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CARDIAC, RENAL, AND RESPIRATORY INTEGRATION
Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University, Washington, District of Columbia 20007
Submitted 9 August 2002 ; accepted in final form 18 February 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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(8-Iso) and
malonyldialdehyde (MDA) were related to renal cortical mRNA abundance for
subunits of NADPH oxidase and superoxide dismutases (SODs) using real-time
PCR. Subsets of ANG II-infused rats were given the AT1-R antagonist
candesartan cilexetil (Cand) or the AT2-R antagonist PD-123,319
(PD). Compared to vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh,
5.4 ± 0.8 vs. ANG II, 7.6 ± 0.5 pg/24 h; P < 0.05).
This was prevented by Cand (5.6 ± 0.5 pg/24 h; P < 0.05)
and increased by PD (15.8 ± 2.0 pg/24 h; P < 0.005). There
were similar changes in MDA excretion. Compared to Veh, ANG II significantly
(P < 0.005) increased the renal cortical mRNA expression of
p22phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold)
and decreased expression of Nox-4 (2.1-fold) and extracellular (EC)-SOD
(2.1-fold). Cand prevented all of these changes except for the increase in
Mn-SOD. PD accentuated changes in p22phox and Nox-1 and
increased p67phox. We conclude that ANG II infusion
stimulates oxidative stress via AT1-R, which increases the renal
cortical mRNA expression of p22phox and Nox-1 and reduces
abundance of Nox-4 and EC-SOD. This is offset by strong protective effects of
AT2-R, which are accompanied by decreased expression of
p22phox, Nox-1, and p67phox. candesartan; isoprostane; angiotensin receptor blocker; PD-123,319; malonyldialdehyde
Oxidative stress implies an imbalance between the generation and the scavenging of ROS such as O2-· or hydrogen peroxide (H2O2). O2-· is metabolized by superoxide dismutases (SODs). ROS are implicated in cell signaling (44) and bioinactivation of nitric oxide (NO; Ref. 14). They contribute to aging, hypertension (9, 49), and cardiovascular and kidney diseases (13, 49). NADPH oxidase has been identified as a major source of O2-· in the vessel wall (1). This electron-transport system was first described in phagocytes, where it is composed of the membrane-associated glycoprotein gp91phox with p22phox and three cytosolic components, p40phox, p47phox, and p67phox (1). Several isoforms of the gp91phox (now termed Nox-2) component have been described including Nox-1 in vascular smooth muscle cells (formerly Mox-1; Ref. 43), gp91phox in endothelial cells (16), and Nox-4 in kidney and colon (formerly RENOX; Ref. 12). The kidney cortex contains a complete complement of phagocyte-type NADPH oxidase and all three Nox isoforms (4).
O2-· interacts with esterified or free arachidonate to yield a family of isoprostanes that includes 8-isoprostane prostaglandin F2 (8-Iso). The steady-state excretion of 8-Iso reflects oxidative stress
(38). There is evidence of
enhanced oxidative stress during prolonged infusion of ANG II
(36) and in models of ANG
II-dependent hypertension (2,
8,
22,
24,
48). However, the roles of
AT1-R vs. AT2-R in the generation of oxidative stress
and the expression of NADPH oxidase and SOD in kidneys has not been
established.
The first aim of this study was to determine the effects of AT1- and AT2-R blockade on the excretion of 8-Iso during a "slow-pressor" dose of ANG II. Because isoprostanes also can be generated by metabolism of arachidonate via cyclooxygenase (19, 33), additional studies assessed the excretion of an arachidonate-independent marker of lipid peroxidation, malonyldialdehyde (MDA). The second aim was to investigate the effects of these perturbations on the renal expression of the mRNAs for the components of NADPH oxidase and SOD isoforms.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Studies were approved by the Georgetown University Animal Care and Use Committee. They were performed according to the Guide for the Care and Use of Laboratory Animals [DHEW Publication No. (NIH) 93-23, revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda, MD 20205] and the Guidelines of the Animal Welfare Act.
