(Hypertension. 2001;37:547.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Production and Actions of Superoxide in the Renal Medulla
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
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Abstract |
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The present study characterized the biochemical pathways responsible for superoxide (O2-·) production in different regions of the rat kidney and determined the role of O2-·in the control of renal medullary blood flow (MBF) and renal function. By use of dihydroethidium/DNA fluorescence spectrometry with microtiter plates, the production of O2-· was monitored when tissue homogenate from different kidney regions was incubated with substrates for the major O2-·-producing enzymes, such as NADH/NADPH oxidase, xanthine oxidase, and mitochondrial respiratory chain enzymes. The production of O2-· via NADH oxidase was greater (P<0.05) in the renal cortex and outer medulla (OM) than in the papilla. The mitochondrial enzyme activity for O2-·production was higher (P<0.05) in the OM than in the cortex and papilla. Compared with NADH oxidase and mitochondrial enzymes, xanthine oxidase and NADPH oxidase produced much less O2-· in the kidney under this condition. Overall, the renal OM exhibited the greatest enzyme activities for O2-·production. In anesthetized rats, renal medullary interstitial infusion of a superoxide dismutase inhibitor, diethyldithiocarbamate, markedly decreased renal MBF and sodium excretion. Diethyldithiocarbamate (5 mg/kg per minute by renal medullary interstitial infusion [RI]) reduced the renal medullary laser-Doppler flow signal from 0.6±0.04 to 0.4±0.03 V, a reduction of 33%, and both urine flow and sodium excretion decreased by 49%. In contrast, a membrane-permeable superoxide dismutase mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL, 30 µmol/kg per minute RI) increased MBF and sodium excretion by 34% and 69%, respectively. These effects of TEMPOL on renal MBF and sodium excretion were not altered by pretreatment with NG-nitro-L-arginine methyl ester (10 µg/kg per minute RI). We conclude that (1) renal medullary O2-· is primarily produced in the renal OM; (2) both NADH oxidase and mitochondrial enzymes are responsible for the O2-·production in this kidney region; and (3) O2-· exerts a tonic regulatory action on renal MBF.
Key Words: free radicals • oxygen • hemodynamics, renal • kidney
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Introduction |
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In contrast to the conventional idea that reactive oxygen species (ROS) are of only pathological consequence, recent studies have indicated that under physiological conditions, low concentrations of ROS play an important role in the normal regulation of cell and organ function.1 2 3 4 Redox-mediated signaling is emerging as a fundamental regulatory mechanism in cell biology and physiology.2 4 In this regard, ROS have been reported to participate in the control of vascular tone, and the interaction of superoxide (O2-·) and NO has been considered as one of the important mechanisms regulating cardiovascular function.1 2 4 5 It has been demonstrated that O2-·inactivates the endothelium-dependent relaxing factor, thereby reducing the arteriolar dilation to acetylcholine or other endothelium-dependent vasodilators6 and that endothelial superoxide dismutase (SOD) activity significantly increased the half-life of the endothelium-dependent relaxing factor produced by acetylcholine.5 Recent studies have provided direct evidence that inactivation of SOD activity with diethyldithiocarbamate (DETC) selectively inhibits NO-induced vasorelaxation in coronary arteries.7 These results have indicated that the production or scavenging of O2-· may profoundly affect the level and activity of NO in the vascular wall. This interaction of NO and O2-·is of importance in the regulation of endothelial function and thereby the control of vascular tone.2 4
There is accumulating evidence indicating that oxidant stress critically contributes to the pathogenesis of hypertension and its related vascular disease.2 8 9 10 The first evidence that O2-·may play an important role in hypertension was provided by experiments demonstrating that an acute increase in arterial blood pressure markedly increased O2-·production in arterioles. Increase in O2-· may impair endothelial function and set a stage for increased reactivity to vasoconstrictor stimuli, resulting in the development of hypertension.3 4 Recent studies have demonstrated that increased ROS importantly participate in the development of hypertension in different animal models. In angiotensin II–induced hypertension, NADH/NADPH oxidase, which is primarily responsible for O2-·production under physiological conditions, was activated in the arterial wall.11 12 13 Increased O2-·production may contribute to remodeling of the vascular wall and an increase in peripheral resistance, resulting in hypertension.2 11 12 13 In spontaneously hypertensive rats, O2-·production was found to be increased in different arterioles, and administration of SOD or a chemical SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL), lowered arterial pressure in these hypertensive rats.1 8 14 Moreover, high salt intake significantly increased xanthine oxidase (XO)-mediated ROS production in response to high salt intake in Dahl salt-sensitive rats but not in Dahl salt-resistant rats. Treatment of Dahl S rats with ROS scavengers prevented hypertension.15 16 17 Taken together, these findings indicate that ROS play an important role in the development of hypertension.
