Increased H2O2 counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla
Increased H2O2 counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla
复制标题
DOI：
10.1152/ajpregu.00636.2002
复制
发表时间：
2003-10-01
影响因子：
2.8
通讯作者：
Zou, AP
中科院分区：
文献类型：
--
作者：
Chen, YF;Cowley, AW;Zou, AP
一种膜渗透性超氧化物歧化酶模拟物，4-羟基四甲基哌啶-1-氧（tempol），已被用作抗氧化剂来预防高血压。我们最近发现，这种SOD模拟物不能阻止二乙基二硫代氨基甲酸抑制肾髓质SOD引起的高血压的发展。本研究验证了一种假设，即H2O2的增加抵消了tempol对肾髓血流量（MBF）和Na+排泄（UNaV）的影响，从而抑制了这种SOD模拟物的降压作用。通过体内微透析和Amplex red H2O2微量测定，麻醉大鼠肾皮质和肾髓质间质H2O2水平平均分别为55.91 +/- 3.66和102.18 +/- 5.16 nM。肾髓质间质灌注tempol (30 mol.min)（-1）。kg(-1))显著提高髓质H2O2水平46%，过氧化氢酶共输注（10 mg.min(-1)）。Kg(-1))完全抵消了这种增长。在功能上，过氧化氢酶去除H2O2使MBF、尿流量和UNaV分别增加了28%、41%和30%。通过肾髓质间质输注直接输送H2O2 （7.5-30 nmol.min）。kg(-1))显著降低肾MBF、尿流量和UNaV，过氧化氢酶逆转H2O2的作用。我们的结论是，丹酚产生肾髓血管扩张作用，导致利尿和尿钠。然而，这种SOD模拟物增加H2O2的形成，使髓质血管收缩，从而抵消其血管舒张作用。H2O2的这种抵消作用可能会限制tempol在肾脏过度氧化应激下作为降压药的使用。
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 mumol.min(-1).kg(-1)) significantly increased medullary H2O2 levels by 46%, and coinfusion of catalase (10 mg.min(-1).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.min(-1).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.