title: Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91phox subunit of NAD(P)H oxidase.
abstract: Both short-term and long-term nitric oxide (NO) blockade were shown to cause an increase in O(2)(-) activity. To assess the contribution of such enhanced O(2)(-) activity in the kidney, responses to administration of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 200 microg.min(-1).kg body wt(-1)) were assessed in knockout mice the lacking NAD(P)H oxidase subunit gp91(phox) (KO; n = 10) and in wild-type (WT; n = 10) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances, respectively. Baseline RBF was higher in KO compared with WT mice (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 min 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 with WT mice (-7 +/- 3 vs. -17 +/- 3%; P < 0.02), although GFR remained unchanged in both groups. The natriuretic response to systemic L-NAME infusion was attenuated in KO compared with WT mice (Delta: 3.1 +/- 0.7 vs. 5.2 +/- 0.6 micromol.min(-1).g(-1)). L-NAME increased urinary 8-isoprostane excretion rate in WT (5.9 +/- 1 to 7.7 +/- 1 pg.min(-1).g(-1); P < 0.02) but not in KO mice (5.6 +/- 1 to 4.9 +/- 0.3 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 O(2)(-) activity that influences renal hemodynamics and excretory function in the condition of NO deficiency.
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, USA.
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Haque
authors.forename: Dewan S A
authors.initials: DS
authors.lastname: Majid
mesh_terms: D000818:Animals; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D012079:Renal Circulation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D014662:Vasoconstrictor Agents; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine