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Role of Oxidative Stress in Endothelial Dysfunction and Enhanced Responses to Angiotensin II of Afferent Arterioles from Rabbits Infused with Angiotensin II

Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University, Washington, DC

Correspondence to Dr. Christopher S. Wilcox, Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Road, NW, PHC F6003, Washington, DC 20007. Phone: 202-687-9183; Fax: 202-687-7893;

	Abstract

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ABSTRACT. The hypothesis that O₂^·- enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII–induced hypertension was investigated. Rabbits (n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean ± SD; 103 ± 9 versus 73 ± 6 mmHg; P < 0.01), plasma lipid peroxides (2.6 ± 0.3 versus 2.0 ± 0.3 nM; P < 0.05), renal cortical NADPH- and NADH-dependent O₂^·- generation, and Aff mRNA for p22^phox 5-fold (P < 0.001) but decreased that for AT₁-receptor 2.4-fold (P < 0.01). AngII 60 increased only NADH-dependent O₂^·- generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 ± 4 versus +85 ± 6%; P < 0.001), but these became similar in the presence of nitro-L-arginine (10^-4 M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10^-7 M) but significantly (P < 0.05) enhanced AngII contractions (10^-8 M: Sham -52 ± 5 versus AngII 60 to 77 ± 5 versus AngII 200 to 110 ± 10%). The superoxide dismutase mimetic tempol (10^-4 M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (-64 ± 7%). The AngII slow pressor response enhances renal cortical O₂^·- and p22^phox expression. Increased O₂^·- generation in Aff mediates an impaired nitric oxide synthase–dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT₁ receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O₂^·-. E-mail: wilcoxch@georgetown.edu

	Introduction

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The angiotensin II (AngII) slow pressor response in mice (1), rats (2), rabbits (3), and humans (4) is a gradually developing increase in BP during an infusion of AngII at doses that are initially subpressor. It has been proposed as a model of human essential hypertension (2,3,5). It is specific for AngII because similar infusions of norepinephrine (NE) lead only to tachyphylaxis (4,6). An increase in renal vascular resistance (RVR) precedes hypertension (1,7).

Rats or mice developing a slow pressor response have evidence of oxidative stress (1,6,8–10). Blood vessels and kidneys have an enhanced expression of the p22^phox and Nox-1 components of NADPH oxidase and enhanced NADPH oxidase activity (11–15). Moreover, the infusion of a permeant nitroxide superoxide dismutase (SOD) mimetic, tempol, and/or vitamin E reverses oxidative stress, hypertension, and renal vasoconstriction in rats or mice infused with AngII at a slow pressor rate (1,8). Studies in large conduit vessels have shown that superoxide anion (O₂^·-) can diminish the bioactivity of nitric oxide (NO) by conversion to peroxynitrite (ONOO^-) (16), but the mechanisms in renal microvessels are largely unexplored.

We tested the hypothesis that an enhanced generation of O₂^·- within the renal afferent arterioles (Aff) from animals undergoing an AngII slow pressor response mediates an impaired endothelium-derived relaxing factor response and enhanced contractile response to AngII.

	Materials and Methods

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Animal Protocols
The study protocol was approved by the Institutional Animal Care and Use Committee of Georgetown University Medical Center. It was performed according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the guidelines of the Animal Welfare Act. Male New Zealand White rabbits (1.6 to 1.8 kg) were maintained on tap water and standard diet. Under local anesthesia with EMLA cream (2.5% lidocaine and 2.5% prilocaine), groups of rabbits (n = 6 per group) received a subcutaneous implant of a sterile osmotic minipump (Alzet; DURET Corporation, CA) to infuse 0.154 M NaCl (Sham) or human AngII (Peninsula Laboratories, Belmont, CA) at 60 ng/kg per min (AngII 60) or 200 ng/kg per min (AngII 200) for 14 d. Mean arterial pressure (MAP) was measured by a pressure transducer and recorder (model DPM-1B; Bio Tek Instruments, Winooski, VT) on the experiment day in conscious rabbits via an ear artery cannulated under local anesthesia with EMLA cream.

Plasma Lipid Peroxides
Plasma lipid peroxide (LPO) was measured from thiobarbituric acid reactive substance (Oxi-Tek TBARS assay kit, Zeptometrix Corp., NY) (15).

