Role of Na+/H+ exchanger NHE3 in nephron function: micropuncture studies with S3226, an inhibitor of NHE3

Na+/H+ exchanger NHE3 is expressed in the luminal membrane of proximal tubu le and thin and thick ascending limb of Henle's loop. To further define its role, the novel NHE3 inhibitor S3226 was employed in micropuncture experim ents in nephrons with superficial glomeruli of anesthetized rats. Microperf usion of proximal convoluted tubule with S3226 revealed a dose-dependent in hibition of reabsorption (IC50 of 4-5 mu M) with a maximum inhibition of 30 % for fluid and Na+. During microperfusion of Henle's loop (last superficia l proximal to first superficial distal tubular loop), no effect of S3226 (1 0 or 30 mu M) on the reabsorption of fluid or Na+ was observed. Finally, S3 226 (30 mu M) left the tubuloglomerular feedback response unaltered as dete rmined by the fall in proximal tubular stop-flow pressure in response to in creasing loop of Henle perfusion rate. These studies indicate that NHE3 sig nificantly contributes to fluid and Na+ reabsorption in proximal convoluted tubule. NHE3 appears not to significantly contribute to fluid or Na+ reabs orption in the loop of Henle (including the S3 segment of proximal tubule) or macula densa control of nephron filtration.