Despite a considerable amount of data indicating the role of ROS in the development of hypertension, the mechanisms by which ROS participate in the long-term control of arterial blood pressure remain to be clarified. Given the central role of the kidney and, in particular, renal medullary blood flow (MBF) in the long-term control of arterial blood pressure,18 19 20 we hypothesized that increased oxidant stress or an impaired antioxidant mechanism in the renal medulla may lead to reduction of renal MBF and sodium excretion and hypertension. The present study was designed to determine O2-·production through different pathways in the renal medulla by fluorescence spectrometric analysis and to examine the role of O2-·in the control of renal MBF and water/sodium excretion.
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Methods |
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Preparation of the Homogenate From Renal Tissues
The dissected cortical, outer medullary, and papillary tissues were homogenized with a glass homogenizer in ice-cold HEPES buffer containing (mmol/L) sodium HEPES 25, EDTA 1, and phenylmethylsulfonyl fluoride 0.1. After centrifugation of the homogenate at 6000g for 5 minutes at 4°C, the supernatant containing membrane and cytosolic components, termed homogenate, was separated into aliquots, frozen in liquid N2, and stored at -80°C until use.
Fluorescence Spectrometric Assay of
O2-·Production
Fluorescence spectrometry of tissue
O2-·production was performed by using a modification
of methods described by Benov et
al21 and Mohazzab et
al.7 Briefly, the fluorogenic
oxidation of dihydroethidine to ethidium (Eth) was used as a measure of
O2-·. Tissue
homogenates (20 µg) freshly prepared from the different
kidney regions were incubated with dihydroethidium (DHE, 10 µmol/L),
salmon testes DNA (0.5 mg/mL) and the corresponding substrate for
NADH/NADPH oxidase, mitochondrial respiratory enzymes, or XO in a
microtiter plate at 37°C for 30 minutes, and Eth-DNA
fluorescence was measured at an excitation of 475 nm and an
emission of 610 nm by using a BLJ-fluorescence microplate
reader (Beckman). NADH or NADPH oxidase activity to produce
O2-· was examined
by the addition of NADH (0.1 mmol/L) or NADPH (0.1 mmol/L) as
a substrate in the reaction mixture. Succinate (5 mmol/L) was used
as a substrate for intramitochondrial
O2-·production, and antimycin (80 µmol/L) was used
to block the normal reaction in the respiratory chain. It has
been demonstrated that the incomplete hydrolysis of the substrates in
the respiratory chain produces a large amount of
O2-·. Under
normal conditions, respiratory chain enzymes use their substrates, such
as NADH or succinate, to produce ATP rather than
O2-·.22 23
Xanthine (0.1 mmol/L) was used as a substrate of XO. Salmon DNA
(0.5 mg/mL) was added to bind to Eth and consequently stabilize Eth
fluorescence, thereby increasing the sensitivity of
O2-· measurement
(>40-fold).3 22 23
The enzyme activity of different pathways was presented as
fluorescence units per minute per milligram tissue
homogenate.