O₂^·- Generation from Renal NADH and NADPH
The kidney was removed and perfused with ice-cold PBS. The cortex and outer medulla were collected separately and stored at -80°C. Samples were homogenized, and NADH, NADPH, or xanthine (17) (final concentrations of each 200 µM) were added to stimulate production of O₂^·-, which was detected using lucigenin-enhanced (final concentration 5 µM) chemiluminescence (Auto-LumatPlus LB 953, EG&G Berthhold, Germany). Data were converted to superoxide production by comparison with cytochrome c reduction (18).

mRNA Isolation and Real-time Quantitative RT-PCR
A single Aff from six Sham, AngII 60, and AngII 200 rabbits was dissected, washed in PBS, and transferred to a tube containing 10 µl of ice-cold PBS with 1 unit/µl of human placental RNaseOut (Life Technologies BRL, Rockville, MD) and 5 mM dithiothreitol, snap-frozen, and stored at -80°C. An aliquot of dissection solution was used to exclude contamination. RNA isolation and RT were performed as described previously (19). Primers and probes for the AT₁-R_, AT₂-Randp22^phox were designed using Primer Express software 101 (Table 1). As an active reference, endogenous 18S ribosomal RNA (r18S) was amplified using specific primers and probes labeled with VIC (ABI). The comparative C_T method was used for relative quantification and statistical analysis (20) and fold changes to present data graphically. A unit increase in cycle value represents a twofold changed mRNA abundance.

The viability of the arteriole was tested at the beginning and the end of the experiment. Only vessels that showed a >50% contractile response to NE (10^-7 M) were selected. Thereafter, there was 10 min for recovery, after which baseline luminal diameter was obtained. Each experiment in each series used a separate arteriole.

Experimental Protocols
Series 1.
The aim was to compare the MAP, plasma LPO, renal O₂^·- generation, and mRNA abundance of AngII type I (AT₁) and type II (AT₂) receptors and the p22^phox component of NADPH oxidase in arterioles from the three groups (n = 6 per group).

Series 2.
The aim was to compare the relaxation and contraction responses of Aff from AngII 60 and AngII 200 with Sham rabbits (n = 6 per group). Maximal endothelium-dependent relaxation was assessed with 10^-5 M acetylcholine (Ach), and maximal endothelium-independent relaxation was assessed with 10^-3 M sodium nitroprusside (SNP) in arteriole preconstricted with 10^-7 M NE.

A standard contraction, referred to as -100%, was first established with NE 10^-7 M and 40 mM KCl (NAK). The diameter during contraction with NAK was similar in each of the three groups and was not affected by tempol. Aff contractions were assessed by superfusion for 3 min with NE (10^-7 M) or AngII (10^-8 M). Vessels were recovered for 10 min between studies.

Series 3.
The aim was to compare the effects of metabolism of O₂^·- on responses of Aff from AngII 60 and AngII 200 with Sham rabbits (n = 6 per group). Aff were incubated with the permeant SOD mimetic nitroxide tempol (10^-4 M) for 20 min (23). Luminal diameters were measured during basal conditions and after superfusions that followed the protocol of series 2.

Series 4.
The aim was to assess the role of NO and O₂^·- in endothelium-dependent relaxation responses of arterioles from AngII 60 and AngII 200 with Sham rabbits (n = 6 per group). Aff were preconstricted with NE (10^-7 M) and relaxed with ACh (10^-5 M). They were pretreated for 20 min with nitro-L-arginine (L-NNA; 10^-4 M) to test the role of NO synthase (NOS). Thereafter, the bath was washed out and tempol (10^-4 M) was added for 20 min to test the role of O₂^·-.

Drugs and Solutions
All solutions were prepared fresh daily. All reagents were purchased from Sigma (St. Louis, MO).

Statistical Analyses
Statistical tests of the percentage of vasoconstriction or vasodilation under different treatments used two-factor repeated-measures ANOVA (Statistica software v.5.0; University of Hamburg, Hamburg, Germany). When appropriate, post hoc comparisons between groups were made with t tests. Statistical significance was defined as P < 0.05. Data are presented as mean ± SD.

	Results

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Series 1
AngII 60 rabbits did not differ significantly from Sham for MAP (Figure 1A) or plasma LPO concentration (Figure 1B). In contrast, AngII 200 rabbits had a significant increase in MAP (103 ± 9 versus 73 ± 6 mmHg; P < 0.01; Figure 1A) and plasma LPO (2.6 ± 0.3 versus 2.0 ± 0.3 nM MDA; P < 0.05; Figure 1B).

View larger version (36K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Mean ± SD values for mean BP (A) and plasma lipid peroxide (LPO) concentration (B) from three groups of rabbits. Compared with control: *P < 0.05; **P < 0.01.

View larger version (32K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Mean ± SD values for basal and NADH-, NADPH-, and xanthine-stimulated O2·- generation in the renal cortex (A) or renal outer medulla (B) of the three groups of rabbits. Compared with control: *P < 0.05; **P < 0.01.

