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CARDIAC, RENAL, AND RESPIRATORY INTEGRATION
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Submitted 15 October 2002 ; accepted in final form 4 June 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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free radicals; renal hemodynamics; renal medulla; kidney; rat
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Then this cation form of tempol directly reacts with O2-· to produce O2 and regenerate tempol. In this reaction, tempol produces H2O2 with a rate constant of 107 M-1 · s-1 (20). As a catalyst, however, tempol concentrations remain constant; therefore, it will more efficiently remove O2-· than will the stoichiometric scavengers (23).
Recent studies have indicated that excessive production of reactive oxygen species contributes to the development of hypertension in different animal models (9, 27, 28). Administration of antioxidant enzymes such as SOD and catalase has been shown to prevent or treat hypertension (1, 8). However, the potential benefits of systemic administration of SOD are limited, because SOD does not permeate biological membranes and is therefore unable to remove O2-· produced intracellularly (5). To overcome these limitations, tempol, a membrane-permeable and metal-independent SOD mimetic, has been utilized as an antioxidant for the removal of intracellular and extracellular O2-·. Indeed, it has been found that arterial blood pressure could be lowered by tempol in several models of hypertension (2, 25, 27).
More recently, we reported that increased oxidative stress in the renal medulla results in a reduction of medullary blood flow (MBF) and Na+ retention, leading to hypertension (14). Given the vasodilator and natriuretic effect of tempol infused into the renal medulla and its chronic antihypertensive action in other models, we used this SOD mimetic to block the hypertension induced by enhanced renal medullary oxidative stress. However, chronic renal medullary infusion of tempol at a dose similar to that used in other animal models (50 µmol · kg-1 · day-1) failed to prevent hypertension induced by enhanced medullary oxidative stress, unless catalase was administered (14). It appears that increased H2O2 production by tempol in the renal medulla is counteracting vasodilator, natriuretic, and, ultimately, antihypertensive effects of tempol. The present study was designed to test this hypothesis. First, using Amplex red fluorescent spectrometry and microdialysis techniques, we determined tempol-induced H2O2 production in the renal medulla and the effects of the tempol-induced increase in H2O2 on renal MBF and Na+ excretion. By infusion of H2O2 in the renal medulla, we also examined the direct effects of H2O2 on the renal MBF and urinary excretion functions.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Animal preparation for microdialysis and renal medullary
flowmetry. Male Sprague-Dawley rats (250-300 g) were purchased from
Harlan Sprague Dawley (Madison, WI) and housed in the Animal Resource Center
at the Medical College of Wisconsin. The rats were fed pellet diets with
normal salt (1% NaCl), and water was provided ad libitum. To prepare for
microdialysis, the rats were anesthetized with ketamine (Ketaject; 30 mg/kg
body wt im) and thiobutabarbital (Inactin; 50 mg/kg body wt ip) and then
placed on a thermostatically controlled warming table to maintain body
temperature at 37°C. One catheter was placed in the left femoral vein for
a continuous infusion of 0.9% NaCl solution containing 2% albumin at a rate of
3.0 ml/h throughout the experiment to replace fluid loss and maintain a
constant hematocrit (
40%), which was measured during equilibration or
when blood samples were taken during the experiment. The left femoral artery
was cannulated and connected to a Statham pressure transducer for monitoring
of mean arterial pressure (MAP) throughout the experiment. The left kidney was
exposed by a midline abdominal incision and placed in a stainless steel cup
for implantation of microdialysis probes to dialyze H2O2
from the renal interstitium or for implantation of optical fibers to measure
cortical and medullary blood flows (CBF and MBF, respectively), as we
described previously (3,
33). 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 until the infusions of tempol, catalase,
and H2O2 (see protocols 1-4). Urine from the
left and right kidney was collected via a ureteral catheter. The rats were
allowed to stabilize after the surgical procedure for 1.5-2 h. Animals were
euthanized at the end of experiments with an excess intravenous dose of
pentobarbital sodium (150 mg/kg). The left kidney was excised and weighed, and
the position of the dialysis probes or laser optic fibers was confirmed. If
the probes or fibers were positioned incorrectly, the data of these dialysates
or data for blood flow signals were discarded.
