Macula densa stimulation of renin is reversed by selective inhibition of neuronal nitric oxide synthase

The neuronal isoform of nitric oxide synthase (nNOS) exists in the renal cortex predominantly in the macula densa, suggesting that nitric oxide (NO) derived from the macula densa plays a role in feedback regulation of renin in response to altered sodium metabolism. To determine if nNOS is a critical component in renin stimulation induced by dietary sodium restriction, rats received either normal sodium or a sodium-restricted diet (0.03%) for 7 days and subsequently were or were not treated with the selective inhibitor of nNOS 7-nitroindazole (7-NI) either acutely (50 mg/kg body wt ip) on the final day or chronically (20 mg/kg body wt ip 2 x/day) over the final 5 days. On the last day, rats were anesthetized with Inactin and fitted with arterial and renal venous catheters to collect blood and monitor blood pressure (BP) and a flow probe to measure renal blood flow (RBF). BP (105 vs. 108 mmHg) was similar in normal and low-sodium dietary groups, respectively, whereas RBF tended to be higher in the sodium-restricted group (6.5 +/- 0.3 vs. 7.6 +/- 0.4 ml.min(-1).g kidney wt(-1)). Both renal venous renin (RR) and renin secretion rate (RSR) were elevated approximately fourfold by sodium restriction [RR = 5.8 +/- 0.8 vs. 20.5 +/- 2.7 ng angiotensin (ANG) I.ml(-1).h(-1); P < 0.001; RSR = 3.0 +/- 0.9 vs. 13.1 +/- 4.1 ng ANG I.h(-1).min(-1); P < 0.025]. Acute 7-NI did not change BP, RR, or RSR, but reduced RBF in sodium-restricted rats by 8% (P < 0.05). Chronic 7-NI had no effect on renin in rats on a normal diet, but reduced RR by one-halfin the sodium-restricted group (to 9.9 +/- 1.6 ng ANG I.ml(-1).h(-1); P < 0.001) and reduced RSR to normal (diet) levels (to 3.9 +/- 1.4 ng ANG I.h(-1).min(-1); P < 0.05). Although selective NOS inhibition by 7-NI did not affect BP, RBF, or renin in control rats on a normal diet, chronic 7-NI reversed the stimulation of renin induced by dietary sodium restriction. These data suggest that nNOS-derived NO plays an important role in the macula densa during feedback stimulation of renin induced by dietary sodium restriction.