Defective fluid and HCO3- absorption in proximal tubule of neuronal nitricoxide synthase-knockout mice

Using renal clearance techniques and in situ microperfusion of proximal tub ules, we examined the effects of N-G-monomethyl-L-arginine methyl ester (L- NAME) on fluid and HCO3- transport in wild-type mice and also investigated proximal tubule transport in neuronal nitric oxide synthase (nNOS)-knockout mice. In wild-type mice, administration of L-NAME (3 mg/kg bolus iv) signi ficantly increased mean blood pressure, urine volume, and urinary Na+ excre tion. L-NAME, given by intravenous bolus and added to the luminal perfusion solution, decreased absorption of fluid (60%) and HCO3- (49%) in the proxi mal tubule. In nNOS-knockout mice, the urinary excretion of HCO3- was signi ficantly higher than in the wild-type mice (3.12 +/- 0.52 vs. 1.40 +/- 0.33 mM) and the rates of HCO3- and fluid absorption were 62 and 72% lower, res pectively. Both arterial blood HCO3- concentration (20.7 vs. 25.7 mM) and b lood pH (7.27 vs. 7.34) were lower, indicating a significant metabolic acid osis in nNOS-knockout mice. Blood pressure was lower in nNOS-knockout mice (76.2 +/- 4.6 mmHg) than in wild-type control animals (102.9 +/- 8.4 mmHg); however, it increased in response to L-NAME (125.5 +/- 5.07 mmHg). Plasma Na+ and K+ were not significantly different from control values. Our data s how that a large component of HCO3- and fluid absorption in the proximal tu bule is controlled by nNOS. Mice without this isozyme are defective in abso rption of fluid and HCO3- in the proximal tubule and develop metabolic acid osis, suggesting that nNOS plays an important role in the regulation of aci d-base balance.