Published online before print July 21, 2003, doi: 10.1161/01.HYP.0000085195.38870.44
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(Hypertension. 2003;42:754.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension
From the Department of Pharmacology (A.N., G.-X.Z, L.Y., M.R., H.H., S.K., Y.A.) and the Second Department of Internal Medicine (T.F., H.Kiyomoto, T.S., M.K.), Kagawa Medical University, Kagawa, Japan; and the Department of Physiology (H.Kobori), Tulane University Health Sciences Center, New Orleans, La.
Correspondence to Akira Nishiyama, MD, PhD, Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail akira{at}kms.ac.jp
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Abstract |
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Treatment with cyclosporine A (CysA), a potent immunosuppressive agent, is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119±2 to 145±3 mm Hg (n=7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136±10 fmol/mL and 516±70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76±10 fmol/mL and 222±21 fmol/g, n=7). CysA treatment increased AT1 receptor protein expression in the aorta (by 251±35%), whereas it was reduced in the kidney (by -32±4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid–reactive substance (TBARS) contents were higher in CysA-treated rats (26±2 counts/min per milligram and 37±3 nmol/g) than in vehicle-treated rats (17±1 counts/min per milligram and 24±3 nmol/g). Concurrent administration of an AT1 receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (n=7) significantly decreased SBP (113±4 mm Hg) and prevented increases in vascular superoxide (16±2 counts/min per milligram) and kidney TBARS contents (21±3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, n=7), prevented CysA-induced increases in SBP (115±3 mm Hg), vascular superoxide (16±1 counts/min per milligram), and kidney TBARS contents (19±2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension.
Key Words: angiotensin antagonist • antioxidants • receptors, angiotensin II • renin
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Introduction |
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Cyclosporine A (CysA) is a potent immunosuppressive agent and is widely used after organ transplantation and in the treatment of several autoimmune diseases.1 However, its clinical use is frequently complicated by systemic and renal vasoconstriction, leading to arterial hypertension.2 Although numerous factors have been implicated,2 several lines of evidence suggest an involvement of the renin-angiotensin system in the development of CysA-induced hypertension.3–10 Increased plasma renin activity and renin content in kidney tissues were observed in rats treated with long-term CysA4. It was also shown that CysA treatment augmented angiotensin II (Ang II)-induced vasoconstriction in isolated arterioles5 or calcium response in vascular smooth muscle cells.6 Lasssila et al7,8 demonstrated that treatment with an ACE inhibitor or an AT1 receptor antagonist abrogates CysA-induced hypertension and vascular dysfunction in spontaneously hypertensive rats (SHR) fed a high salt diet. Further clinical studies showed that treatment with an ACE inhibitor or an AT1 receptor antagonist reduced blood pressure in hypertensive CysA-treated patients after renal transplantation.9,10 Collectively, these data suggest that augmented Ang II formation contributes to CysA-induced hypertension.
The mechanisms responsible for the progressive nature of Ang II–induced hypertension are multifarious11,12; however, recent studies have implicated a role of reactive oxygen species (ROS) in the pathogenesis of Ang II–dependent hypertension.12,13 Interestingly, there is also accumulating evidence that ROS production is stimulated by CysA treatment. For example, administration of CysA markedly increased renal cortical lipid perioxidation14 and urinary excretion of ROS that were trapped by the spin-trapping agent 
-(4-pyridyl-1-oxide)-N-tert-butylnitrone.15 Clinical studies by Calo et al10 showed that plasma hydroperoxide levels were markedly increased in kidney and heart transplant patients treated with CysA. The authors also showed that mRNA expression of monocyte p22-phox, an essential membrane component of NAD(P)H oxidase, was significantly increased in posttransplantation hypertensive patients treated with long-term CysA10. Galle et al16 showed that superoxide release from isolated rat aortic rings was significantly increased by incubation with CysA. In addition, impaired acetylcholine-induced relaxation in arteries isolated from CysA-treated rats was normalized by pretreatment with a superoxide dismutase (SOD).17 These observations suggest that an increased ROS production participates in CysA-induced endothelial dysfunction that might be responsible for the development of hypertension.
The aim of the present study was to elucidate the contribution of Ang II to CysA-induced hypertension and ROS generation. Accordingly, studies were performed to determine if the renin-angiotensin system is actually activated and ROS production is increased in CysA-induced hypertensive rats. We also investigated whether AT1 receptor blockade or treatment with an antioxidant prevents CysA-induced hypertension and ROS generation. In this study, we used an AT1 receptor antagonist, valsartan, and a membrane-permeable, metal-independent SOD mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol). Tempol has been shown to be specific for superoxide anion18 and to reduce blood pressure in hypertensive animals.13,19
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Methods |
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Animal Preparation
All experimental procedures were performed under the guidelines for the care and use of animals as established by the Kagawa Medical University and Tulane University Health Sciences Center. Male Sprague-Dawley (SD) rats (Clea Japan) weighing 162 to 184 g at the beginning of the experiments were selected at random to receive daily subcutaneous injection of CysA (Novartis Pharma) at a dose of 30 mg/kg per day (n=7) or vehicle (1 mL of olive oil, n=7) for a period of 3 weeks. In a separate experimental series, CysA-treated rats were treated with valsartan (Novartis Pharma, 30 mg/kg body weight per day in the drinking water) or Tempol (Sigma Chemical Co, 3 mmol/L in the drinking water) (n=7, respectively). The doses of CysA, valsartan, and Tempol were chosen on the basis of results from previous studies in rats.4,7,8,19 We previously observed that treatment with Tempol (3 mmol/L in drinking water) did not alter blood pressure or plasma and kidney thiobarbituric acid reactive substances (TBARS) levels in normotensive animals, including Dahl salt-resistant rats maintained on low or high salt diets,19 Dahl salt-sensitive rats maintained on low sodium diets,19 and SD rats (Nishiyama and Abe, unpublished data, 2003). In agreement with previous studies performed in Wistar rats,20 preliminary data also showed that this dose of valsartan did not alter blood pressure in SD rats. Furthermore, vascular superoxide anion production was not altered by treatment with valsartan in these animals.
Systolic blood pressure (SBP) was measured in conscious rats by tail-cuff plethysmography (BP-98A, Softron Co) every week. Twenty-four-hour urine samples were collected 1 day before harvesting for measuring urinary protein excretion. Blood, aorta, and kidney samples were harvested at the end of 3 weeks. After decapitation, trunk blood was collected into chilled tubes containing an inhibitor mixture [5 mmol/L EDTA+20 µmol/L enalaprilat +1.25 mmol/L O-phenanthroline+10 µmol/L pepstatin] and processed for measurements of plasma Ang II concentrations and angiotensinogen protein levels.21,22 Blood was also collected into chilled tubes containing 5 mmol/L EDTA for measuring plasma renin activity and creatinine concentration or lipid hydroperoxide (LOOH) and TBARS levels. Just after removal of kidneys, the right kidney was homogenized in cold methanol and processed for measurement of kidney Ang II contents.21,22 The left kidney was snap-frozen in liquid nitrogen and stored at -80°C until processed for protein extraction or analyses of renin and TBARS contents. The aorta was also quickly taken, and perivascular tissues were removed. Five-millimeter ring segments were taken for measuring superoxide anion production.13,23 The remaining aorta samples were snap-frozen in liquid nitrogen and stored at -80°C until processed for protein extraction.
