Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide.
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.
Hasdan
Galit
G
Department of Nephrology and Hypertension, Sapir Medical Center, Kfar Saba and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Benchetrit
Sydney
S
Rashid
Gloria
G
Green
Janice
J
Bernheim
Jacques
J
Rathaus
Mauro
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism*; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D013113:Spin Labels; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D000109:Acetylcholine; C001803:tempol