Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia-induced pulmonary hypertension

Nitric oxide (NO) is thought to play an important role in the regulation of neonatal pulmonary vasculature. It has been suggested that neonates with p ulmonary hypertension have a defective NO pathway. Therefore, we measured i n 1-day-old piglets exposed to hypoxia (fraction of inspired O-2 = 0.10) fo r 3 or 14 days to induce pulmonary hypertension 1) the activity of NO synth ase (NOS) via conversion of L-arginine to L-citrulline and the concentratio n of the NO precursor L-arginine in isolated pulmonary vessels, 2) the vaso dilator response to the NO donor 3-morpholinosydnonimine-N-ethylcarbamide ( SIN-1) and the cGMP analog 8-bromo-cGMP in isolated perfused lungs, and 3) the production of cGMP in response to SIN-1 in isolated perfused lungs. Aft er 3 days of exposure to hypoxia, endothelial NOS (eNOS) activity was unaff ected, whereas, after 14 days of hypoxia, eNOS activity was decreased in th e cytosolic fraction of pulmonary artery (P < 0.05) but not of pulmonary ve in homogenates. Inducible NOS activity was decreased in the cytosolic fract ion of pulmonary artery homogenates after both 3 (P < 0.05) and 14 (P < 0.0 5) days of hypoxia but was unchanged in pulmonary veins. Pulmonary artery l evels of L-arginine were unaffected by hypoxic exposure. After 3 days of ex posure to hypoxia, the reduction in the dilator response to SIN-1 (P < 0.05 ) coincided with a decrease in cGMP production (P < 0.005), suggesting that soluble guanylate cyclase activity may be altered. When the exposure was p rolonged to 14 days, dilation to SIN-1 remained decreased (P < 0.05) and, a lthough cGMP production normalized, the dilator response to 8-bromo-cGMP de creased (P < 0.05), suggesting that, after prolonged exposure to hypoxia, c GMP-dependent mechanisms may also be impaired. In conclusion, neonatal hypo xia-induced pulmonary hypertension is associated with multiple disruptions in the NO pathway.