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Am J Physiol Lung Cell Mol Physiol 278: L276-L283, 2000;
1040-0605/00 $5.00
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Vol. 278, Issue 2, L276-L283, February 2000

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

John W. Berkenbosch1, Johanne Baribeau2, and Thérèse Perreault2

Divisions of 1 Pediatric Critical Care and 2 Newborn Medicine, Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada H3H 1P3

Nitric oxide (NO) is thought to play an important role in the regulation of neonatal pulmonary vasculature. It has been suggested that neonates with pulmonary hypertension have a defective NO pathway. Therefore, we measured in 1-day-old piglets exposed to hypoxia (fraction of inspired O2 = 0.10) for 3 or 14 days to induce pulmonary hypertension 1) the activity of NO synthase (NOS) via conversion of L-arginine to L-citrulline and the concentration of the NO precursor L-arginine in isolated pulmonary vessels, 2) the vasodilator 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. After 3 days of exposure to hypoxia, endothelial NOS (eNOS) activity was unaffected, whereas, after 14 days of hypoxia, eNOS activity was decreased in the cytosolic fraction of pulmonary artery (P < 0.05) but not of pulmonary vein homogenates. Inducible NOS activity was decreased in the cytosolic fraction of pulmonary artery homogenates after both 3 (P < 0.05) and 14 (P < 0.05) days of hypoxia but was unchanged in pulmonary veins. Pulmonary artery levels of L-arginine were unaffected by hypoxic exposure. After 3 days of exposure 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 prolonged to 14 days, dilation to SIN-1 remained decreased (P < 0.05) and, although cGMP production normalized, the dilator response to 8-bromo-cGMP decreased (P < 0.05), suggesting that, after prolonged exposure to hypoxia, cGMP-dependent mechanisms may also be impaired. In conclusion, neonatal hypoxia-induced pulmonary hypertension is associated with multiple disruptions in the NO pathway.

endothelial nitric oxide synthase; inducible nitric oxide synthase; L-arginine; 3-morpholinosydnonimine-N-ethylcarbamide; guanosine 3',5'-cyclic monophosphate; isolated perfused lungs; pulmonary arteries; pulmonary veins


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