Animal Preparation for Renal Medullary
Flowmetry
Male Sprague-Dawley rats weighing between 250 and
300 g were fasted overnight but allowed free access to water. They
were anesthetized with ketamine (30 mg/kg body wt IM)
and thiobutabarbital (Inactin, 50 mg/kg body wt IP) and placed
on a thermostatically controlled warming table to maintain body
temperature at 37°C. After tracheotomy, cannulas were placed in the
right femoral vein and artery for intravenous infusions and
measurements of arterial pressure. An abdominal incision
was made, and the left kidney was placed in a stainless-steel cup to
stabilize the organ for implantation of optical fibers to measure MBF
and cortical blood flow (CBF) as previously
described.24 25 For
renal medullary interstitial infusion of drugs, a
polyethylene catheter was implanted into the renal medulla. After
implantations, a 0.9% NaCl solution was infused continuously at a rate
of 0.6 mL/h to maintain the patency of interstitial
infusion. The animals received an intravenous infusion of
2% BSA in a 0.9% sodium chloride solution at a rate of 1 mL/100 g per
hour throughout the experiment to replace fluid losses and maintain a
stable hematocrit of
43±3%.24
Laser-Doppler Flowmetry of CBF and
MBF
Sprague-Dawley rats (250 to 300 g) were
anesthetized and surgically prepared as described above.
Laser-Doppler flowmeters (model Pf3, PERIMED) were used to
simultaneously determine the changes in CBF and MBF.
Optical fibers were implanted, and laser-Doppler flow (LDF) signals
were measured as we described
previously.25 Mean
arterial pressure, CBF, and MBF were continuously monitored
before and after renal medullary interstitial infusion of
the SOD inhibitor DETC (0.5, 1, and 5 mg/min per kilogram
body weight) or the SOD mimetic TEMPOL (30 µmol/min per kilogram body
weight). Inasmuch as DETC has been reported to have a short half-life
in vivo of 5 to 20
minutes,26 continuous renal
medullary interstitial infusion was used to examine the
effect of SOD inhibition on renal MBF and renal function. Doses of DETC
chosen for the present study were the doses shown to produce 80%
to 100% inhibition of SOD activity in previous
studies.27 The dose of TEMPOL
used in our experiments has been reported to induce
NG-nitro-L-arginine
methyl ester (L-NAME)–blockable reduction of arterial
pressure.14 A single dose of
TEMPOL was used because its action duration is relatively long, as has
been reported previously.14
To determine the effect of NO synthase (NOS) inhibition on the response
of MBF to TEMPOL, L-NAME (10 µg/kg per minute, a dose that blocked
acetylcholine-induced increase in
MBF28 ) was infused into the
renal medullary interstitial space for 1.5 hours, and then
TEMPOL was infused. In these experiments, all compounds were infused
into the renal medullary interstitial space to confine
their effects in the renal medulla and limit systemic effects.
Throughout the infusion of all these compounds, mean
arterial pressure, CBF, and MBF were
monitored.
Effect of SOD Inhibitor or Mimetic
on Renal Sodium and Water Excretion
The rats were surgically prepared as described above.
After surgery and a 1-hour equilibration period, urine was collected
from both the left and right kidneys during two 20-minute control
periods. DETC, TEMPOL, and L-NAME were infused as described above.
Fifteen minutes after starting the infusion of these drugs, 2 or 3
twenty-minute urine samples were collected. Urine flow rate was
determined gravimetrically. Sodium and potassium concentrations of
urine and plasma samples were measured by use of a flame photometer.
Urinary excretion data and renal blood flows were all factored per gram
kidney
weight.25
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Results |
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Determination of a Concentration-Dependent Eth Fluorescence and Superoxide-Induced Oxidation of DHE
As shown in Figure 1A, a linear relationship between fluorescence intensity and Eth concentrations was observed at a wave length of 475 nm for excitation and 610 nm for emission in the presence of salmon DNA. The minimal detectable concentration was 2 nmol/L. By use of xanthine and purified XO as an O2-·-producing system, DHE was oxidized into Eth. Eth fluorescence intensity converted from DHE was xanthine/XO concentration dependent. However, the NO donor nonoate did not oxidize DHE into Eth; thus, there was no fluorescence detected when nonoate was added into the assay system even at a high concentration (1 mmol/L) (Figure 1B).