Experiments were performed on male Sprague-Dawley rats that weighed 210–300 g. Rats (n = 8/group) were maintained on a standard rat chow (Na+ content, 0.3 g/100 g) for 8–10 days before they were randomly assigned to different study protocols. Rats were anesthetized with halothane. Under sterile conditions, osmotic minipumps (model 2002, Alzet) that contained ANG II, vehicle (Veh; 0.154 M NaCl), or PD-123,319 (PD) were placed for subcutaneous infusion on day 1 in the nape of the neck. The PD group had one minipump with ANG II and a second with PD. ANG II or vehicle was infused for 7 days, after which the animals were studied.
Rats were housed in individual cages under conditions of constant temperature and humidity. They were exposed to a 12:12-h light-dark cycle and had unrestricted water intake. On the last day of study, rats were placed in clean individual metabolism cages. A 24-h urine sample was collected into containers that contained streptomycin (2,000 IU), penicillin G (2,000 IU), and amphotericin B (5 µg) to prevent microbial overgrowth. The urine was centrifuged, separated from the sediments, and stored at -70°C until it was analyzed. Urine was analyzed for volume, 8-Iso, and MDA. At completion of the urine collections, rats were anesthetized and the kidneys were flushed with ice-cold phosphate-buffered saline (PBS). Kidneys were removed immediately and the cortex was separated by dissection for extraction of mRNA and stored at -70°C.
Study Protocols
We tested the hypothesis that a prolonged subcutaneous infusion of ANG II increases the excretion of 8-Iso and MDA via type 1 or 2 receptors. Four groups of rats had osmotic minipumps inserted to infuse subcutaneously a Veh or ANG II at 200 ng·kg-1·min-1 for 1 wk. The third group received the ANG II infusion and candesartan cilexetil (Cand). Cand was added to the drinking water in a dose calculated to deliver 10 mg·kg-1·24 h-1. This dose of Cand given to spontaneously hypertensive rats (SHR) over 10–14 days normalizes the elevated mean arterial pressure and renal vascular resistance and also normalizes the depressed glomerular filtration rate (GFR; Ref. 48). The fourth group received separate subcutaneous infusions of ANG II and PD. PD was added to osmotic minipumps to deliver 60 mg·kg-1·24 h-1. This dose of PD was selected because when given intravenously to normal rats, it is shown to increase renal interstitial generation of NO metabolites and cyclic guanosine monophosphate (41). A lower dose of PD given by subcutaneous infusion to rats after a myocardial infarction reduces aortic compliance (3).
mRNA Isolation and Real-Time Quantitative RT-PCR
RNA isolation and RT were performed as described previously (4). Briefly, total RNA was isolated from the kidney cortex with guanidinium isothiocyanate (Qiagen, Valencia, CA) and treated with DNase. RT reactions were performed using the SuperScript Preamplification System (GIBCOBRL, Rockville, MD) for the first-strand cDNA synthesis. Real-time quantitative PCR was done using an ABI Prism 7700 (Applied Biosystems) sequence-detection system. Primers and probes for the NADPH oxidase subunits [p22phox, gp91phox, p47phox, p67phox, Nox-4, Nox-1, intracellular (IC)-SOD, Mn-SOD, and EC-SOD] were designed using Primer Express 101 software (Table 1). The probes were labeled with 6-carboxyfluorescein (FAM) phosphoramidite as a reporter at the 5' end and with 6-carboxy-tetramethylrhodamine (TAMRA) as a quencher at the 3' end. ROX was used as a passive reference in each sample to normalize for non-PCR related fluctuations in fluorescence signal. As an active reference, endogenous 18S ribosomal RNA (r18S) or glyceraldehyde-3-phoshate dehydrogenase (GAPDH) was amplified using specific primers and probes labeled with VIC (Applied Biosystems) at the 5' end as a reporter and TAMRA at the 3' end as a quencher. The sensitivity and specificity of the assays were assessed from serial dilutions of reference and target templates in separate PCR reactions. Optimal primer concentrations were determined as the minimum primer concentration to yield maximum change in emission intensity (Rn) and minimum cycle number of fluorescence signal of the product that crosses an arbitrary threshold set within the exponential phase of the PCR (CT). Optimal probe concentrations were chosen as those that yielded minimum CT. The comparative CT method was used for relative quantification and statistical analysis (50).
