Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats
Stephen Adler and
Harer Huang
New York Medical College, Department of Medicine, Division of Nephrology, Hawthorne, New York.
Correspondence to Dr. Stephen Adler, Division of Nephrology, Department of Medicine, 19 Bradhurst Avenue, Suite 0100, Hawthorne, NY 10532. Phone: 914 493-7701; Fax: 914 345-0652; E-mail: stephen{at}nymc.edu
ABSTRACT. Abnormalities of nitric oxide (NO) and oxygen radicalsynthesis and of oxygen consumption have been described in thespontaneously hypertensive rat (SHR) and may contribute to thepathogenesis of hypertension. NO plays a role in the regulationof renal oxygen consumption in normal kidney, so the responseof renal cortical oxygen consumption to stimulators of NO productionbefore and after the addition of the superoxide scavenging agenttempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) wasstudied. Baseline cortical oxygen consumption was similar inSHR and Wistar-Kyoto (WKY) rats (SHR: 600 ± 55 nmol O2/minper g, WKY: 611 ± 51 nmol O2/min per g, P > 0.05).Addition of bradykinin, enalaprilat, and amlodipine decreasedoxygen consumption significantly less in SHR than WKY (SHR:bradykinin -13.9 ± 1.9%, enalaprilat -15.3 ± 1.6%,amlodipine -11.9 ± 0.7%; WKY: bradykinin -22.8 ±1.0%, enalaprilat -24.1 ± 2.0%, amlodipine -20.7 ±2.3%; P < 0.05), consistent with less NO effect in SHR. Additionof tempol reversed the defects in responsiveness to enalaprilatand amlodipine, suggesting that inactivation of NO by superoxidecontributes to decreased NO availability. The response to anNO donor was similar in both groups and was unaffected by theaddition of tempol. These results demonstrate that NO availabilityin the kidney is decreased in SHR, resulting in increased oxygenconsumption. This effect is due to enhanced production of superoxidein SHR. By lowering intrarenal oxygen levels, reduced NO maycontribute to susceptibility to injury and renal fibrosis. IncreasingNO production, decreasing oxidant stress, or both might preventthese changes by improving renal oxygenation.
Nitric oxide (NO) plays an important role in regulation of vasculartone. Absence of the NO generating enzyme endothelial nitricoxide synthase (eNOS) or impairment of NO production leads tohypertension in animal models and can increase vascular tonein humans (1–4). In a model of genetic hypertension inthe rat, the spontaneously hypertensive rat (SHR), abnormalitiesin synthesis of NO, expression of the NO-synthesizing enzymes,or both have been described both in vitro and in vivo, but withconflicting results. Thus, several studies have been performedto provide evidence of impaired vasodilation in response toacetylcholine, an effect mediated by endothelium-derived relaxingfactor or NO, decreased eNOS expression, or decreased NO synthesisin SHR (5–11). These abnormalities are present as earlyas 5 wk of age, a period before the development of hypertension(7). However, several of these studies have shown a decreasedeffect of NO rather than direct evidence of decreased production.
On the other hand, evidence of increased expression of NO synthesizingenzymes (eNOS and inducible NO synthase), increased NO production,or both have also been noted (12–18), both before andafter the onset of hypertension. One possible explanation forthis discrepancy is inactivation of NO, explaining increasedproduction but less effect in SHR. NO is inactivated by reactionwith superoxide (O2-) to produce peroxynitrite and increasedproduction of superoxide has been demonstrated in SHR (13,19–21).Manipulations that reduce superoxide production have also beenshown to lower BP in these animals (19–21).
NO also modulates oxygen consumption in the whole animal andin isolated tissues, such as heart and kidney, with an inverserelationship between NO production and oxygen consumption (22–24).We have previously shown that NO production by the eNOS isoenzymein the kidney is responsible for regulation of renal oxygenconsumption (25). Whole-body oxygen consumption is increasedin SHR, an observation consistent with a decreased effect ofNO (26). More recently, studies in SHR have demonstrated a relativeincrease in oxygen consumption in kidney when compared withsodium reabsorption, indicating relative inefficiency of oxygenusage in these animals (27). Therefore, we hypothesized thatNO regulation of oxygen consumption is impaired in the kidneyof SHR and that interference with superoxide production wouldrestore the normal effects of agonists of NO production on renaloxygen consumption.
