Nitric Oxide in the Early Phase of Hypoxia-Induced Pulmonary Hypertension in Newborn Piglets † 1764

We have previously shown that pulmonary hypertension develops when newborn pigs are exposed to chronic hypoxia and consists of at least two phases (JAP 77:2853, 1994), an early phase (3-5 days) and a late phase (10-12 days). The early phase is characterized by increased pulmonary vascular tone and an augmented response to acute hypoxia, and the later phase is characterized by a remodeled pulmonary circulation without the augmented acute hypoxic response. We also have found that nitric oxide (NO) production is decreased in the later phase (FASEB J 10:A307, 1996, and Ped Res 41:301A, 1997). The purpose of this study was to determine if decreased lung NO production is involved in the early phase of hypoxia-induced pulmonary hypertension. To do this, we used 1-3 day old piglets exposed to room air (control, n=5), or 10% O₂ (hypoxia n=5) for 3-5 days. We anesthetized the piglets and placed catheters to measure pulmonary artery pressure, pulmonary wedge pressure, and cardiac output by the thermodilution technique. We isolated and perfused the lungs with an artificial perfusate at constant flow. Perfusate samples were collected at 15 minute intervals for 90 minutes for measurement of nitrite and nitrate(NO_x^-), the stable metabolites of NO. The amount of endothelial NO synthase (cNOS) was measured in whole lung homogenates by an immunoblot technique. We also evaluated cNOS in homogcnates of 100-600 micron diameter pulmonary arteries (PA) dissected from lungs of control and hypoxic piglets. In the anesthetized piglets, we found that the catculated pulmonary vascular resistance was greater in hypoxic than in control animals (0.06±0.01 vs 0.03±0.01 mmHg ml^-1min kg). In isolated lungs, the perfusate NO_x^- accumulation was not significantly less in hypoxic(1.8±0.4 nmol/min) than control (2.8±0.5 nmol/min) piglets. In addition, as assessed by laser densitometry, neither whole lung nor PA homogenate cNOS differed between hypoxic and control piglets. These findings suggest that 3-5 days of hypoxia caused pulmonary hypertension but did not alter lung NO production in newborn piglets. Thus, decreased NO may be involved in the later phase of hypoxia-induced pulmonary hypertension and may contribute to the progression of the disease process. However, mechanisms other than altered NO production appear to be responsible for the early phase of hypoxia-induced pulmonary hypertension in newborn piglets.