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Experiments were conducted in two series. Series 1 compared rats infused with Veh or ANG II. Series 2 compared ANG II-infused rats with ANG II vs. Cand and ANG II vs. PD rats.
Chemical Methods
8-Iso. Urine for 8-Iso was extracted, purified, and analyzed using an enzyme immunoassay kit (Cayman Chemical) and methods described in detail and validated in a prior study (39). Our assay has a limit of detection of 1 pg/ml, an intraassay coefficient of variation of 8% (n = 10), and an interassay coefficient of variation of 10% (n = 6). A blinded comparison of 12 rat-urine samples analyzed using both our RIA method and gas spectrometry-mass spectrometry (GC-MS; kindly undertaken by Jack Roberts, M.D., University of Vanderbilt) showed a good correlation (r = 0.85; P < 0.001) without systematic bias. The variation includes those due to RIA and GC-MS. Briefly, samples were diluted to fall in the midportion of the standard curve (10–100 pg/ml). Samples were extracted using a polyboronic acid column, eluted with ethyl acetate that contained 1% methanol, and evaporated under nitrogen. The 8-Iso was assayed using an enzyme-linked competitive binding assay (ELISA) with mouse anti-rabbit IgG monoclonal antibody in a 96-well plate. Concentrations of the reaction product were determined from absorbency at 405 nm using a standard curve. Samples were assayed in duplicate. Recovery of 3H-8-Iso averaged 76 ± 3% (n = 12).
MDA. MDA in the urine was measured using a commercial kit (Oxi-Tek TBARS Assay Kit, Zeptometrix, Buffalo, NY) that utilizes the measurement of thiobarbituric acid-reactive substances (TBARS). Briefly, urine (100 µl) was mixed with 100 µl of 8.1% sodium dodecyl sulfate (SDS). The TBA-buffer reagent was prepared by mixing 0.5 g of thiobarbituric acid with 50 ml of acetic acid and 50 ml of NaOH. Then 2.5 ml of TBA-buffer reagent was added to 200 µl of sample-SDS mixture and incubated in capped tubes at 95°C for 60 min. Thereafter, the sample was cooled to room temperature in an ice bath for 10 min and centrifuged at 3,000 rpm for 15 min. The supernatant was removed and its absorbance was measured at 532 nm in semi-microcuvettes in a spectrophotometer (Genesys 10 Vis). The concentration of TBARS was expressed in nanonmoles per milliliter of MDA equivalents by interpolation from a standard curve of MDA in concentration from 0–10 nmol/ml.
Drugs
ANG II (Sigma Chemical, St. Louis, MO) was dissolved in 0.9% saline. Cand (a generous gift of Peter Morsing, Ph.D., AstraZeneca, Moldal, Sweden) was prepared daily and mixed in the drinking water according to the manufacturer's instructions as described previously (31). The trifluoroacetate salt PD-123,319–121B (a generous gift from Joan Keiser, Ph.D., Parke-Davis, Chicago, IL) was prepared as described previously (41) and was added to the osmotic minipumps.
