title: Increased H(2)O(2) counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla.
abstract: A membrane-permeable SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (tempol), has been used as an antioxidant to prevent hypertension. We recently found that this SOD mimetic could not prevent development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid. The present study tested a hypothesis that increased H2O2 counteracts the effects of tempol on renal medullary blood flow (MBF) and Na+ excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic. By in vivo microdialysis and Amplex 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 of tempol (30 micromol x min-1x kg-1) significantly increased medullary H2O2 levels by 46%, and coinfusion of catalase (10 mg x min-1x kg-1) completely abolished this increase. Functionally, removal of H2O2 by catalase enhanced the tempol-induced increase in MBF, urine flow, and UNaV by 28, 41, and 30%, respectively. Direct delivery of H2O2 by renal medullary interstitial infusion (7.5-30 nmol x min-1x kg-1) significantly decreased renal MBF, urine flow, and UNaV, and catalase reversed the effects of H2O2. We conclude that tempol produces a 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 limit the use of tempol as an antihypertensive agent under exaggerated oxidative stress in the kidney.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Chen
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cowley
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Zou
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007679:Kidney Medulla / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D010078:Oxazines; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism*; D014556:Urine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D003497:Cyclic N-Oxides; D005609:Free Radicals; D010078:Oxazines; D016877:Oxidants; D013113:Spin Labels; C014180:resorufin; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C001803:tempol