Recent evidence suggests that, in adult animals with
hypoxia-induced
pulmonary hypertension,
atrial natriuretic factor (
ANF) may modulate pulmonary vascular tone and may have a protective effect. However, its role in the pathogenesis of
pulmonary hypertension of the newborn is unknown. We hypothesized that, in the newborn,
hypoxia-induced
pulmonary hypertension would result in
ANF receptor downregulation, resulting in decreased dilator response, favoring pulmonary vasoconstriction and
vascular remodeling. Therefore, we studied, in 1-day-old piglets exposed to
hypoxia (fraction of inspired O2 0.10) for 3 or 14 days to induce
pulmonary hypertension, 1)
ANF release by measuring circulating levels of
ANF by radioimmunoassay in pulmonary artery and veins, 2) pulmonary vascular reactivity to
ANF using isolated perfused lungs, and 3) binding characteristics by examining the concentration dependence of
ANF binding and competitive binding of 125I-labeled
ANF with
ANF,
brain natriuretic peptide,
C-type natriuretic peptide, and the specific
ligand for
ANF clearance receptor on microsomes from pulmonary arteries (down to 100 microns).
ANF circulating levels are increased after exposure to
hypoxia compared with normoxia, reaching significance at 14 days (P < 0.005). The magnitude of
ANF dilator response is diminished after exposure to
hypoxia (P < 0.05). Saturation studies reveal that the number of
ANF receptors is diminished in
hypoxia after 3 days but reaches significance after 14 days (P < 0.01) compared with their respective normoxic control. At either condition, the majority of these receptors are of the functional type, whereas clearance receptors are virtually undectable. These results suggest that
hypoxia increases circulating
ANF and causes a decreased responsiveness of the pulmonary vasculature to
ANF. Receptor down-regulation may explain part of the reduced dilator response, although the involvement of other mechanisms is not excluded.