Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide

Abstract

Nitric oxide inactivation by superoxide impairs endothelium-dependent vasodilation and plays a role in various forms of hypertension. Almost no data exist regarding hypertension secondary to chronic renal failure. Previous studies have shown that endothelium-related relaxations, secondary to decreased nitric oxide bioactivity, are impaired in resistance vessels from rats 3 to 10 days after renal mass reduction (RMR). The membrane-permeable superoxide dismutase (SOD)-mimetic (tempol) was administered IP (1.5 mmol/kg/day for 10 days) to RMR rats and sham-operated controls (SN). Systolic blood pressure (SBP) was measured by tail cuff manometry at days 0, 3, 6 and 10. The increase of flow induced by acetylcholine (10-6 mol/L) was measured in isolated perfused mesenteric arteries from RMR and SN rats pre-contracted with noradrenaline (1 to 5 micromol/L), with or without exogenous SOD. Plasma levels of advanced oxidative protein products (AOPPs; chloramine-T equivalents) were measured in SN and RMR rats. Tempol prevented the increase of SBP: 118 +/- 2.2 mm Hg at baseline and 122 +/- 1.6 mm Hg at 10 days in tempol-treated vs 118.14 +/- 1.65 mm Hg at baseline and 145 +/- 7.69 mm Hg at 10 days in untreated RMR rats (P < 0.01). Responsiveness to acetylcholine was reduced in RMR rats (peak flow increase: 139 +/- 7.8% vs. 176 +/- 11% in SN, P=0.028 at 3 days and 140 +/- 6.4% vs. 187 +/- 16.9% in SN at 10 days, P=0.007). In arteries pre-incubated with SOD (200 U/mL) the peak flows were 175 +/- 9.4% at 3 days and 157 +/- 5.8% at 10 days (P=0.007 and P=0.051, respectively, vs. control RMR vessels). AOPP values were significantly increased in plasma from RMR rats 3 days after 5/6 nephrectomy (747 +/- 107 vs. 481 +/- 77 micromol/L, P < 0.05) but returned to normal by day 10. AOPP levels were not significantly reduced by tempol. Increased vascular superoxide production plays a central role in the development of vascular endothelial dysfunction and hypertension early after 5/6 nephrectomy.