Measurement of Vascular Superoxide Anion Production
Superoxide anion production in aortic segments was determined through the use of lucigenin chemiluminescence, as described previously.13,23 In brief, the aortic ring was placed in bicarbonate buffer with the following composition (in mmol/L): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.2 MgSO4, 25.0 NaHCO3, 5.5 glucose, and 0.026 EDTA, which was bubbled continuously with 95% O2–5% CO2 to maintain the pH at 7.4 and allowed to equilibrate for 30 minutes at 37°C. After equilibration, the ring was rinsed with prewarmed (37°C) modified Krebs-HEPES buffer with the following composition (in mmol/L): 119 NaCl, 20 HEPES, 4.6 KCl, 1.0 MgSO4, 0.15 Na2HPO4, 0.4 KH2PO4, 25 NaHCO3, 1.2 CaCl2, and 5.5 glucose (pH 7.4). The ring was placed in 1 mL of Krebs-HEPES buffer containing lucigenin (Sigma Chemical Co; 20 µmol/L) and equilibrated in the dark for 10 minutes at 37°C. Recent studies indicate that lucigenin itself could act as a source of superoxide anion through auto-oxidation of the lucigenin cation radical.24 However, it was shown that auto-oxidation of lucigenin did not occur at <100 µmol/L in rat renal cortical tissues.25 Our preliminary data showed that vascular superoxide anion levels could be detected with the use of 20 µmol/L of lucigenin. Furthermore, these levels were significantly decreased by treatment with Tiron, which is often used as an alternative for native superoxide dismutase.26 On the basis of these preliminary data, we decided to use 20 µmol/L of lucigenin in the present study. The chemiluminescence was then recorded every 15 seconds for 5 minutes, with the use of a luminescence reader (BLR-301, Aloka). The lucigenin chemiluminescence was expressed as counts per minute per milligram if dry tissue weight.
Analysis of Kidney Samples for Angiotensinogen and Ang II Receptors
Protein levels of angiotensinogen as well as AT1 and AT2 receptors in the aorta and kidney tissues were analyzed by Western blot, as previously described in detail.22,27,28 To check for equal loading, membranes were reprobed with an antibody against ß-actin. All values were normalized by arbitrarily setting the densitometry of vehicle-treated rats to 1.0. Protein levels of angiotensinogen in plasma were also measured, as previously described.22
Analytical Procedures
Urinary protein excretion was determined with the use of a protein assay kit (microTP-test, Wako). We determined the degree of lipid peroxidation by using biochemical assays of LOOH and TBARS levels in plasma as well as TBARS contents in kidney tissues, as described previously in detail.29,30 Plasma renin activity, kidney renin content, and Ang II levels were measured by radioimmunoassay, as previously reported.21,27
Statistical Analysis
The values are presented as mean±SEM. Statistical comparisons of the differences were performed with the use of 1-way or 2-way ANOVA combined with the Newman-Keuls post hoc test. A value of P<0.05 was considered statistically significant.
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Results |
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Blood Pressure, Plasma Creatinine Concentration, and Urinary Protein Excretion
SBP was identical among 4 groups at the beginning of the protocol. As shown in Figure 1, daily administration of CysA for 3 weeks at a dose of 30 mg/kg per day significantly increased SBP from 119±2 to 145±3 mm Hg (P<0.05). Concurrent administration of valsartan or Tempol prevented the development of CysA-induced hypertension (113±4 and 115±3 mm Hg at week 3, respectively). At week 3, plasma creatinine levels in CysA-treated rats (0.55±0.03 mg/dL) were higher than those in vehicle-treated rats (0.37±0.03 mg/dL). Concurrent administration of valsartan or Tempol significantly decreased plasma creatinine levels in CysA-treated animals (0.37±0.02 and 0.36±0.01 mg/dL, respectively). Urinary protein excretion of vehicle-treated rats was 4.8±0.5 mg/d. Treatment with CysA for 3 weeks did not alter urinary protein excretion (5.0±0.8 mg/d). Furthermore, valsartan or Tempol did not alter urinary protein excretion in CysA-treated rats (3.5±0.4 and 4.7±0.6 mg/d, respectively).
