Using renal clearance techniques and in situ microperfusion of proximal tubules, 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) significantly increased mean blood pressure, urine volume, and urinary Na+ excretion. l-NAME, given by intravenous bolus and added to the luminal perfusion solution, decreased absorption of fluid (60%) and HCO3 − (49%) in the proximal tubule. In nNOS-knockout mice, the urinary excretion of HCO3 − was significantly 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, respectively. Both arterial blood HCO3 − concentration (20.7 vs. 25.7 mM) and blood pH (7.27 vs. 7.34) were lower, indicating a significant metabolic acidosis 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 show that a large component of HCO3 − and fluid absorption in the proximal tubule is controlled by nNOS. Mice without this isozyme are defective in absorption of fluid and HCO3 − in the proximal tubule and develop metabolic acidosis, suggesting that nNOS plays an important role in the regulation of acid-base balance.
Angiotensin II Inhibits Neuronal Nitric Oxide Synthase Activation Through the ERK1/2-RSK Signaling Pathway to Modulate Central Control of Blood Pressure