Protocol 1: effects of renal medullary interstitial infusion of tempol and catalase on renal interstitial concentrations of H2O2. In vivo microdialysis was performed as we described previously (3, 31). Briefly, the left kidney of anesthetized rats was immobilized by placement of its dorsal side up in a kidney cup. A microdialysis probe (Bioanalytical Systems, West Lafayette, IN) with a 0.5-mm tip diameter, 2-mm dialysis length, and 20-kDa transmembrane diffusion cutoff was gently implanted into the renal cortex (1.5 mm deep) horizontally from the kidney pole, and another was implanted into the renal medulla (5-5.5 mm deep) vertically from the dorsal surface. The cortical probe was connected to a microinfusion pump and perfused with PBS containing (in mM) 80 NaCl, 40.5 Na2HPO4, and 9.5 NaH2PO4 (pH 7.4, 300 mosM). The medullary probe was perfused with PBS containing (in mM) 205 NaCl, 40.5 Na2HPO4, and 9.5 NaH2PO4 (pH 7.4, 550 mosM) at a rate of 2.0 µl/min throughout the experiment. The microdialysis probe was also constructed with an incorporated infusion line, which could be used for renal medullary interstitial infusion during collection of the dialysate when it was implanted into the renal medulla. After a 1.5-h equilibration period, two 30-min control dialysates from the renal cortex and medulla were collected for the analysis of basal renal interstitial H2O2 levels. Then tempol (30 µmol · min-1 · kg-1) or tempol + catalase (10 mg · min-1 · kg-1) was infused into the renal medullary interstitium for 60 min, and two additional 30-min samples of cortical and medullary dialysates were collected. Doses of tempol and catalase for renal medullary interstitial infusions were chosen on the basis of previous in vivo studies (14, 32) showing that they can effectively reduce oxidative stress. Especially, the dose of tempol was chosen to simulate its effect on H2O2 production shown in our chronic experiments (14), so that a similar increase in H2O2 levels in the renal medulla could be reached. All dialysate samples (50 µl) were reacted with fluorescence dye (Amplex red reagent) immediately at the end of each experiment, and then the fluorescence intensity was measured in Falcon 96-well microplates as described above.
Protocol 2: effects of renal medullary interstitial infusion of tempol
and catalase on MBF and renal function. The rats were anesthetized and
surgically prepared as described for protocol 1. An extruded
polyethylene interstitial catheter (100-µm tip diameter) was implanted
into the renal medulla (5 mm deep) for interstitial infusion, and laser
optical fibers (0.5-mm diameter) were implanted into the renal medulla (5-5.5
mm deep) and renal cortex (1.5 mm deep), respectively. These laser fibers were
connected to laser-Doppler flowmeter probes to record blood flow signals (red
cell capability x velocity), as we described previously
(32,
33). After control recordings,
tempol (30 µmol · min-1 · kg-1) was
infused into the renal medullary interstitium for 60 min, and MAP and cortical
and medullary laser-Doppler flow (LDF) signals were recorded throughout the
experiment. In additional groups of rats, catalase (10 mg ·
min-1 · kg-1) was infused into the renal medulla
30 min before tempol infusion and continued during tempol infusion to test
whether the effects of tempol could be blocked by catalase. In experiments to
determine whether endogenous medullary H2O2 contributes
to the control of water and Na+ excretion, urine was collected from
ureteral catheters during tempol and catalase infusions. The urine samples
over two 20-min periods from left and right kidneys were used to determine
Na+ and K+ concentrations with a flame photometer. Urine
flow rates were determined gravimetrically and used to determine electrolyte
excretion rates. Urinary excretion data and renal blood flow were factored per
gram kidney weight.