Statistical Methods
Results are reported as means ± SE. Data were analyzed using SPSS software. Comparisons between multiple groups were by ANOVA. When appropriate, post hoc comparisons between groups were made by Dunnett's t-test. The mRNA expression for ANG II-infused animals relative to Veh and for coadministration of Cand and PD with ANG II are reported as the ratios ± the central limit SE with the 95% confidence intervals based on the assumption of an approximate log-normal distribution of the ratios.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Compared with Veh-infused rats, subcutaneous ANG II infusion increased the excretion of 8-Iso by 41% (Veh, 5.4 ± 0.8 vs. ANG II, 7.6 ± 0.5 pg/24 h; P < 0.05) as is shown in Fig. 1A. The increase with subcutaneous ANG II was prevented by Cand (5.6 ± 0.5 pg/24 h; P < 0.05 vs. ANG+Veh), but during PD infusion the increase with ANG II was 2.1-fold greater than with ANG II alone (15.8 ± 2.0 pg/24 h; P < 0.005). Subcutaneous ANG II also increased the excretion of MDA by 47% (Veh, 17.9 ± 1.2 vs. ANG II, 26.4 ± 1.5 nmol/24 h; P < 0.002) as shown in Fig. 1B. This too was prevented by Cand (20.2 ± 1.9 nmol/24 h vs. ANG II+Veh), but, during PD infusion, the increase with ANG II was increased further (33.2 ± 1.3 nmol/24 h; P < 0.002). We conclude that ANG II increased oxidative stress as reflected by changes in excretion of 8-Iso and MDA and that these effects are dependent on the AT1-Rs and are offset by the AT2-Rs.
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The data for mRNA expression in the kidney cortex relative to GAPDH and r18S are presented in Table 2 and in Figs. 2 and 3. Because these figures represent changes compared with the mean values for the Veh- or ANG II-alone groups, only mean changes can be calculated. A unit increase in cycle value represents a two-fold increase in mRNA abundance. Reported probability values for mRNA expression in Table 2 should be interpreted cautiously in light of the increased chance of a type I error because of multiple comparisons. A ninefold Bonferroni adjustment for the examination of nine subunits requires P < (0.05/9) or P < 0.0056 for a decisive conclusion of significance. Only those results that remain significant under the Bonferroni adjustment are shown in Figs. 2 and 3. Compared to Veh, subcutaneous infusion of ANG II significantly (P < 0.0056) increased the expression of p22phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold) and decreased the expression of Nox-4 (2.1-fold) and EC-SOD (2.1-fold). All of the changes caused by ANG II except for those on Mn-SOD were reversed in rats receiving ANG II plus Cand (P < 0.005). Coinfusion of PD with ANG II significantly (P < 0.0056) increased the expression of p22phox (twofold), Nox-1 (2.3-fold), and p67phox (1.9-fold).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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One limitation of this study is the use of mRNA rather than protein. However, we found good general agreement between changes in mRNA and protein for NADPH oxidase subunits in the kidney of the SHR (4). Because our antibodies to
gp91phox cross-react with other isoforms, we elected for
the specificity of the mRNA method. Another limitation is the absence of
physiological data. We elected not to instrument the animals to prevent
confounding effects on mRNA expression. Moreover, some effects of ANG II
infusion under similar conditions and the effects of AT1- or
AT2-R blockade on renal function and blood pressure have been
reported. This dose of ANG II leads to a slow pressor response that raises the
blood pressure by 
22 mmHg and reduces the renal blood flow by 20%
over 7–12 days (7). The
blood pressure during ANG II infusion is reportedly reduced by
AT1-R blockade but is not altered by AT2-R blockade
(23). Therefore, in this
study, changes in oxidative stress with ANG II and ANG II + Cand likely were
complicated by parallel changes in blood pressure. However, we have shown
recently that oxidative stress in the kidney cortex of the SHR is reversed in
full by 2 wk of administration of an AT1-R antagonist but not by
equally effective anti-hypertensive therapy that does not block ANG II
(28). Moreover, in both the
young SHR (4) and in the young
stroke-prone SHR (27), the
oxidative stress and/or enhanced expression of NADPH oxidase preceded the
development of hypertension. Therefore, the effects of AT1-R
blockade have been dissociated from blood pressure.
