Defective fluid and HCO(3)(-) absorption in proximal tubule of neuronal nitric oxide synthase-knockout mice.
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 HCO(3)(-) 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 HCO(3)(-) (49%) in the proximal tubule. In nNOS-knockout mice, the urinary excretion of HCO(3)(-) was significantly higher than in the wild-type mice (3.12 +/- 0.52 vs. 1. 40 +/- 0.33 mM) and the rates of HCO(3)(-) and fluid absorption were 62 and 72% lower, respectively. Both arterial blood HCO(3)(-) 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 HCO(3)(-) and fluid absorption in the proximal tubule is controlled by nNOS. Mice without this isozyme are defective in absorption of fluid and HCO(3)(-) in the proximal tubule and develop metabolic acidosis, suggesting that nNOS plays an important role in the regulation of acid-base balance.
Wang
T
T
Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Inglis
F M
FM
Kalb
R G
RG
D000136:Acid-Base Equilibrium / Q000235:genetics*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001784:Blood Gas Analysis; D001826:Body Fluids / Q000378:metabolism*; D004573:Electrolytes / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007275:Injections, Intravenous; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine
D001639:Bicarbonates; D004573:Electrolytes; D004791:Enzyme Inhibitors; D012964:Sodium; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester