Potentiation of urinary atrial natriuretic peptide interferes with macula densa function

Objectives: Neutral endopeptidase (NEP) inhibition potentiated the renal ac tion of Atrial Natriuretic Peptide (ANP) and was associated with appearance of the peptide in the urine, providing evidence of protection of the filtr ated peptide along the course of the nephron. The macula densa, composed of epithelial cells, receives ionic information from the urinary compartment via Na-K-2Cl cotransport and influences renin secretion by the myoepithelio id cells in the afferent arteriole. bNOS constitutively expressed in the ep ithelial cells of the macula densa. is involved in this feed-back. NEP inhi bition was associated with the absence of any increase in renin secretion. The hypothesis is that potentiation of urinary ANP by NEP inhibition could limit renin secretion by directly or indirectly targeting the macula densa in vivo. Methods and results: We tested the interaction between NEP inhibit ion (candoxatril) and Na-K-2Cl inhibition (bumetanide) on electrolyte and A NP urinary excretion, renin secretion, macula densa activity (NADPH diaphor ase activity and bNOS mRNA) and TSC-1 mRNA expression in the renal cortex a nd BSC-1 in the renal medulla of rats treated for 5 days. Bumetanide increa sed urinary electrolyte excretion whereas candoxatril did not. Candoxatril increased urinary ANP and cyclic GMP excretion. Bumetanide increased renin and aldosterone secretion whereas candoxatril decreased renin secretion. Th is effect on renin release was associated with an increase in macula densa NADPH diaphorase activity in the bumetanide-treated group which was blunted by candoxatril. Lastly, bumetanide increased TSC-1 mRNA expression in the cortex and this effect was blunted by candoxatril. Conclusion: These result s suggest that potentiation of ANP by NEP inhibition could interfere with t ubular function at different levels and limit renin secretion by a urinary pathway involving macula densa activity. (C) 2001 Elsevier Science BY All r ights reserved.