O2-· interacts with arachidonate that is esterified into membrane phospholipids and yields free isoprostanes after hydrolysis by phospholipases (38). Therefore, a short-term increase in 8-Iso excretion may relate to release of preformed isoprostanes. ANG II is a potent stimulus to phospholipase activity (47). However, the sustained increase in 8-Iso detected after 1 wk of ANG II administration likely represents increased generation. Isoprostanes also can be generated enzymically by cyclooxygenase-1 in platelets (34) or cyclooxygenase-2 in monocytes (32) or isolated glomeruli (18). However, we found the same pattern of changes in excretion of 8-Iso and MDA that is not generated by cyclooxygenase (Fig. 1, A and B). Moreover, the enhanced excretion of 8-Iso in the SHR (39) and the ANG II-infused mouse (17) is reversed by coinfusion of the membrane-permeable SOD mimetic tempol to obviate associated oxidative stress. These markers of lipid peroxidation apparently reflect systemic rather than renal-limited oxidative stress (37, 38).
AT1- and AT2-Rs are widely distributed in the cortex and medulla of the kidneys of adult rats except for the glomerulus, which lacks the mRNA or immunocytochemial staining for AT2-Rs (25). The increase in O2-· by ANG II in cultured endothelial cells is prevented by blockade of AT1-Rs and enhanced by blockade of AT2-Rs (42). AT2-Rs in the kidney are upregulated by salt depletion or ANG II infusion (40). An enhanced expression of AT2-Rs may explain why blockade of the AT2-Rs had such potent effects in enhancement of oxidative stress during ANG II infusion. Our results assign the oxidative stress during ANG II infusion to activation of AT1-Rs. They demonstrate that the relatively modest effects of prolonged ANG II administration are due to offsetting activation of AT2-Rs.
Three isoforms of a gp91phox family (Nox-1, gp91phox, and Nox-4) have been reported in blood vessels or kidney. These form the catalytic center of the enzyme (1), and the normal rat kidney expresses the mRNA for each of them (4). There is a prominent expression of gp91phox in vascular smooth muscle cells (VSMCs) of resistance arterioles from humans (46), in fibroblasts (30), and in endothelial cells (16). In microvessels, gp91phox is upregulated by ANG II (46). Our failure to detect this change in kidney cortex may relate to the small contribution of microvessels to whole kidney mRNA. Nox-1 is expressed in VSMCs and rodent colon (20). Nox-1 is a major isoform in larger blood vessels, where it can replace gp91phox and mediate ANG II-induced O2-· formation and redox signaling (20). We confirmed that ANG II upregulates Nox-1 in the kidney and showed that this can be ascribed to effects of AT1-Rs that are offset by opposite effects of AT2-Rs. Nox-4 has been located in the proximal tubules and medullary collecting ducts (12). Nox-4 is upregulated by ANG II in VSMCs of transgenic rats with extra renin genes (51), whereas we detected a reduction in Nox-4 in kidney with ANG II. This may relate to differences in the kidney compared with VSMCs or to the fact that ANG II stimulates Nox-4 in VSMCs only for the first 24 h (26). Moreover, renin-transgenic rats have a severe malignant form of hypertension in contrast to the relatively moderate increase in blood pressure that is associated with ANG II infusion. Indeed, our observation is in agreement with that of Lassegue et al. (20), who reported downregulation of Nox-4 by ANG II in VSMCs. The increase in renal cortical Nox-1 mRNA expression in ANG II-infused rats was accompanied by increased p22phox expression. This change is apparently mediated by AT1-Rs, because it is blocked by Cand, which is similar to results reported for the vasculature (9). Blockade of AT2-Rs with PD accentuates the effects of ANG II to increase expression of p22phox and Nox-1. The parallel upregulation of p22phox and Nox-1 by ANG II, which is prevented by Cand and accentuated by PD, is accompanied by parallel changes in oxidative stress. This suggests that p22phox and Nox-1 may be critical in transducing the effects of AT1-Rs to increase and AT2-Rs to decrease the activity of NADPH oxidase to generate O2-· in the kidney.
