TRANSIENT DOWN-REGULATION OF GLOMERULAR ATRIAL-NATRIURETIC-FACTOR RECEPTORS IN HIGH-OUTPUT HEART-FAILURE IN THE RAT

Objective: The renal response to exogenous atrial natriuretic factor ( ANF) is blunted in chronic heart failure. The aim of the present studi es was to investigate whether renal ANF receptor regulation in chronic heart failure is a time related event. Methods: Glomerular ANF recept ors were analysed in radioligand binding experiments at 0, 1, 2, 6, 12 , 24, and 48 h, as well as at 1, 2, 4, and 8 weeks after the induction of an aortocaval shunt. Results: Rats with aortocaval shunts had lowe r packed cell volume and body weight and higher relative heart weight than sham operated controls. Plasma ANF C and N terminal levels were i ncreased in shunt rats as early as 5 min after establishment of the sh unt. Right and left atrial ANF concentrations were decreased and ventr icular ANF concentration was increased in shunt rats at 6 and 12 h res pectively. Competitive inhibition of I-125-ANF binding showed that at 6 h the density (B-max) of glomerular ANF receptors was significantly lower than in the controls [518(SEM 10) v 759(12) fmol.mg(-1) protein] without differences in their affinity (Kd). The low B-max in shunt an imals persisted at 12, 24, and 48 h, even at 1 week [B-max : 400(29) a nd 713(28) fmol.mg(-1) protein; Kd: 80(2) and 70(4) pM, for AC rats an d controls, respectively]. B-max values were not significantly differe nt at 2, 4, and 8 weeks. In 24 h animals, C-ANF displaced 65% of total binding, with both total and C ANF binding sites being 38% lower in s hunt animals. Conclusion: Downregulation of glomerular ANF receptors i s a transient event during the development of high output heart failur e in the rat. Thus the blunted renal response to ANF during chronic he art failure is not likely to be due to a decrease in renal ANF recepto r density or affinity.