Reagents
Bradykinin, enalaprilat, S-nitroso-N-acetylpenicillamine (SNAP),N-nitro-L-arginine methyl ester (L-NAME), tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), sodium succinate, and sodium cyanide werepurchased from Sigma Chemical Company (St. Louis, MO). Amlodipinewas provided by Pfizer (Groton, CT).
Animals
Male SHR (n = 6) and Wistar-Kyoto (WKY; n = 6) rats were purchasedfrom Taconic Farms, Inc. (Germantown, NY) when they were 10wk old and studied after 1 wk of acclimatization. Rats weremaintained on a standard rat chow with 0.4% sodium content (LaboratoryRodent Diet, Richmond, IN). The rats were allowed free accessto food and water until the day they were killed. Before theywere killed, BP and heart rate were measured with a noninvasiveBP monitor (Columbus Instruments, Columbus, OH), and blood wasdrawn from the femoral vein for measurement of hemoglobin, bloodurea nitrogen, and creatinine assessment. After the animalswere killed, the left kidneys were removed, decapsulated, andweighed.
Preparation of Kidney Tissue Slices and Measurement of O2 Consumption
Thin slices of renal cortex (approximately 1 mm, weight 10 to20 mg) were prepared and incubated in Krebs bicarbonate solution(containing, in mmol/L, NaCl 118, KCl 4.7, CaCl2 1.5, NaHCO325, KH2PO4 1.2, MgSO4 1.1 and glucose 5.6, pH 7.4) bubbled with21% O2/5% CO2/74% N2 at 37°C for 2 h. At the end of incubation,each piece of tissue was placed in a stirred chamber with 3ml of air-saturated Krebs bicarbonate solution containing 10mmol/L N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acidand 5.6 mmol/L glucose (pH 7.4). The chamber was sealed witha Clark-type platinum O2 electrode (Yellow Springs Instruments,Yellow Springs, OH). O2 consumption was measured polarographicallywith an O2 monitor (model YSI 5300) connected to a linear chartrecorder (model 1202, Barnstead/Thermolyne Corp., Dubuque, IA).Dose-response curves of the effect of different agonists onkidney O2 consumption were then measured. Succinate (10-3 mol/L)and then sodium cyanide (10-3 mol/L) were added at the end ofeach experiment to confirm that changes in O2 consumption originatedfrom mitochondrial respiration.
Renal cortical O2 consumption is calculated as the rate of decreasein O2 concentration, assuming an initial O2 concentration of224 nmol/ml (calculated from O2 solubility at 37°C and 1atm pressure) and is expressed as nanomoles of O2 consumed perminute per gram of tissue. O2 consumption due to the electrodeis less than 5% of that observed in the presence of tissue.The effects of drugs used on O2 consumption are expressed asa percentage change from baseline O2 consumption. Baseline O2consumption was measured in the cortex in the absence and presenceof L-NAME (10-3 mol/L) in six rats from each group.
Effect of Agonists on O2 Consumption
Bradykinin or enalaprilat at concentrations of 10-7 to 10-4mol/L, or amlodipine at concentrations of 10-7 to 10-5 mol/L,were added in a cumulative concentration-dependent manner. Theywere used to measure the effects of stimulation of endogenousNO production on renal O2 uptake. The response to these drugswas also examined after preincubation with the NOS inhibitorL-NAME (10-3 mol/L) to verify the role of NO production by NOSin the regulation of O2 uptake. Each drug was assayed in sixrats from each group in the presence or absence of L-NAME. Theeffects of the superoxide dismutase mimetic tempol (10-3 mol/L)were studied in an additional four rats from each group.
