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Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide
Galit Hasdan1, Sydney Benchetrit, Gloria Rashid
1Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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 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.
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 micromol/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.