Protocol 3: effects of renal medullary interstitial infusion of H2O2 and catalase on renal interstitial concentrations of H2O2. To study the effects of exogenous H2O2 on renal blood flow and renal function, we first tested the efficiency of renal medullary infusion of H2O2 to increase its concentration. In vivo microdialysis was performed as described in protocol 1. After two 30-min control dialysates from the renal cortex and medulla were collected, increasing concentrations of H2O2 (7.5, 15, and 30 nmol · min-1 · kg-1) or H2O2 (30 nmol · min-1 · kg-1) + catalase (10 mg · min-1 · kg-1) were infused into the renal medullary interstitium for 60 min. The cortical and medullary dialysates were collected repeatedly after H2O2 or catalase treatment. The H2O2 concentrations in the dialysates were quantitated by Amplex red reagent as described above.
Protocol 4: effects of renal medullary interstitial infusion of H2O2 and catalase on MBF and renal function. The rats were surgically prepared, and optical fibers and ureters were implanted as described in protocol 2. MAP, CBF, and MBF were recorded throughout the experiment. After control recording, increasing doses of H2O2 (7.5, 15, and 30 nmol · min-1 · kg-1) were infused into the renal medullary interstitium for 60 min. Then catalase (10 mg · min-1 · kg-1) was added to the infusion solution and infused for another 60 min. During all infusion periods, MAP, CBF, and MBF were continuously recorded, and urine samples from the left and right kidneys were collected for measurement of water and Na+ excretion.
Statistics. Values are means ± SE. The significance of differences within and between groups in multiple groups of experiments was evaluated using an analysis of variance for repeated measures followed by Duncan's multiple range tests. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Effects of renal medullary interstitial infusion of tempol and catalase on renal interstitial concentrations of H2O2. Interstitial H2O2 concentrations achieved in renal cortical and medullary dialysate under control conditions and after different treatments are presented in Fig. 2. Basal H2O2 concentrations in the renal medulla averaged 102.18 ± 5.16 nM, which were significantly higher than 55.91 ± 3.66 nM in cortical dialysate. After interstitial infusion of tempol (30 µmol · min-1 · kg-1) for 60 min, H2O2 concentrations in renal medullary dialysates were significantly increased to 164.16 ± 11.22 nM, and H2O2 concentration in cortical dialysates rose to 93.04 ± 10.34 nM. In rats receiving an interstitial infusion of tempol + catalase (10 mg · min-1 · kg-1) for 60 min, H2O2 concentrations in renal cortical and medullary dialysates were reduced to levels averaging 50.58 ± 6.28 and 52.53 ± 7.86 nM, respectively. In these experiments, the increase in H2O2 levels in the renal medulla by acute infusion of 30 µmol · min-1 · kg-1 tempol was less than that found during chronic renal medullary infusion of tempol in our previous study (14).
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Effects of renal medullary interstitial infusion of tempol and catalase on MBF and renal function. The effects of renal medullary interstitial infusion of tempol and catalase on CBF and MBF are summarized in Fig. 3. In control periods, the LDF signals from the fibers implanted in the renal cortex and outer medulla averaged 1.12 ± 0.04 and 0.48 ± 0.01 V, respectively. Renal medullary interstitial infusion of tempol increased medullary LDF signals by a maximum of 42% compared with control values. In the presence of catalase, renal interstitial infusion of tempol had no effect on LDF signals in the cortical regions but significantly increased medullary flow signals by a maximum of 67%. Renal medullary infusion of catalase alone increased medullary LDF signals by 10% but had no effect on cortical LDF signals.
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The effects of renal medullary interstitial infusion of tempol and catalase on renal function are summarized in Fig. 4. Medullary infusion of tempol increased urine flow rate and Na+ excretion in infused kidney by 35 and 47%, respectively. In the presence of catalase, tempol increased urine flow rate and Na+ excretion by a maximum of 76 and 77%, respectively. Catalase alone also increased urine flow rate and Na+ excretion by 12 and 16%, respectively. In the contralateral kidneys, urine flow rate and Na+ excretion were not significantly altered during these treatments. MAP remained unchanged throughout all the above studies.