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Renin-Angiotensin System in CysA–Induced Hypertensive Rats
Analyses of integrated densitometric values (IDV) showed that CysA treatment did not alter plasma angiotensinogen levels (densitometric value/average control value ratios of 0.97±0.06 versus 1.00±0.06). Similarly, kidney angiotensinogen levels were similar between CysA-treated and vehicle-treated rats (densitometric value/average control value ratios of 0.95±0.07 versus 1.00±0.07). CysA-treated rats showed higher plasma renin activity (8.7±1.0 ng Ang I/mL per hour) and kidney renin content (5.2±0.9x103 ng Ang I/g per hour) compared with vehicle-treated rats (3.2±0.8 ng Ang I/mL per hour and 3.4±0.7x103 ng Ang I/g per hour, respectively, Figures 2A and 2B). Plasma Ang II levels were significantly higher in CysA-treated rats (136±10 fmol/mL) than in vehicle-treated rats (76±10 fmol/mL, Figure 2C). Similarly, CysA-treated rats showed higher Ang II contents in the kidney (516±70 fmol/g) compared with vehicle-treated rats (222±21 fmol/g, Figure 2D). Concurrent administration of valsartan markedly increased plasma Ang II levels in CysA-treated rats (411±11 fmol/mL, Figure 2C). In contrast, kidney Ang II contents were significantly decreased by treatment with valsartan (146±14 fmol/g, Figure 2D). On the other hand, Tempol did not alter plasma Ang II levels in CysA-treated rats (91±16 fmol/mL, Figure 2C) but significantly decreased kidney Ang II contents in CysA-treated rats (292±53 fmol/g, Figure 2D). CysA-treated rats showed augmented AT1 receptor protein expression in the aorta, whereas AT1 receptor expression in the kidney was reduced (Figure 3). Analyses of IDV showed that the ratios of aorta samples for AT1 receptors were 2.5±0.4-fold higher in CysA-treated rats compared with vehicle-treated rats, whereas those of kidney samples were significantly lower in CysA-treated rats (Figure 3). On the other hand, both aorta and kidney AT2 receptor expressions were increased by long-term treatment with CysA (Figure 4). Analyses of IDV showed that the ratios of both aorta and kidney samples for AT2 receptors were increased in CysA-treated rats by 2.8±0.3- and 3.9±0.3-fold, respectively (Figure 4). As a control study to check the equal loading, membranes were reprobed with an antibody against ß-actin. The results showed that IDV were unaltered between both groups.
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Effects of Valsartan and Tempol on ROS Levels
Plasma LOOH and TBARS levels in CysA-treated rats averaged 7.6±0.4 and 25.0±2.1 µmol/L, respectively. These levels were significantly higher than those of vehicle-treated rats (4.2±0.5 and 10.7±1.4 µmol/L, respectively). Concurrent administration of valsartan to CysA-treated rats significantly reduced plasma LOOH and TBARS levels (5.2±0.5 and 12.4±1.4 µmol/L, respectively). On the basis of group comparisons, these levels were not significantly different from those of vehicle-treated rats. Administration of Tempol resulted in similar decreases in plasma LOOH and TBARS levels (5.1±0.5 and 13.1±0.9 µmol/L, respectively). The lucigenin chemiluminescence from aortic segments of vehicle-treated rats averaged 17±1 counts/min per milligram dry tissue wt. In CysA-treated rats, the lucigenin chemiluminescence was significantly higher than in vehicle-treated rats (26±2 counts/min per milligram dry tissue wt, Figure 5A). In CysA-treated rats, valsartan or Tempol significantly decreased the lucigenin chemiluminescence to levels that were the same as those of vehicle-treated rats (16±2 and 16±1 counts/min per milligram dry tissue wt, respectively, Figure 5A). Kidney TBARS contents in CysA-treated rats averaged 37±3 nmol/g, which was significantly higher than those in vehicle-treated rats (24±3 nmol/g). As shown in Figure 5B, administration of valsartan or Tempol significantly reduced kidney TBARS contents in CysA-treated rats (21±3 and 19±2 nmol/g, respectively).
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Discussion |
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In this study, we have demonstrated that circulating and intrarenal Ang II levels are increased in CysA-induced hypertensive rats. The present study also demonstrated that in CysA-induced hypertensive rats, increases in ROS production are associated with elevated Ang II levels. Furthermore, AT1 receptor blockade prevents both increases in ROS levels and the development of hypertension induced by CysA. In addition, treatment with a SOD mimetic, Tempol, has a similar antihypertensive effect in these animals. These data suggest that ROS production induced by elevated Ang II levels contributes to the development of CysA-induced hypertension.
