Inhibition of apical Na+/H+ exchangers on the macula densa cells augments tubuloglomerular feedback.

Abstract

NO produced by neuronal NO synthase (nNOS) in the macula densa blunts tubuloglomerular feedback (TGF). nNOS activity is strongly pH-dependent. Increasing luminal NaCl concentration increases nNOS activity, NO production, and apical Na+/H+ exchange. Na+/H+ exchange alkalinizes the macula densa. We hypothesized that inhibiting apical Na+/H+ exchange in macula densa cells would augment TGF by blunting nNOS activation caused by increasing luminal NaCl concentration. Rabbit afferent arterioles and attached macula densas were microperfused in vitro. TGF response was defined as the change in afferent arteriole diameter caused by increasing the NaCl concentration in the macula densa perfusate. 7-Nitroindazole (7-NI; 10 micromol/L) alone in the macula densa lumen increased the TGF response from 2.4+/-0.1 to 3.8+/-0.2 microm (P<0.01). When dimethyl amiloride (100 micromol/L), a Na+/H+ exchange inhibitor, was added to the macula densa lumen, it increased the TGF response from 2.5+/-0.3 to 3.7+/-0.5 microm (P<0.01). In the presence of dimethyl amiloride, 7-NI had no effect on the TGF response (from 2.6+/-0.2 to 2.7+/-0.2 microm). Our data indicate that inhibiting apical Na+/H+ exchange in the macula densa mimics the effect of inhibiting NO production by nNOS in the macula densa on TGF. Thus, it is possible that increased apical Na+/H+ exchange caused by increasing the sodium concentration in the lumen of the macula densa activates macula densa nNOS. The link between nNOS and Na+/H+ exchange may be intracellular pH.