Effect of NO Donor on O2 Consumption
SNAP at concentrations of 10-7 to 10-4 mol/L was added in acumulative concentration-dependent manner to assess the effectsof exogenous NO on renal cortical O2 uptake. The response toSNAP was also examined after preincubation with L-NAME (10-3mol/L). Each condition was tested in six rats from each group.
Statistical Analyses
All data are expressed as mean ± SEM. Statistical analysesof baseline O2 consumption were performed by t test. Changesin O2 consumption caused by drug treatment were analyzed bytwo-way ANOVA followed by multiple comparisons by the Tukeytest (Sigma-Stat; SPSS, Chicago, IL). Statistical significancewas achieved at P < 0.05.
Baseline characteristics of the rats used in these studies arelisted in Table 1. Kidney/body weight, heart rate, hemoglobinlevels, and creatinine levels were similar in the two groups.SHR rats had significantly higher systolic, diastolic, and meanarterial pressures (P < 0.01).
Baseline Renal Cortical O2 Consumption
Baseline renal cortical O2 consumption was similar in the twogroups (WKY: 611 ± 51 nmol O2/min per g, n = 6; SHR:600 ± 55 nmol O2/min per g, n = 6, P > 0.05). Additionof the NOS inhibitor L-NAME (10-3 mol/L) did not significantlyalter O2 consumption (WKY: 638 ± 53 nmol O2/min per g,n = 6; SHR: 634 ± 66 nmol O2/min per g, n = 6, P >0.05).
Effect of Bradykinin on Renal O2 Consumption
Cumulative doses of bradykinin (10-7 to 10-4 mol/L) producedsignificant, concentration-dependent decreases of renal corticalO2 consumption in WKY and SHR rats (WKY: from -2.1 ±1.1% to -22.8 ± 1.0%, n = 6; SHR: from -0 ± 0%to -13.9 ± 1.9% n = 6). The depression of renal corticalO2 consumption by bradykinin was significantly less in SHR thanWKY rats at 10-6 to 10-4 mol/L of bradykinin (P < 0.05 foreach comparison) (Figure 1). Addition of L-NAME significantlyattenuated bradykinin induced decreases in O2 consumption at10-6 to 10-4 mol/L of bradykinin in WKY rats (from -0.5 ±0.5% to -12.0 ± 1.4%, n = 6; P < 0.05 for each comparison),demonstrating the importance of NO synthesis in the effect ofbradykinin (Figure 1). In SHR rats, addition of L-NAME had asmaller and NS effect in reversing the action of bradykininon renal O2 consumption (from -0 ± 0% to -9.4 ±1.5%, n = 6, P > 0.05 for each comparison versus no L-NAME).
Figure 1. Effect of cumulative doses of bradykinin on renal cortical O2 consumption in Wistar-Kyoto rats (WKY) (A) and spontaneously hypertensive rats (SHR) (B) in the absence (solid circles) or presence (open circles) of N-nitro-L-arginine methyl ester (L-NAME). Bradykinin caused dose-dependent decreases in O2 consumption in both groups, although the decrease in SHR rats was significantly less than in WKY rats. This effect was significantly attenuated by the addition of the NOS inhibitor L-NAME (open circles) only in WKY rats. *, P < 0.05 versus WKY rats in the presence of L-NAME and SHR rats in the absence of L-NAME.
Effect of Enalaprilat on Renal O2 Consumption
The angiotensin-converting enzyme inhibitor, enalaprilat (10-7to 10-4 mol/L), which stimulates endogenous NO production, similarlycaused concentration dependent decreases in renal cortical O2consumption in WKY and SHR rats (WKY: from -3.5 ± 1.0%to -24.1 ± 2.0%, n = 6; SHR: from -0.4 ± 0.4%to -15.3 ± 1.6% n = 6). The depression of cortical O2consumption was significantly less in SHR than WKY rats at alldose of enalaprilat (P < 0.05 for each comparison) (Figure 2).Addition of L-NAME significantly attenuated the effect ofenalaprilat at all doses in WKY rats (from -0.0 ± 0.0%to -12.2 ± 1.6%, n = 6; P < 0.05 versus each comparisonwithout L-NAME) but had no significant effect in SHR rats (-0.0± 0.0% to -13.8 ± 2.1% n = 6,) verifying the importanceof NO production by NOS in the WKY, but not SHR, rats.