The present study provides evidence that Ang II levels are increased in both plasma and kidney tissues of CysA-induced hypertensive rats. However, the mechanisms by which CysA induces Ang II production remain to be elucidated. In vitro studies have shown that CysA stimulates renin release from cortical slices31 or isolated juxtaglomerular cells.32 In agreement with previous studies,4 we observed that circulating and kidney renin activity was significantly increased in CysA-induced hypertensive rats. We also found that neither plasma nor kidney angiotensinogen levels were affected by treatment with CysA. These data indicate that increases in renin activity rather than angiotensinogen expression are responsible for the elevated Ang II levels in CysA-induced hypertensive rats. As expected, AT1 receptor blockade with valsartan markedly increased plasma Ang II levels in CysA-treated rats. In contrast, kidney Ang II contents were significantly decreased by treatment with valsartan. These observations were consistent with previous studies showing that the progressive increases in intrarenal Ang II levels were prevented by AT1 receptor blockade in Ang II–dependent hypertension.11 Thus, it is possible that CysA-induced augmentation of intrarenal Ang II was also prevented by AT1 receptor blockade with valsartan. Interestingly, we also observed that although Tempol did not alter plasma Ang II levels in CysA-treated rats, kidney Ang II contents were significantly reduced by Tempol. At present, we have no satisfactory explanation why kidney Ang II contents were reduced by Tempol in these animals. Several studies indicate that CysA activates sympathetic nerve activity.15,33,34 Since renal nerve stimulation increases intrarenal Ang II formation,35 it is possible that CysA-induced activation of sympathetic nerve activity is involved in the augmentation of Ang II production. We recently reported that Tempol markedly reduced renal sympathetic nerve activity in spontaneously hypertensive rats.23 Therefore, it can be speculated that Tempol decreases intrarenal Ang II levels through its sympathoinhibitory effects. Clearly, further studies are needed to determine the effects of Tempol on kidney angiotensinogen levels and renin activity/contents as well as sympathetic nerve activity in CysA-induced hypertensive rats.
Avdonin et al6 showed that pretreatment with CysA for 24 hours increased [125I]Ang II binding in vascular smooth muscle cells without changing its affinity, suggesting an enhancement of Ang II receptor expression by acute CysA treatment. In the present study, we observed that long-term treatment with CysA increased protein expression of AT1 receptors in the aorta. These observations are in accordance with previous studies showing that mRNA expression of AT1 receptors in aortic vascular smooth muscle cells36 and endothelial cells37 were significantly increased in CysA-induced hypertensive rats. Thus, it is possible that the combination of elevated circulating Ang II levels and increased vascular AT1 receptor expression contributes to the CysA-induced vascular dysfunction, leading to the development of hypertension. In contrast to the results obtained in the aorta, protein expression of AT1 receptors in renal tissue was significantly reduced in CysA-induced hypertensive rats. These data are consistent with previous observations that AT1 receptor mRNA expression is downregulated in the kidney after chronic CysA treatment in the rat.4 In the present study, we also found that AT2 receptor expression was markedly increased in renal tissues (
4-fold). Although functional roles of AT2 receptors in the kidney are not clear,11 it can be speculated that the regulation of both AT1 and AT2 receptor expression in the kidney may represent an adaptive mechanism to attenuate CysA-induced renal dysfunction.
In agreement with previous studies,14,15,34 we observed that plasma creatinine levels were significantly increased in CysA-induced hypertensive rats, suggesting CysA-induced glomerular dysfunction. We also observed that treatment with valsartan or Tempol significantly decreased plasma creatinine levels in CysA-treated animals. These results indicate that CysA-induced glomerular dysfunction was ameliorated by treatment with valsartan or Tempol. On the other hand, the present study showed that urinary protein excretion of protein was not altered in CysA-induced hypertensive rats, as has been previously reported.38 It is possible that the duration of CysA treatment to the rats conducted in this study is relatively short compared with the duration of CysA treatment in humans. Therefore, a histologically distinguishable lesion resembling the CysA nephropathy identified in sections of human renal biopsies was not seen in the present experimental settings (data not shown). Nevertheless, recent studies showed that this lesion is produced by CysA treatment in SHR fed a high salt diet7,8 and salt-depleted normotensive rats.39 Further investigations in these animals are required to determine the role of intrarenal Ang II in the progression of CysA nephropathy.
