Feedback control of glomerular vascular tone in neuronal nitric oxide synthase knockout mice

For further elucidation of the role of neuronal nitric oxide synthase (nNOS ) in macula densa (MD) cells, experiments were performed in anesthetized nN OS knockout mice (nNOS -/-). At comparable levels of arterial BP, renal blo od flow was not significantly different between nNOS+/+ and nNOS-/- (1.7 +/ - 0.2 versus 1.4 +/- 0.1 ml/min), and autoregulation of renal blood flow wa s maintained to a pressure level of approximately 85 mmHg in both groups of mice (n = 6 in each group). The fall in proximal tubular stop-flow pressur e in response to an increase in loop of Henle perfusion rate from 0 to 30 n l/min was comparable in nNOS+/+ and -/- mice (40.7 +/- 1.6 to 32 +/- 2 mmHg versus 40.6 +/- 1.6 to 31.6 +/- 2 mmHg; not significant; n = 13 versus 18 nephrons). Luminal application of the nonselective NOS inhibitor nitro-L-ar ginine (10(-3) and 10(-2) M) enhanced the perfusion-dependent fall in stop- flow pressure in nNOS +/+ (7 +/- 1 to 13 +/- 2 mmHg; P < 0.05) but not in n NOS-/- (7 +/- 1 to 8 +/- 1 mmHg; not significant) mice, nNOS-/- mice exhibi ted a lower nephron filtration rate, compared with nNOS+/+, during free-flo w collections from early distal tubules (influence of MD intact, 7 +/- 0.7 versus 10.9 +/- 1 nl/min; P = 0.002) but not from late proximal tubule (inf luence of MD minimized, 10.1 +/- 1 versus 11.7 +/- 1 nl/min; not significan t; n = 16 nephrons). Distal Cl concentration and fractional absorption of f luid or chloride up to the early distal tubule was not different between nN OS -/- and +/+ mice. The data indicate that nNOS in MD tonically attenuates the GFR-lowering influence of ambient luminal NaCl, which may serve to inc rease the fluid and electrolyte load to the distal tubule, consistent with a role of MD nNOS in tubuloglomerular feedback resetting.