Figure 2. Effect of cumulative doses of enalaprilat on renal cortical O2 consumption in Wistar-Kyoto (WKY) (A) and spontaneously hypertensive rat (SHR) (B) rats in the absence (solid circles) or presence (open circles) of N-nitro-L-arginine methyl ester (L-NAME). Enalaprilat caused dose-dependent decreases in O2 consumption in both groups, although the decrease in SHR rats was significantly less than in WKY rats at all doses of enalaprilat. This effect was significantly attenuated by the addition of L-NAME (open circles) only in WKY rats. *, P < 0.05 versus WKY rats in the presence of L-NAME and SHR rats in the absence of L-NAME.
Effect of Amlodipine on Renal O2 Consumption
Amlodipine (10-7 to 10-5 mol/L), which stimulates renal NO production,significantly decreased renal cortical O2 consumption in WKYand SHR rats (WKY: from -4.5 ± 1.4% to -20.7 ±2.3%, n = 6; SHR: from -1.9 ± 0.6% to -11.9 ±0.7% n = 6). The depression of cortical O2 consumption was significantlyless in SHR than WKY rats at all doses of amlodipine (P <0.05 for each comparison) (Figure 3). Addition of L-NAME againsignificantly attenuated the effect of amlodipine at all dosesonly in the WKY rats (WKY: from -1.0 ± 0.6% to -13.0± 1.6%, n = 6, P < 0.05 versus each comparison withoutL-NAME; SHR: from -0.5 ± 0.5% to -10.0 ± 2.5%n = 6, P > 0.05).
Figure 3. Effect of cumulative doses of amlodipine on renal cortical O2 consumption in Wistar-Kyoto (WKY) (A) and spontaneously hypertensive rat (SHR) (B) rats in the absence (solid circles) or presence (open circles) of N-nitro-L-arginine methyl ester (L-NAME). Amlodipine caused dose-dependent decreases in O2 consumption in both groups. The decrease in SHR rats was significantly less than in WKY rats at all doses of amlodipine. Addition of L-NAME (open circles) significantly attenuated the effect of amlodipine only in WKY rats. *, P < 0.05 versus WKY rats in the presence of L-NAME and SHR rats in the absence of L-NAME.
Effect of an NO Donor (SNAP) on Renal O2 Consumption
Administration of cumulative doses of the NO donor SNAP (10-7to 10-4 mol/L) decreased renal cortical O2 consumption in WKYand SHR rats to similar degrees (WKY: from -0.0 ± 0.0%to -41.7 ± 1.9%, n = 6; SHR: from -0.0 ± 0.0%to -39.7 ± 1.7%, n = 6, P > 0.05 at all doses), demonstratingno inherent difference between the strains in responsivenessof O2 consumption to NO (Figure 4). Addition of L-NAME had noeffect on the response to SNAP (data not shown).
Figure 4. Effect of cumulative doses of S-nitroso-N-acetylpenicillamine (SNAP) on renal cortical O2 consumption in Wistar-Kyoto (WKY) (A) and spontaneously hypertensive rat (SHR) (B) rats in the absence (solid circles) or presence (open circles) of N-nitro-L-arginine methyl ester (L-NAME). SNAP caused similar dose-dependent decrease in O2 consumption in both groups (P > 0.05). Addition of L-NAME did not alter the effect of SNAP (data not shown).
