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432 RENAL AND SYSTEMIC RESPONSES TO NITRIC OXIDE BLOCKADE IN GP91PHOX KNOCKOUT MICE
  1. M. Z. Haque,
  2. A. Castillo,
  3. D. S.A. Majid
  1. Tulane Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center

Abstract

An interactive role of nitric oxide (NO) and superoxide (O2-) in the regulation of renal function has been suggested in recent studies. NAD(P)H oxidase is known to be a major source of O2- production in the kidney. To understand further this NO-O2- interaction in the kidney, we have assessed the renal responses to systemic administration of NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME; 0.2 μg/min/g BW) in inactin anesthetized knockout (KO, n = 8) mice, deficient of gene for gp91phox and compared these responses to that in wild-type (WT, C57BL/6, n = 7) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by PAH and inulin clearances respectively. Baseline mean arterial blood pressure (BP) recorded from a carotid arterial cannula was not different between KO (91 ± 4 mm Hg) and WT mice (92 ± 6 mm Hg). Basal RBF was higher in KO compared to WT (5.4 ± 0.5 vs. 4.3 ± 0.3 mL.min-1.g-1, p < .05). However, basal levels of renal vascular resistance (RVR, 18.5 ± 2.5 and 22.2 ± 1.8 mm Hg.mL-1.min-1.g-1), GFR (0.56 ± 0.06 and 0.64 ± 0.06 mL.min-1.g-1), urine flow (V, 6.9 ± 1.5 and 9.5 ± 2.2 μL.min-1.g-1) and sodium excretion (UNaV, 0.67 ± 0.1 and 0.84 ± 0.3 μmoL.min-1.g-1) were not significantly different between KO and WT mice respectively. In WT mice, L-NAME infusion for 60 minutes resulted in a reduction of 17 ± 4 % in RBF and an increase of 55 ± 9% in RVR. Interestingly, L-NAME caused less reduction in RBF (10 ± 3%) and less increases in RVR 34 ± 6% in KO mice compared to WT. There were no changes in GFR during L-NAME infusion in both the KO (0.56 ± 0.06 mL.min-1.g-1) and in WT (0.69 ± 0.08 mL.min-1.g-1) mice. Systemic infusion of L-NAME also caused increases in BP (109 ± 5 and 115 ± 4 mm Hg), V (21 ± 4 and 30 ± 5 μL.min-1.g-1) and UNaV (4.0 ± 0.8 and 5.5 ± 1.0 μmoL.min-1.g-1) in KO and WT mice respectively. Although the excretory responses to L-NAME were generally lower in KO mice compared to WT mice, but these changes were not significantly different. L-NAME increased urinary excretion of 8-isoprostane in WT (4.7 ± 0.7 to 8.7 ± 1.2 pg/min/g, p < .05) but not in KO mice (4.8 ± 0.6 to 5 ± 0.4 pg/min/g) indicating increased O2- activity in WT mice during NO blockade. These data further support the notion that renal responses to NO blockade are influenced by enhancement of O2- activity induced by NAD(P)H oxidase.

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