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Effects of renal medullary interstitial infusion of H2O2 and catalase on local tissue concentrations of H2O2. H2O2 concentrations in renal cortical and medullary dialysates under control conditions and after treatments are presented in Fig. 5. After medullary interstitial infusion of H2O2 at 30 nmol · min-1 · kg-1, the highest dose used in this study for 60 min, H2O2 concentration in renal medullary dialysates was significantly increased from 116.23 ± 4.02 to 210.94 ± 13.2 nM, which was similar to that found during acute (see above) and chronic tempol infusion (14). In the presence of catalase, renal medullary interstitial infusion of H2O2 (30 nmol · min-1 · kg-1) did not increase H2O2 concentration in the renal medulla, which remained at a low level (43.46 ± 7.39 nM). H2O2 concentration in the cortical dialysates was not changed during renal medullary infusion of H2O2 alone or H2O2 + catalase.
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Effects of renal medullary interstitial infusion of H2O2 and catalase on MBF and renal function. Having determined the effects of exogenous infusions of H2O2 on medullary interstitial concentrations, the effects of these elevations on renal blood flow and renal functions were examined. The results of these experiments are summarized in Fig. 6. Renal medullary interstitial infusion of H2O2 (30 nmol · min-1 · kg-1) decreased medullary LDF signals by 31%. Coinfusion of H2O2 with catalase (10 mg · min-1 · kg-1) significantly restored medullary flow signals to normal. CBF and MAP were not altered whether H2O2 was infused alone or coinfused with catalase. H2O2 at infusion rates of 7.5 and 15 nmol · min-1 · kg-1 also decreased renal MBF by 5 and 20%, respectively (data not shown).
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The effects of renal medullary interstitial infusion of H2O2 and catalase on renal excretory function are presented in Fig. 7. Medullary interstitial infusion of H2O2 at 30 nmol · min-1 · kg-1 produced a marked decrease in urine flow rate and Na+ excretion. Maximal reduction of urine flow rate and Na+ excretion was 50 and 47%, respectively. However, infusion of H2O2 into the renal medulla at 7.5 nmol · min-1 · kg-1 did not significantly alter urine flow rate and Na+ excretion (data not shown). In the presence of catalase (10 mg · min-1 · kg-1), infusion of H2O2, even at the highest dose used in the present study (30 nmol · min-1 · kg-1), had no effect on urine flow rate and Na+ excretion. In all these experiments, MAP, urine flow rate, and Na+ excretion in the contralateral kidney were not significantly altered.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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It is well known that H2O2 freely crosses biological membranes, and the rate of its production is closely related to O2-· and ·OOH (7). Therefore, the measurement of H2O2 has been often used to reflect oxidative status in the tissues or cells. In the present study, we detected H2O2 concentrations in interstitial microdialysates from the renal cortex and medulla. Because the dialysis efficiency of H2O2 across the membrane of the probe was 96% at a perfusion rate of 2 µl/min, measured H2O2 concentrations in the microdialysates largely represent its tissue concentrations in the inter-stitium. Interestingly, the basal level of H2O2 in the renal medulla was twofold higher than that in the renal cortex. This suggests that, under physiological conditions, the renal medulla is exposed to higher levels of oxidative stress than the cortex. These results are consistent with those obtained by detecting the production of O2-· (32). The present results also show that basal levels of H2O2 in the renal medulla exerted a moderate action on renal medullary basal vascular tone and renal excretory function. Reduction of basal renal medullary H2O2 levels by infusion of catalase only increased renal MBF by 10% and water and Na+ excretion by 12 and 16%, respectively.