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Production of
O2-· Through
Different Pathways in the Renal Cortex, OM, and IM
The results of these experiments are presented
in
Figure 2. When the tissue homogenates from the
renal cortex, outer medulla (OM), and inner medulla (IM) were incubated
with NADH and succinate acid, which are substrates for NADH oxidase and
mitochondrial respiratory chain enzymes, respectively, the formation of
O2-· was detected
in the reaction mixtures from all 3 kidney regions (n=6 rats). The
renal cortex and OM exhibited greater NADH oxidase activity than did
the IM. Intramitochondrial enzyme activity for
O2-·production was higher in the OM than in the
cortex and IM. Compared with NADH and succinate acid, the addition of
xanthine and NADPH as substrates produced much less
O2-· in the
kidney tissue homogenate. Overall, the renal OM exhibited
greatest enzyme activities for
O2-·production.
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Effect of Renal Medullary
Interstitial Infusion of SOD Inhibitor (DETC)
on CBF and MBF
The results of these experiments are presented
in
Figure 3A. Renal medullary infusion of the SOD
inhibitor DETC (0.5 to 5 mg/kg per minute) produced a
concentration-dependent decrease in renal MBF, but it had no effect on
CBF (n=6). The renal medullary LDF signal was decreased from 0.6±0.04
to 0.4±0.03 V, a 33% reduction when DETC (5 mg/kg per minute) was
infused into the renal medullary interstitium. During a 1-hour
postcontrol period, MBF slowly returned but remained significantly
lower than the control value at the end of 60 minutes. Renal medullary
infusion of DETC had no effect on mean arterial pressure
and CBF even at the highest dose (5 mg/kg per minute) examined in the
present study.
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Effect of Renal Medullary
Interstitial Infusion of SOD Inhibitor (DETC)
on Renal Water and Sodium Excretion
As depicted in
Figure 3B, renal medullary interstitial infusion
of DETC significantly reduced urine flow and sodium excretion (n=6).
DETC at the highest dose studied (5 mg/kg per minute) reduced urine
flow and sodium excretion by 49% and 48%, respectively. Potassium
excretion was slightly decreased during renal medullary
interstitial infusion of DETC at 5 mg/kg per
minute.
Effect of Renal Medullary
Interstitial Infusion of SOD Mimetic (TEMPOL) on CBF and
MBF in Absence and Presence of L-NAME
Figure 4A presents the effects of renal medullary
interstitial infusion of TEMPOL on CBF and MBF. TEMPOL
produced a time-dependent increase in renal MBF, but it had no effect
on CBF. During a 1-hour infusion, the renal medullary LDF signal
increased to 0.82±0.04 V from a control level of 0.61±0.04 V, an
increase of 34% (n=6). Renal medullary interstitial
infusion of the NOS inhibitor L-NAME at a dose of 10
µg/kg per minute significantly decreased renal MBF with a 30%
decrease in renal medullary LDF signal during 1.5 hours of infusion. In
the presence of L-NAME, TEMPOL still increased the renal medullary LDF
signal from 0.41±0.03 to 0.65±0.04 V (n=6). Under this condition, the
renal cortical LDF signal was not significantly altered by
TEMPOL.
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Effect of Renal Medullary
Interstitial Infusion of SOD Mimetic (TEMPOL) on Water and
Sodium Excretion in Absence and Presence of L-NAME
The results of these experiments are presented
in
Figure 4B. Renal medullary interstitial infusion
of TEMPOL for 60 minutes increased the urine flow from 16±0.8 to 29±2
µL/min per gram kidney weight and renal sodium excretion from
1.6±0.3 to 2.7±0.6 µmol/min per gram kidney weight, which
represented an 81% increase in urine flow and a 69%
increase in sodium excretion (n=6). TEMPOL was without effect on
potassium excretion. In the presence of L-NAME in the renal medulla,
TEMPOL still produced increases in urine flow and sodium excretion that
were comparable to those observed in the absence of
L-NAME.
