title: Increased renal medullary H2O2 leads to hypertension.
abstract: We have recently reported that exaggerated oxidative stress in the renal medulla due to superoxide dismutase inhibition resulted in a reduction of renal medullary blood flow and sustained hypertension. The present study tested the hypothesis that selective scavenging of O2*- in the renal medulla would prevent hypertension associated with this exaggerated oxidative stress. An indwelling, aortic catheter was implanted in nonnephrectomized Sprague-Dawley rats for daily measurement of arterial blood pressure, and a renal medullary interstitial catheter was implanted for continuous delivery of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC, 7.5 mg x kg(-1) x d(-1)) and a chemical superoxide dismutase mimetic, 4-hydroxytetramethyl piperidine-1-oxyl (TEMPOL, 10 mg. kg-1. d-1). Renal medullary interstitial infusion of TEMPOL completely blocked DETC-induced accumulation of O2*- in the renal medulla, as measured by the conversion rate of dihydroethidium to ethidium in the dialysate and by urinary excretion of 8-isoprostanes. However, TEMPOL infusion failed to prevent DETC-induced hypertension, unless catalase (5 mg x kg(-1) d(-1)) was coinfused. Direct infusion of H2O2 into the renal medulla resulted in increases of mean arterial pressure from 115+/-2.5 to 131+/-2.1 mm Hg, which was similar to that observed in rats receiving the medullary infusion of both TEMPOL and DETC. The results indicate that sufficient catalase activity in the renal medulla is a prerequisite for the antihypertensive action of TEMPOL and that accumulated H2O2 in the renal medulla associated with exaggerated oxidative stress might have a hypertensive consequence.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Skelton
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Zou
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cowley
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D002408:Catheters, Indwelling; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives*; D004050:Ditiocarb / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D028441:F2-Isoprostanes / Q000652:urine; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D016166:Free Radical Scavengers; D013113:Spin Labels; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; D004050:Ditiocarb; D015237:Dinoprost; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C001803:tempol