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

Abstract

Background. 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). Methods. 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 μmol/L), with or without exogenous SOD. Plasma levels of advanced oxidative protein products (AOPPs; chloramine-T equivalents) were measured in SN and RMR rats. Results. 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 μmol/L, P = 0.05) but returned to normal by day 10. AOPP levels were not significantly reduced by tempol. Conclusions. Increased vascular superoxide production plays a central role in the development of vascular endothelial dysfunction and hypertension early after 5/6 nephrectomy.