Consistent with the findings reported previously, the present study suggests that O2-· is more importantly involved than H2O2 in the control of renal MBF and renal water and Na+ excretion. Tempol, an SOD mimetic of O2-·, increased MBF by 42% and water and Na+ excretion by 35 and 47%, respectively. In the presence of catalase, tempol-induced increases in renal MBF and renal water and Na+ excretion were markedly enhanced. The results indicate that H2O2 production by tempol may counteract the action of tempol. By microdialysis, we indeed found that tempol produced H2O2 when infused into the renal medulla and that exogenous catalase infusion blocked this tempol-induced H2O2 production. It seems that although tempol largely blocks the detrimental effects of O2-· in the renal medulla, H2O2 production during dismutation of O2-· may limit its beneficial antioxidant action. This counteracting action of H2O2 on tempol-induced renal medullary vasodilation and natriuresis may be one of the important reasons for the failure to prevent hypertension induced by exaggerated oxidative stress in the renal medulla, as reported in our previous study (14). In that study, it was found that chronic infusion of tempol into the renal medulla could not prevent the development of hypertension induced by SOD inhibition. In the presence of exogenous catalase, however, chronic infusion of tempol effectively prevented hypertension. Taken together, these results indicate that tempol as an antioxidant dilates renal medullary vessels, increases MBF, and enhances renal water and Na+ excretion, thereby producing an antihypertensive effect. These effects may represent the important therapeutic basis for the prevention or treatment of some forms of hypertension. However, because tempol produces H2O2 during dismutation of O2-·, especially when its concentrations are high in tissues such as the renal medulla because of local infusion or exaggerated oxidative stress, it may not be very effective in preventing hypertension associated with exaggerated oxidative stress.
The present findings do not imply that the antihypertensive effects of tempol observed by others in various models of hypertension were due to lack of H2O2 production. There is no doubt that tempol could react with O2-· to produce H2O2, but it seems that the hypertensive effect of H2O2 was not exhibited in those studies (2, 15, 25, 27). It is most likely that tissue H2O2 levels, especially those in the renal medulla, were probably lower in previous experiments than in the present study. First, the local delivery of tempol into the renal medulla produced high concentrations of H2O2 in this region, which counteracted its renal antihypertensive action, as shown in our chronic experiments (13). In previous studies where tempol was administered orally or intravenously, tempol could be converted to other active components through the liver or other systems, or tempol-induced H2O2 could be metabolized systemically. Second, in the present study, tempol was administrated to simulate a condition with an exaggerated local oxidative stress induced by an SOD inhibitor, diethyldithiocarbamic acid (14). Under this circumstance, large amounts of H2O2 could be produced by infusion of a high dose of tempol or achieved by direct infusion of H2O2. In previous studies, however, tempol was administered to hypertensive animals such as spontaneously hypertensive or Dahl salt-sensitive rats to simply determine whether it prevents hypertension. It is likely that the degree of renal medullary oxidative stress in those rats does not achieve the levels seen with the direct administration of SOD inhibitors. The results of the present studies, therefore, indicate that, especially in forms of hypertension with exaggerated renal oxidative stress, tempol should be used with caution.
Previous studies have reported that high levels of H2O2 are cytotoxic through its oxidant effect. It is therefore thought that H2O2 as an oxygen reactive species must be rapidly eliminated from tissues and cells. Although H2O2 was also reported to be increased in patients with hypertension, chronic renal failure, and other diseases (12), the detrimental effects of H2O2 in the kidney have not been studied. The present study examined whether H2O2 has direct effects to produce renal dysfunction. It was found that direct delivery of H2O2 into the renal medulla significantly increased the concentration of H2O2 in this kidney region and largely decreased MBF and water and Na+ excretion. These results suggest that excessive H2O2 in the renal medulla produces vasoconstriction and antinatriuresis. Given the importance of renal MBF and Na+ excretion in the development of hypertension, elevations of H2O2 in the region could contribute to medullary vasoconstriction and Na+ retention, thereby contributing to the development of hypertension.
In summary, the present study found that H2O2 was detectable in the renal tissue in vivo using microdialysis. Tempol-induced H2O2 production was found to counteract the vasodilator or natriuretic actions of this SOD mimetic. Increased H2O2 directly constricted medullary vessels and decreased Na+ excretion. We concluded that the increase of H2O2 in the renal medulla may result in the development of hypertension. Because of its H2O2-producing action, tempol must be used with caution as an antihypertensive compound in forms of hypertension with exaggerated oxidative stress.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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