View larger version (28K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Mean ± SD values (calculated from CT) for fold changes in mRNA abundance (relative to 18S) in individual afferent arterioles (Aff) of angiotensin II (AngII) 60 and AngII 200 rabbits, compared with vehicle-infused controls. Significance of difference: **P < 0.01; ***P < 0.005.

The mRNA for p22^phox in Aff from AngII 60 rabbits was not significantly different from Sham rabbits (C_T 11.69 ± 0.34 versus 12.56 ± 0.26; NS). However, the mRNA for p22^phox from arterioles from AngII 200 rabbits was increased significantly (C_T 10.09 ± 0.28; P < 0.005).

Series 2
The diameter of Aff in the basal state averaged 17.3 ± 1.2 µm. Basal luminal diameter was decreased significantly (P < 0.001) by NAK to 6.5 ± 0.5 µm in Sham, 6.3 ± 0.6 µm in AngII 60, and 6.4 ± 0.5 µm in AngII 200 (NS between groups).

As shown in Figure 4, vasodilator responses of arterioles from AngII 60 rabbits to ACh and SNP were not significantly different from Sham. Arterioles from AngII 200 rabbits had a significantly blunted vasodilator response to ACh (50 ± 4 versus 85 ± 6%; P < 0.001) but an unchanged response to SNP.

View larger version (46K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Mean ± SD values for percentage change in luminal diameter with acetylcholine (Ach; 10-5 M) and sodium nitroprusside (SNP; 10-3 M) in norepinephrine (NE)-preconstricted arterioles. Compared with control rabbits: **P < 0.01.

View larger version (43K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Mean ± SD values for percentage changes in luminal diameter of Aff to NE (10-7 M) and AngII (10-8 M). Compared with control rabbits: **P < 0.001; ***P < 0.001.

View larger version (39K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 6. Mean ± SD for percentage changes in luminal diameter of Aff to NE (10-7 M) and AngII (10-8 M) in the presence of bath with tempol (10-4 M). Compared with control rabbits: **P < 0.001; ***P < 0.001.

View larger version (49K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 7. Mean ± SD values for luminal diameter changes of Aff during addition to the bath of vehicle, nitro-L-arginine (L-NNA; 10-4 M), or tempol (10-4 M). Compared with vehicle: ***P < 0.005. Compared with control rabbits: bP < 0.01.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The main new findings of this study are that renal Aff from rabbits infused with AngII at a slow pressor rate that causes lipid peroxidation and enhances renal cortical NADPH-stimulated O₂^·- generation also exhibit impaired ACh-induced, endothelium-dependent relaxation and enhanced contractile responses to AngII. The effect is specific because there are no changes in response to NE or NE plus high [K⁺]. The arterioles have a profound downregulation of the mRNA for AT₁ receptors but an upregulation of the p22^phox component of NADPH oxidase. Inactivation of O₂^·- in these vessels by tempol normalizes the blunted responses to ACh and moderates but does not normalize the enhanced response to AngII. A lower rate of subcutaneous AngII infusion that is insufficient to raise the MAP, to cause lipid peroxidation, to enhance renal cortical NADPH-stimulated O₂^·- generation, or to enhance p22^phox expression does not impair responses to ACh but nevertheless augments the Aff contractile response to AngII. During tempol, there remains an enhanced response to AngII in vessels from AngII 60 and AngII 200 rabbits.

Imig (7) showed that prolonged infusion of AngII into rats increases the resistance of the renal Aff before that in other organs. Kawada et al. (1) showed similarly that prolonged infusion of AngII into mice raises renal vascular resistance before there is a detectable change in MAP. The finding that renal Aff from AngII 60 rabbits have a selective increase in response to AngII in the absence of hypertension indicates that there is an inherent adaptive change in the Aff and that this is not a response to systemic hypertension.

A limitation of this study is the reliance on mRNA to quantify AT₁ receptor expression on the Aff. The mRNA technique has unsurpassed specificity. The results obtained with the mRNA analysis are consistent with previous findings of downregulation of AT₁ receptor protein in the kidney cortex and downregulation of immunocytochemical expression of AT₁ receptors in the intrarenal vasculature during prolonged AngII infusion (24). However, the changes in the mRNA do not exclude the possibility that there may have been different changes in AT₁ receptor protein or an alteration in AT₁ receptor affinity that would not have been detected with these measurements. Previous studies of ligand binding have shown AT₁ but not AT₂ receptors on the renal preglomerular vessels of the rat (25).

Prolonged infusions of AngII cause oxidative stress in large vessels (26) and the kidney cortex (15). These effects are due to activation of AT₁ receptors and are offset in the kidney cortex by activation of AT₂ receptors (15). The development of oxidative stress was confirmed during subcutaneous infusion of AngII 200 by increased plasma levels of LPO, increased renal cortex NADPH- and NADH-stimulated O₂^·- generation, and increased p22^phox expression in isolated Aff.

