher in PPHN lambs (p<0.05). We conclude that chronic pulmonary hypertension abolishes flow or shear stress-induced vasodilation and increases the MR in the fetal pulmonary circulation. We speculate that an inability to produce NO blunts vasodilation and unmasks a potent myogenic response in the perinatal lung, contributing to abnormal pulmonary vasoreactivity in PPHN.