Reduced vasodilator response to ANF in hypoxia-induced pulmonary hypertension in the newborn piglet

Abstract

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.