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Discussion |
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The present study detected O2-·production in renal cortical and medullary tissues in the presence of different substrates for O2-· -producing enzymes by use of fluorescence spectrometry. This assay was based on the fluorogenic oxidation of DHE to Eth as a measure of O2-· and modified by the addition of salmon DNA in the assay mixture as a fluorescence enhancer. By use of a microtiter plate reader, this Eth-DNA fluorescence measurement can detect a minimal Eth con- centration of 2 nmol/L. Before application of this assay to measure O2-·production in the renal tissues, a classic O2-·-producing system, xanthine and purified XO, was used to determine the sensitivity and specificity of O2-·-dependent fluorogenic conversion of DHE to Eth. After the addition of xanthine and XO into the assay mixture containing DHE and salmon DNA, an enzyme activity–dependent increase in Eth-DNA fluorescence intensity was observed. However, the addition of another well-known free radical, NO (nonoate), did not cause fluorogenic oxidation of DHE. These results suggest that the Eth-DNA fluorescence is dependent on the formation of O2-·in this assay mixture, which is suitable for the determination of enzyme activity for O2-·production.
There have been a number of approaches used in an effort to determine O2-·production in tissues or cells. In early studies, ferricytochrome c was used to quantify O2-· in in vitro experiments, because it can be reduced by O2-·.29 30 However, this protein was found to react not only with O2-· but also with other compounds with reducing activity. Moreover, it can serve as a substrate for cytochrome c reductase and cytochrome c oxidase.29 30 31 Therefore, the nonspecificity of this ferricytochrome c–based assay plagued its usefulness in the measurement of O2-·. Electron paramagnetic resonance and mass spectrometry were also used for the measurement of O2-·. These methods require expensive equipment and a large sample volume for assays.32 33 Many studies used lucigenin-enhanced chemiluminescence to estimate O2-·production in cultured cells, tissue homogenate, and intact vascular tissue.34 35 36 More recently, however, it was found that lucigenin can be auto-oxidized to produce O2-·during assay, which led to inaccurate and artifactual overestimation of the rates of tissue O2-·production.31 37 These properties of lucigenin limited its use in most tissues or cells with low rates of O2-·production.
Fluorescence spectrometric assay by oxidation of DHE has been extensively used for the measurement of intracellular O2-· concentration or enzyme activity for O2-·production in intact cells and vessels, because DHE easily enters into cells and produces fluorescence by the oxidation of O2-·only, not O2, H2O2, and other free radicals.22 23 In addition, Eth formed by oxidation of DHE can bind to DNA, which enhances fluorescence intensity by >40-fold. Therefore, this method is the most sensitive assay suitable for the measurement of intracellular O2-·.23 Recently, this fluorescence assay of O2-· was extended to quantify O2-·concentrations in solutions. However, it was found that when a large amount of free O2-· or Eth is accumulated in the reaction mixtures, a chemical dismutation of O2-· can be activated. This may lead to an underestimation of O2-·concentration or production.21 In the present study, salmon DNA was added into the assay mixtures to bind Eth, which increased the sensitivity of this assay and decreased the accumulation of free Eth in the assay mixture. We did not observe decreased Eth-DNA formation due to chemical dismutation even at 80 mU purified XO, an XO concentration that can produce 150 µmol/L O2-· by calculation,22 suggesting that this fluorescence assay can be used to accurately measure O2-·, at least at this concentration range.
By use of this fluorescence spectrometry, O2-·production was detected in the renal cortical and medullary homogenates. It was found that the activity of NADH oxidase in the renal cortex was similar to that in the outer medulla and was much higher than that in the renal papilla. Mitochondrial respiratory chain enzymes to produce O2-· were mostly active in the outer medulla, among the 3 kidney regions. NADPH oxidase and XO expressed relatively less activity to produce O2-· in all kidney regions compared with NADH oxidase and mitochondrial enzyme–mediated O2-·production. These results suggest that under physiological conditions, O2-· in the kidney may be produced primarily by NADH oxidase and the mitochondrial enzyme system. In arterial tissues or cells, NADH oxidase has been indicated as a major enzyme responsible for O2-·production, which may contribute to endothelial dysfunction and remodeling of the vascular wall in hypertension.2 10 13 Our findings indicate that both NADH oxidase and mitochondrial enzymes may represent the major resource of O2-·production in the kidney. A recent study has demonstrated that XO activity can be detected in the rat kidney and increased in response to high salt intake in Dahl salt-sensitive rats. However, the activity of other enzymes responsible for O2-·production was not determined in those studies.15
With respect to the regional distribution of NADH oxidase and the mitochondrial enzyme system for O2-·production in the kidney, we found that overall, the renal outer medulla exhibited a greater capability for producing O2-· than did the renal cortex and IM (papilla). Both NADH oxidase and the mitochondrial enzyme system exhibited great activity to produce O2-· in this kidney region. It is indicated that renal medullary O2-· may be derived primarily from NADH oxidase and mitochondrial enzyme systems. Inasmuch as both enzymes were found to produce more O2-· in response to tissue hypoxia,22 23 a low PO2 milieu in the renal medulla38 may activate these enzymes to produce a large amount of O2-·, resulting in increased oxidant stress in this kidney region even under physiological conditions.
