REDUCED VASODILATOR RESPONSE TO ANF IN HYPOXIA-INDUCED PULMONARY-HYPERTENSION IN THE NEWBORN PIGLET

Recent evidence suggests that, in adult animals with hypoxia-induced p ulmonary hypertension, atrial natriuretic factor (ANF) may modulate pu lmonary vascular tone and may have a protective effect. However, its r ole in the pathogenesis of pulmonary hypertension of the newborn is un known. We hypothesized that, in the newborn, hypoxia-induced pulmonary hypertension would result in ANF receptor downregulation, resulting i n decreased dilator response, favoring pulmonary vasoconstriction and vascular remodeling. Therefore, we studied, in 1-day-old piglets expos ed to hypoxia (fraction of inspired O-2 0.10) for 3 or 14 days to indu ce pulmonary hypertension, 1) ANF release by measuring circulating lev els of ANF by radioimmunoassay in pulmonary artery and veins, 2) pulmo nary vascular reactivity to ANF using isolated perfused lungs, and 3) binding characteristics by examining the concentration dependence of A NF binding and competitive binding of I-125-labeled ANF with ANF, brai n natriuretic peptide, C-type natriuretic peptide, and the specific li gand for ANF clearance receptor on microsomes from pulmonary arteries (down to 100 mu m) 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 num ber 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 undetectable. These results suggest that hypoxia increases circulatin g ANF and causes a decreased responsiveness of the pulmonary vasculatu re to ANF. Receptor downregulation may explain part of the reduced dil ator response, although the involvement of other mechanisms is not exc luded.