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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: azou{at}mcw.edu.
A membrane-permeable superoxide dismutase (SOD) mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL) has been used as an antioxidant to prevent hypertension. However, we recently found that this SOD mimetic could not prevent the development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid (DETC), unless catalase was co-administrated in the renal medulla. Since TEMPOL dismutes superoxide (O2.-) to produce H2O2, it is possible that increased H2O2 counteracts the effects of TEMPOL on renal medullary blood flow (MBF) and sodium excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic during exaggerated oxidative stress in the kidney. The present study was designed to test this hypothesis. By in vivo microdialysis and AmplexTM Red H2O2 microassay, it was found that interstitial H2O2 levels in the renal cortex and medulla in anesthetized rats averaged 55.91 ± 3.66 and 102.18 ± 5.16 nM, respectively. Renal medullary interstitial infusion (R.I.) of TEMPOL (30 µmol/min/kg) significantly increased medullary H2O2 levels by 46%, which was completely abolished by co-infusion of catalase (10 mg/min/kg). Functionally, the removal of H2O2 by catalase enhanced TEMPOL-induced increase in MBF, urine flow (UV) and UNaV by 28%, 41% and 30%, respectively. This suggests that H2O2 may produce renal medullary vasoconstriction and decrease water and sodium excretion. Indeed, direct delivery of H2O2 (7.5-30 nmol/min/kg, R.I.) into the renal medulla significantly decreased renal MBF, UV and UNaV, and catalase reversed the effects of H2O2. We conclude that TEMPOL produces renal medullary vasodilator effect and results in diuresis and natriuresis. However, this SOD mimetic increases the formation of H2O2, which constricts medullary vessels and thereby counteracts its vasodilator actions. This counteracting effect of H2O2 may plague the use of TEMPOL as an antihypertensive agent under exaggerated oxidative stress in the kidney.
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