We hypothesized that neuronal nitric oxide synthase and cyclooxygenase-2, which both exist in the renal cortex, predominantly in the macula densa, play a role in the control of renal renin tissue content. We studied the possible role of neuronal nitric oxide synthase in regulating renal renin content by using mice in which the neuronal nitric oxide synthase gene has been disrupted (nNOS -/-) compared with its two progenitor strains, the 129/SvEv and the C57BL/6, to determine if the absence of neuronal nitric oxide synthase would result in decreased renal renin content or blunt the increase observed during low sodium intake. Renal renin content from cortical slices was determined in adult mice from all three strains maintained on a normal sodium diet. Renal renin content was significantly reduced in the nNOS -/- mice compared with the 129/SvEv and the C57BL/6 mice (3.11 +/- 0.23 versus 5.66 +/- 0.50 and 7.55 +/- 1.17 micro gram angiotensin I/mg dry weight, respectively; P < .005), suggesting that neuronal nitric oxide synthase may stimulate renal renin content under basal conditions. Neither selective pharmacological inhibition of neuronal nitric oxide synthase using 7-nitroindazole or disruption of the neuronal nitric oxide synthase gene affected the increase in renal renin content observed during dietary sodium restriction. The influence of cyclooxygenase-2 on renal renin content through a macula densa-mediated pathway was studied using a selective cyclooxygenase-2 inhibitor, NS398, in 129/SvEv mice. A low-sodium diet increased renal renin content from 6.97 +/- 0.52 to 11.59 +/- 0.79 micro gram angiotensin I/mg dry weight (P < .005); but this increase was blocked by NS398. In addition, treatment with NS398 reduced renin mRNA in response to a low-sodium diet. Thus, increased renal renin content in response to dietary sodium restriction appears to require the induction of cyclooxygenase-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renin content. (Hypertension. 1997;29[part 2]:297-302.)