Submitted on May 5, 2008
Revised on June 23, 2008
Accepted on June 25, 2008
REDUCED RENAL RESPONSES TO NITRIC OXIDE SYNTHASE INHIBITION IN MICE LACKING THE GENE FOR GP91PHOX SUBUNIT OF NAD(P)H OXIDASE
Mohammed Z. Haque1 and Dewan S.A. Majid2*
1 Wayne State University
2 Tulane University School of Medicine
* To whom correspondence should be addressed. E-mail: majid{at}tulane.edu.
Both short-term and long-term nitric oxide (NO) blockade were shown to cause an increase in superoxide (O2-) activity. To assess the contribution of such enhanced O2- activity in the kidney, responses to administration of NO synthase inhibitor, nitro-L-arginine methyl ester, (L-NAME; 200µg.min-1.kg-1 BW) were assessed in knockout mice lacking NAD(P)H oxidase subunit Gp91phox (KO; n=8) and in wild type mice (WT; n=7). Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by para-aminohippuric acid (PAH) and inulin clearances respectively. Baseline RBF was higher in KO compared to WT (5.8±0.5 vs. 4.5±0.3 mL.min-1.g-1, P<0.04) without significant differences in GFR (0.62±0.04 vs. 0.73±0.05 mL.min-1.g-1) and in mean arterial pressure (MAP; 91 ± 6 vs. 88 ± 4 mmHg). L-NAME infusion for 60 minutes caused similar increases in MAP (114 ± 6 vs. 113 ± 3 mmHg) in both groups but resulted in a lesser degree of reduction in RBF in KO compared to WT (-7±3% vs. -17±3 %, P<0.02), though GFR remained unchanged in both groups. The natriuretic response to systemic L-NAME infusion was attenuated in KO compared to WT (
, 3.1± 0.7 vs. 5.2 ± 0.6 µmol.min-1.g-1). L-NAME increased urinary 8-isoprostane excretion rate in WT (4.7±0.7 to 8.7±1.2 pg.min-1.g-1, P<0.02) but not in KO (4.8±0.6 to 5.0±0.4 pg.min-1.g-1). In contrast, responses to another vasoconstrictor, norepinephrine, were similar in both strains of mice. These data indicate that activation of NAD(P)H oxidase results in the enhancement of O2- activity that influences renal hemodynamics and excretory function in the condition of NO deficiency.
