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 pulmonary hypertension have a defective NO pathway. Therefore, we measured in 1-day-old piglets exposed to hypoxia (fraction of inspired O(2) = 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.
Berkenbosch
J W
JW
Division of Pediatric Critical Care, Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada H3H 1P3.
Baribeau
J
J
Perreault
T
T
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001120:Arginine / Q000097:blood / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications*; D066298:In Vitro Techniques; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011652:Pulmonary Circulation / Q000187:drug effects; D013552:Swine; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C002385:linsidomine; D001120:Arginine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP