Downregulation of pulmonary atrial natriuretic peptide receptors in rats exposed to chronic hypoxia

Abstract

We hypothesized that a downregulation in pulmonary atrial natriuretic peptide (ANP) receptors helps raise plasma ANP levels during chronic hypoxia. We measured in vivo pulmonary uptake and plasma clearance of 125I-ANP and in vitro pulmonary binding kinetics of 125I-ANP in normoxic and chronically hypoxic rats. Exposure to 21 days of hypobaric (0.5 atm) hypoxia did not decrease specific binding of 125I-ANP in the kidney, but pulmonary binding decreased 35 and 75% after 1 and 3 days of hypoxia, respectively, and increased 200% after 3 days of normoxic recovery from 21 days of hypoxia. The total binding capacity for ANP to lung membrane fractions from normoxic rats, chronically hypoxic rats, and rats that had recovered from hypoxia was 488 +/- 59, 109 +/- 17, and 338 +/- 48 fmol/mg, respectively (P < 0.05 for hypoxic vs. normoxic or recovered lung membranes). The area under the 125I-ANP plasma concentration curve for normoxic and hypoxic rats and normoxic rats that were infused with the ANP C-receptor ligand C-ANF-(4-23) was 3,292 +/- 216, 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)-infused rats]. We conclude that pulmonary ANP clearance is reduced during chronic hypoxia secondary to a downregulation in pulmonary ANP clearance receptors. Reduced pulmonary clearance of ANP may represent an adaptation that contributes to increased plasma ANP levels during chronic hypoxia.

Clinical significance of elevated B-type natriuretic peptide in patients with acute lung injury with or without right ventricular dilatation: an observational cohort study

“…Several other mechanisms have been proposed. Hypoxia has been shown to increase cardiac gene expression of BNP [23,24] and decrease lung expression of the NPR-C clearance receptor leading to increased plasma levels of BNP in animal models [25]. Transcription of the BNP gene has been described not only in cardiac myocytes but also in the lung [26].…”

Adenovirus-Mediated Atrial Natriuretic Protein Expression in the Lung Protects Rats from Hypoxia-Induced Pulmonary Hypertension

“…In humans and animals, exposure to chronic hypoxia results in a sustained elevation in circulating ANP levels due to both an increase in ANP synthesis in the right heart and a decrease in pulmonary ANP clearance (Klinger et al, 1996). Studies have shown that ANP is a selective vasorelaxant of the pulmonary vessels and counteracts the pathogenic mechanisms involved in PH (Adnot et al, 1987(Adnot et al, , 1988Jin et al, 1990;Raffestin et al, 1992).…”

Natriuretic Peptides

“…In fact, right heart dysfunction due to severe lung disease from a variety of etiologies can cause elevated NP levels. The mechanism is likely due to release of peptide from the right ventricular myocardium (28), although decreased lung expression of the NPR-C clearance receptor in response to hypoxia has been demonstrated in animal models (29). This scenario can be seen in severe chronic obstructive pulmonary disease, primary pulmonary hypertension, and other causes of pulmonary hypertension (28,30,31).…”