Effect of Oxygen Radical Scavenging with Tempol on Renal O2 Consumption
Elevated levels of oxygen radicals have been noted in SHR ratsand have been postulated to decrease availability of NO. Therefore,we added the superoxide dismutase mimetic tempol (10-3 mol/L)to some incubations to see the effect of decreasing superoxideproduction on the response of renal cortical O2 consumptionto stimulators of NO production. Enalaprilat again decreasedO2 consumption significantly more in WKY as compared with SHRrats (Figure 5A). Addition of tempol significantly restoredthe suppression of O2 consumption by enalaprilat (10-6-10-4mol/L) in SHR rats to a level that was not different from WKYrats. Suppression of O2 consumption by amlodipine (10-5 mol/L)was also significantly enhanced (Figure 5B). Tempol had no effecton the responsiveness of WKY rats to enalaprilat or amlodipineat any dose and had no effect on the responsiveness or eithergroup to SNAP (Figure 5C).
Figure 5. Effect of oxygen radical scavenging with tempol on renal cortical O2 consumption in Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) rats in response to enalaprilat (A), amlodipine (B), and S-nitroso-N-acetylpenicillamine (SNAP) (C). All drugs caused dose-dependent decreases in O2 consumption in WKY (solid circles) and SHR (solid triangles) rats. Addition of tempol (open symbols) significantly decreased O2 consumption in SHR (open triangles) rats at the concentrations indicated but had no effect in WKY (open circles) rats. Suppression of O2 consumption by SNAP was unaffected by tempol. *, P < 0.05 versus SHR in the presence of tempol.
The results presented here provide evidence for the hypothesisthat regulation of renal oxygen consumption by NO is impairedin SHR and that this impairment is due to ineffective NO productionas a result of NO inactivation by superoxide. Bradykinin, enalaprilat,and amlodipine, all stimulators of NO production, decreasedrenal cortical oxygen consumption in a dose-dependent mannerin WKY rats, similar to results previously reported in normalmice and dogs (25,28). In SHR, there was a significant decreasein the response to all three of these stimulators of endogenousNO production, suggesting a defect in renal NO production. Theabsence of a difference in basal oxygen consumption betweenthe two groups, despite evidence for a defect in NO productionin SHR, is most likely due to the absence of flow in this preparation,which results in little eNOS activation and suggests very lowbasal NO production. Thus, the difference between the two groupsdoes not become evident until NO production is stimulated. Inthe presence of tempol, a superoxide dismutase mimetic thatreduces superoxide levels, the response of oxygen consumptionin SHR kidney to amlodipine and enalaprilat was restored tolevels seen in control rats. Thus, production of NO in the renalcortex in SHR appears to be adequate to produce a similar decreasein oxygen consumption as in controls as long as superoxide productionis inhibited. The responsiveness of kidneys from both SHR andWKY to SNAP, and the lack of effect of tempol on the SNAP responsesuggest that there is no difference in the ability of NO toalter oxygen consumption in the two groups.
The major effect of NO on oxygen consumption occurs througha direct action of NO on mitochondrial respiration (22,29,30).NO binds to several enzymes in the mitochondrial electron transportchain, including aconitase, complex I and II, and cytochromeoxidase (reviewed in [30]). In the kidney, NO may also decreaseoxygen consumption through an effect on sodium transport, amajor determinant of oxygen usage. NO inhibits thick ascendinglimb chloride flux, perhaps through an effect on the Na+-K+-2Cl-transporter, and has also been shown to directly inhibit sodium-potassiumATPase (31–33).
Our results are consistent with and extend observations by otherson NO production and the role of superoxide on NO availabilityin SHR. Both short- and long-term treatment with tempol normalizedBP and renal vascular resistance in SHR, an effect that wasshown to be dependent on NO synthesis (19,20). Treatment withanother antioxidant, lazaroid, also lowered BP in SHR, alongwith decreases in the renal expression of eNOS and inducibleNO synthase (21), an effect suggested to be due to inhibitionof NOS synthesis by the newly available NO. In our studies,tempol restored NO inhibition of renal oxygen consumption tonormal levels. These results all substantiate the presence ofincreased oxidant production and decreased NO availability inSHR.
