Biologic role of atrial natriuretic factor clearance receptor in congestive heart failure

Atrial natriuretic factor (ANF) is a circulating 28-amino acid peptide that functions in the regulation of sodium homeostasis and vascular tone. ANF metabolism occurs via degradation by neutral endopeptidase 24.11 and binding to the ANF clearance receptor (ANFR-C). The present study was performed on anesthetized dogs, normal (control) and with experimental congestive heart failure (CHF), and was designed to investigate the ability of an ANF ligand specific for ANFR-C [C-ANF-(4-23)] to increase plasma ANF and also to evaluate the influence of ANFR-C on regional pulmonary and renal ANF clearances. C-ANF-(4-23) increased plasma ANF in controls (51 ± 15 to 123 ± 39 pg/ml; P < 0.05) and further increased plasma ANF in CHF dogs (242 ± 30 to 327 ± 34; P < 0.05), demonstrating that ANFR-C plays a significant role in the overall metabolism and clearance of ANF, even with chronically elevated ANF. Infusion of C-ANF-(4-23) produced a marked decrease in ANF pulmonary clearance (P(CL)ANF) in controls (1,018 ± 405 to -286 ± 383 ml/min; P < 0.05); however, P(CL)ANF was not altered by the ANF ligand in CHF dogs [-137 ± 174 to -106 ± 226 ml/min; not significant (NS)], suggesting an occupancy of ANFR-C or a downregulation of this receptor with chronically elevated plasma ANF. ANF renal clearance (R(CL)ANF) was not altered in either group by C-ANF-(4-23) infusion. Lack of change in P(CL)ANF and R(CL)ANF with ligand infusions during CHF suggests that the plasma ANF increase produced by C-ANF-(4-23) is related to an altered peptide clearance at sites other than the lung or kidney. This study demonstrates the contribution of ANFR-C to metabolism and clearance ANF during CHF and demonstrates cardiovascular and renal responses to C-ANF-(4-23) infusion in this pathophysiological condition characterized by elevated endogenous ANF.