Published Online
on December 30, 2002

A more recent version of this article appeared on March 1, 2003

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Submitted on October 9, 2002
Revised on October 28, 2002

Inhibition of Apical Na⁺/H⁺ Exchangers on the Macula Densa Cells Augments Tubuloglomerular Feedback

Hong Wang; Oscar A. Carretero; and Jeffrey L. Garvin^*

From the Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital (H.W., O.A.C., J.L.G.), Detroit, Mich; and Department of Cardiology, Zhongnan Hospital of Wuhan University (H.W.), Wuhan, People's Republic of China.

^* To whom correspondence should be addressed. E-mail: jgarvin1{at}hfhs.org.

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 µmol/L) alone in the macula densa lumen increased the TGF response from 2.4±0.1 to 3.8±0.2 µm (P<0.01). When dimethyl amiloride (100 µmol/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 µm (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 µm). 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.

Key words: nitric oxide • rabbit • tubuloglomerular feedback • afferent arteriole • loop of Henle

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