To determine the physiological significance of endogenously produced O2-· in the renal medulla, we examined the effect of renal medullary infusion of the SOD inhibitor DETC on renal MBF and water and sodium excretion. DETC markedly reduced renal MBF and urinary water and sodium excretion. These results indicate that endogenously produced O2-· in the renal medulla is largely scavenged by SOD and that O2-· produces vasoconstriction in this kidney region. In contrast, renal medullary interstitial infusion of a SOD mimetic, TEMPOL, significantly increased renal MBF and renal sodium excretion, further suggesting that O2-·is vasoconstrictive and antinatriuretic. Because a TEMPOL-induced increase in renal MBF was observed in the presence of an intact SOD system in the renal medulla, this TEMPOL-induced effect should be related to the scavenging of local free O2-·. It seems that this free O2-·participates in the control of renal MBF and renal function. These results support the view that free O2-· is present and working in normal kidney tissues even with the ubiquity of scavenging systems.1 2 3
There is a large body of evidence indicating that O2-· interacts with NO in the endothelium and thereby results in vasoconstriction because of a decrease in NO-mediated vasodilation.2 5 6 Recently, Schnackenberg et al14 reported that a SOD mimetic, TEMPOL, significantly reduced arterial blood pressure in spontaneously hypertensive rats, and blockade of NOS by intravenous L-NAME abolished the TEMPOL-induced decrease in arterial blood pressure, indicating that the antihypertensive or vasodilatory effect of TEMPOL depends on its action to scavenge O2-·and unmask NO-induced vasodilation. When this interaction of NO and O2-· in the renal medulla is taken into consideration, it is possible that the TEMPOL-induced increase in renal MBF and sodium excretion was the consequence of increased NO concentrations resulting from the scavenging of O2-·. To test this hypothesis, we examined the effects of TEMPOL after the inhibition of NOS by renal medullary infusion of L-NAME. Unexpectedly, in the presence of L-NAME, TEMPOL still significantly increased renal MBF and sodium excretion, suggesting that the increase in NO due to the scavenging of a small amount of O2-· in the renal medulla does not contribute to TEMPOL-induced vasodilation. Other mechanisms may be involved in the effect of scavenging free O2-· by TEMPOL on renal MBF. It has been demonstrated that O2-· may directly increase intracellular calcium concentrations of vascular smooth muscle cells and thereby produce vasoconstriction.1 Scavenging O2-· may reduce intracellular calcium concentrations and result in vasodilation. Moreover, O2-·has been demonstrated to inhibit the production of prostaglandin I2,4 39 which is another potent vasodilator paracrine. In the renal medullary vessels, an increase in prostaglandin I2 by scavenging O2-· may be an important mechanism, resulting in TEMPOL-induced vasodilation. More experiments are needed to further explore the mechanism by which O2-· produces vasoconstriction in the renal medullary circulation.
In summary, the present study has demonstrated that both NADH oxidase and the mitochondrial enzyme system are primarily responsible for O2-·production in the renal medulla and that the renal OM is a major region for O2-·production in the renal medulla. Inhibition of SOD activity reduced renal MBF and water/sodium excretion, whereas scavenging of O2-·by TEMPOL increased renal MBF and water/sodium excretion. These results indicate that endogenously produced O2-· participates in the control of renal MBF and water/sodium excretion.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-29587 and DK-54927.
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Footnotes |
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Reprint requests to Ai-Ping Zou, MD, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Received October 25, 2000; first decision December 8, 2000; accepted December 15, 2000.
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