Our results are also interesting in the context of the increasedwhole-body oxygen consumption observed in SHR (26). In consciousdogs, inhibition of NO synthesis with nitro-L-arginine leadsto increased total body oxygen consumption (22). Thus, one explanationfor the changes observed in SHR is decreased NO synthesis oravailability. More recently, by using an oxygen-sensitive ultramicroelectrode,Welch et al. (27) demonstrated normal total renal oxygen consumptionin SHR, but a 43% reduction in tubular reabsorption of sodium,a major determinant of renal oxygen consumption. Thus, the efficiencyof oxygen usage for sodium transport is decreased in SHR, aneffect similar to that demonstrated in conscious dogs followinginhibition of NO synthesis (24). They hypothesized that thereduction in efficiency of oxygen usage might be due to a relativestate of NO deficiency. The data presented here substantiatethat conjecture.
By regulating oxygen consumption, NO may also play an importantrole in regulation of intrarenal oxygenation and predispositionto injury. Studies by Brezis et al. (34,35) found intrarenalpO2 of approximately 46 mmHg in the cortex and 21 to 23 mmHgin the medulla. Studies that used isolated renal tubules havedemonstrated a markedly enhanced effect of NO on inhibitionof oxygen consumption as pO2 drops to these levels (36). Underthe hypoxic conditions present in the cortex, and even moreso in the medulla, the effect of NO, or the lack thereof, onoxygen consumption will be magnified. Inhibition of NO synthesiswith L-NAME decreases medullary pO2 (34), an effect postulatedto be due to decreased blood flow, but also now explained byincreased oxygen consumption in the face of low NO. L-NAME alsoincreased hypoxic injury to tubules in the medulla in rats,an effect reversed by infusion of the NO donor nitroprusside(34), again an effect mediated either by nitroprusside inducedvasodilation or improved oxygenation through inhibition of oxygenconsumption by NO. Similarly, in congestive heart failure, inwhich we have demonstrated decreased NO effect in the kidney(28), outer medullary hypoxic damage is worsened following injectionof indomethacin and L-NAME (37).
Intrarenal pO2 is also lower in SHR than WKY rats in the proximaland distal tubules and in the outer and deep cortex (27), whichcan be explained by increased oxygen consumption related todecreased NO availability. NO production in the kidney may alsobe impaired in other disease states, including diabetes, othermodels of hypertension, aging, and chronic renal insufficiency(38–41). Thus, increased sensitivity to renal insultsmight be expected in these states, a hypothesis consistent withclinical observations. More importantly, evidence has recentlyaccumulated that intrarenal hypoxia may predispose to fibrosis,leading to progressive loss of renal function.
Hypoxia regulates the production of a broad spectrum of growthfactors, hormones, matrix components, proteases, and proteaseinhibitors (reviewed in [42]). Exposure of human proximal tubularepithelial cells to hypoxia stimulates collagen production,decreases gelatinase A production, and increases productionof tissue inhibitor of metalloproteinase-1, changes that wouldfavor matrix accumulation (43). In human renal fibroblasts,hypoxia also produces changes favoring matrix accumulation,an effect at least partially mediated through the hypoxia-inducibletranscription factor 1 (44). Fine et al. (42) have hypothesizedthat treatments such as angiotensin-converting enzyme inhibitors,which slow progression of renal disease, may work not only bydecreasing proteinuria but by increasing microvascular flowin the interstitium and raising intrarenal pO2. Our data suggestthat angiotensin-converting enzyme inhibitors, such as enalapril,might also increase intrarenal oxygen tension by decreasingoxygen consumption through stimulation of NO synthesis. Furtherstudies of these mechanisms could lead to new treatments toslow the progression of renal disease.
Acknowledgments
This work was supported by a grant from the Westchester ArtificialKidney Center. We acknowledge the generous support and adviceof Dr. T.H. Hintze and the secretarial assistance of Maria Feliciano.
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Received for publication January 25, 2002.
Accepted for publication April 3, 2002.
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Top
Abstract
Introduction
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1–independent mechanism. Kidney Int 52: 637–647, 1997[Medline]