We found that ANG II infused with PD stimulates the expression of p67phox in the kidney. ANG II upregulates p67phox in adventitial fibroblasts (29) and aorta (5). Although the function of the subunits of NADPH oxidase in nonphagocytic cells remains controversial, p67phox facilitates the transfer of electrons to the flavine center of cytochrome b and contains an NADPH-binding site (1, 6). Absence or dysfunction of this subunit results in impaired phagocyte production of superoxide and the clinical condition of chronic granulomatous disease (45). Although p47phox appears to be crucial for the overall activity of the enzyme, it can be substituted for by high abundance of p67phox (1). Upregulation of p67phox might contribute to oxidative stress in ANG II-infused rats given PD.
The finding that ANG II infusion decreases the expression of EC-SOD and that this is reversed by Cand suggests that EC-SOD may contribute to the protective effects of AT1-R blockade on oxidative stress in the kidneys (48). Losartan has also been reported to increase EC-SOD activity in humans (15). In contrast, Fukai et al. (11) reported that losartan prevents the increased expression of EC-SOD in blood vessels of mice infused with ANG II. The cause for these differences is not clear. Moreover, it is uncertain whether EC-SOD is fully effective in the rat (3). Interestingly, NO increases the activity of vascular EC-SOD (10). Cand increases bioactive NO in hypertensive rat kidney (48). Therefore, the enhanced EC-SOD expression induced by Cand during ANG II administration may be a response to increased NO within the kidney.
ANG II increased Mn-SOD expression in the kidney cortex. An increase in Mn-SOD occurs in response to oxidative stress, which could underlie this finding. However, the increased expression was not affected by Cand, which suggests that the effects of ANG II may be mediated via an independent mechanism such as by ANG-(1–7).
In conclusion, these studies confirm that ANG II causes oxidative stress. They ascribe the increased oxidative stress to activation of AT1-Rs, which is offset by AT2-Rs. ANG II infusion enhances the renal cortical mRNA expression of p22phox, Nox-1, and Mn-SOD and reduces the expression of Nox-4 and EC-SOD. Activation of AT1-Rs contributes to increased expression of p22phox and Nox-1 and decreased expression of Nox-4 and EC-SOD, whereas activation of AT2-Rs blunts the increase in p22phox and Nox-1 and reduces the expression of p67phox. Thus there are powerful, countervailing effects of type 1 and 2 receptors on oxidative stress in the kidney.
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ACKNOWLEDGMENTS |
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This work was supported by the National Kidney Foundation of the National Capital Area; the National Institute for Diabetes and Digestive and Kidney Diseases (Grants DK-36079 and DK-49870); the National Heart, Lung, and Blood Institute (Grants HL68686–01); and the George E. Schreiner Chair of Nephrology. C. Kitiyakara was supported by a fellowship training grant from the International Society of Nephrology and the National Kidney Foundation of the National Capital Area.
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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.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
in isolated rat kidney glomeruli
by radical-independent mechanism. Br J Pharmacol
133: 643–650,
2001.[ISI][Medline]
in vitro and
in vivo via the cyclooxygenases. J Pharmacol Exp Ther
282: 1658–1665,
1997. by human monocytes. J Biol
Chem 271:
8919–8924, 1996.. J
Biol Chem 270:
9800–9808, 1995. by human platelets.
Agents Actions Suppl 45:
27–31, 2002.
. Hypertension
33: 424–428,
1999.This article has been cited by other articles:
|
|
 |
|
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|
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C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]
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S. Wesseling, D. A. Ishola Jr., J. A. Joles, H. A. Bluyssen, H. A. Koomans, and B. Braam Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1191 - F1200. [Abstract] [Full Text] [PDF]
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B. Xue, J. Pamidimukkala, and M. Hay Sex differences in the development of angiotensin II-induced hypertension in conscious mice Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2177 - H2184. [Abstract] [Full Text] [PDF]
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