Ang II stimulates NAD(P)H oxidase–dependent superoxide production in different types of cells or isolated vessels.12,40 The superoxide produced on Ang II stimulation is rapidly converted to other ROS, including peroxynitrite and H2O2.12,40 In Ang II–dependent hypertensive animals, the production of vascular superoxide and the levels of other markers of ROS were elevated.12,13 It has been shown that enhanced vascular superoxide formation inactivates endothelial nitric oxide (NO), leading to endothelial dysfunction and hypertension.12,13 Furthermore, peroxynitrite, which is the chemical combination of superoxide with NO, oxidizes arachidonic acid and thus may stimulate the formation of a potent vasoconstrictor isoprostane.12 Recent studies also indicate that ROS can exert vasoconstrictor effects independent of NO mechanism.40 In the present study, we demonstrated that CysA-induced hypertension is associated with elevated Ang II and ROS formation in rats. In addition, AT1 receptor blockade prevented increases in ROS levels and development of hypertension induced by long-term treatment with CysA, suggesting that at least part of increased ROS generation is a consequence of the elevated Ang II levels. Since CysA-induced hypertension was also prevented by treatment with Tempol, it is possible that elevated ROS formation plays a role in the pathogenesis of CysA-induced hypertension.
Although our data suggest a potential participation of Ang II in ROS production in CysA-induced hypertensive rats, other mechanisms may also be involved in CysA-induced ROS production. In vitro studies showed that CysA increased ROS levels in a variety of cells.41,42 Furthermore, it was shown that CysA induced lipid peroxidation in isolated hepatic and renal microsomes.43 These data suggest that CysA or its metabolites directly stimulate ROS production. Furthermore, CysA inhibits mitochondrial respiration, which could also lead to ROS production.44 Zhong et al34 showed that CysA-induced sympathetic nerve activation and ROS production in the kidney were prevented by renal denervation. Therefore, it is possible that CysA increases ROS production by increasing renal sympathetic nerve activity, resulting in vasoconstriction. Several studies also showed that CysA-induced hypertension was attenuated by endothelin receptor blockade.5,45 Furthermore, it was recently shown that CysA-induced superoxide formation in rat aorta was blocked by an endothelin receptor antagonist, suggesting a role of endothelin in CysA-induced ROS production.16 It is well known that Ang II stimulates endothelin production.46 Therefore, the possibility exists that the CysA-induced augmentation of Ang II levels leads to increases endothelin formation, which may also participate in CysA-induced ROS production. Collectively, it seems likely that ROS production is augmented via multiple mechanisms in CysA-induced hypertension.
Perspectives
The involvement of the renin-angiotensin system and ROS in the development of CysA-induced hypertension has been supported by several studies.3,7,8,10,47 The present study provides direct evidence that Ang II and ROS formations are actually augmented in CysA-induced hypertensive rats. We have also demonstrated that antihypertensive effects of AT1 receptor blockade and Tempol are associated with reductions in ROS levels in these animals, indicating the contribution of Ang II–dependent ROS production to the development of CysA-induced hypertension. Recent clinical studies indicate that ROS levels are elevated in CysA-treated hypertensive patients.10,47 Therefore, the antioxidative actions of AT1 receptor blockade could explain some of beneficial effects of AT1 receptor antagonists in recently reported clinical studies.3,9,10
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Acknowledgments |
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This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan (A.N., Y.A.), the Research Foundation for Pharmaceutical Sciences (A.N.), Japan Research Foundation for Clinical Pharmacology (T.F., A.N), the Uehara Memorial Foundation (A.N. and H.K.), the National Kidney Foundation (H.K.) and Health Excellence Found from Louisiana Board of Regents (H.K.). We thank L. Gabriel Navar (Tulane University Health Sciences Center) for critical reading of the manuscript and helpful suggestions. We are also grateful to Kayoko Miyata, Kanako Ogura, and Junko Osada (Kagawa Medical University) for excellent technical assistance and to Novartis Pharma (Basel, Switzerland) for supplying CysA and valsartan.
Received May 12, 2003; first decision June 2, 2003; accepted June 25, 2003.
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