DOWN-REGULATION OF PULMONARY ATRIAL-NATRIURETIC-PEPTIDE RECEPTORS IN RATS EXPOSED TO CHRONIC HYPOXIA

We hypothesized that a downregulation in pulmonary atrial natriuretic peptide (ANP) receptors helps raise plasma ANP levels during chronic h ypoxia. We measured in vivo pulmonary uptake and plasma clearance of I -125-ANP and in vitro pulmonary binding kinetics of I-125-ANP, normoxi c and chronically hypoxic rats. Exposure to 21 days of hypobaric (0.5 atm) hypoxia did not decrease specific binding of I-125-ANP in the kid ney, but pulmonary binding decreased 35 and 75% after 1 and 3 days of hypoxia, respectively, and increased 200% after 3 days of normoxic rec overy from 21 days of hypoxia. The total binding capacity for ANP to l ung membrane fractions from normoxic rats, chronically hypoxic rats, a nd rats that had recovered from hypoxia was 488 +/- 59, 109 +/- 17, an d 338 +/- 48 fmol/mg, respectively (P < 0.05 for hypoxic vs. normoxic or recovered lung membranes). The area under the I-125-ANP plasma conc entration curve for normoxic and hypoxic rats and normoxic rats that w ere infused with the ANP C-receptor ligand C-ANF(4-23) was 3,299 +/- 2 16, 5,022 +/- 466, and 8,205 +/- 1,059 disintegrations.min(-1).ml(-1), respectively [P < 0.05 for hypoxic vs. normoxic or C-ANF-(4-23)-infus ed rats]. We conclude that pulmonary ANP clearance is reduced during c hronic hypoxia secondary to a downregulation in pulmonary ANP clearanc e receptors. Reduced pulmonary clearance of ANP may represent an adapt ation that contributes to increased plasma ANP levels during chronic h ypoxia.