Because the SOD-mimetic tempol antagonized the enhanced afferent arteriolar response to AngII in arterioles from AngII 200 rabbits, we conclude that AngII activates O₂^·- generation in Aff primed by previous AngII infusion at a slow pressor rate (27). These arterioles had no increase in responses to either NE alone or to NE and high [K⁺], and tempol failed to alter responses to these agonists. Thus, the response to AngII seems to be specific. These results extend previous studies in the isolated aorta that show that infusion of AngII but not NE induces oxidative stress (6). Moreover, subpressor infusions of AngII but not NE induce a slow pressor response (4).

The ACh-induced relaxation in this preparation is dependent on the endothelium (21,28). The present study confirms that approximately 60% of this response is dependent on NOS (21,28), and the remainder can be ascribed to an endothelium-derived hyperpolarizing factor. The impaired ACh vasorelaxation of Aff from AngII 200 rabbits extends studies in the spontaneously hypertensive rat (22). In our model, this could be ascribed to impaired NO action because the responses to ACh were normalized during NOS inhibition. The residual ACh-induced relaxation in Aff from AngII 200 rabbits may be mediated by an endothelium-derived hyperpolarizing factor. Because the impaired response to ACh was reversed in full by tempol, we conclude that the endothelial dysfunction is dependent on enhanced vascular O₂^·- that bioinactivates NO rather than a failure to express NOS. Indeed, prolonged AngII infusions into rats upregulates endothelial NOS expression in blood vessels (27) and kidneys (29). Prolonged AngII infusion enhances vascular generation of O₂^·-, which reacts with NO to yield peroxynitrite (ONOO^-) (30) that can uncouple endothelial NOS and direct it to synthesize O₂^·- preferentially (27,31).

AngII infused subcutaneously at 60 ng/kg per min was insufficient to elevate MAP, cause endothelial dysfunction or oxidative stress in arterioles, or activate NADPH oxidase. Nevertheless, arterioles from these rabbits exhibited a selective augmentation of contraction to AngII. This effect is independent of O₂^·- because it is not modified by tempol. This seemingly novel mechanism may represent a truly physiologic adaptation to normal levels of AngII. During tempol, there remained a significantly enhanced response to AngII in arterioles from AngII 200 rabbits that was similar to arterioles from AngII 60 rabbits. This suggests that the enhanced AngII response of the Aff from AngII 200 rabbits is the outcome of two independent processes: an O₂^·--dependent effect and an O₂^·--independent effect common to arterioles from AngII 60 rabbits. The latter may be a prehypertensive mechanism because enhanced resistance in the Aff may be a primary mechanism of hypertension (32–34).

In conclusion, prolonged subcutaneous infusions of AngII at a slow pressor rate enhance renal cortical NADPH expression and oxidative stress, which reinforces the contractile responses of Aff to AngII despite downregulation of the mRNA for AT₁-receptor expression and impairs endothelium-dependent relaxation responses to ACh. Lower rates of AngII infusion enhance AngII responses selectively by a mechanism that is independent of hypertension or oxidative stress.

	Acknowledgments

 
This work was supported by grants from the NKF, Nations Capital Affiliate, and from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-36079 and DK-49870) and the National Heart, Lung, and Blood Institute (HL-68686) and from funds from the George E. Schreiner Chair of Nephrology. Dr. Chen was supported by an American Heart Association Scientist Development Grant (0230308N), and Dr. Borrego was supported by an National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Nephrology and Hypertension Training Grant (DK-59274). We are grateful to Sharon Clements for preparing the manuscript.

	References

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				M. C. Gongora, Z. Qin, K. Laude, H. W. Kim, L. McCann, J. R. Folz, S. Dikalov, T. Fukai, and D. G. Harrison Role of Extracellular Superoxide Dismutase in Hypertension Hypertension, September 1, 2006; 48(3): 473 - 481. [Abstract] [Full Text] [PDF]

				P. Modlinger, T. Chabrashvili, P. S. Gill, M. Mendonca, D. G. Harrison, K. K. Griendling, M. Li, J. Raggio, A. Wellstein, Y. Chen, et al. RNA Silencing In Vivo Reveals Role of p22phox in Rat Angiotensin Slow Pressor Response Hypertension, February 1, 2006; 47(2): 238 - 244. [Abstract] [Full Text] [PDF]

				K. Patel, Y. Chen, K. Dennehy, J. Blau, S. Connors, M. Mendonca, M. Tarpey, M. Krishna, J. B. Mitchell, W. J. Welch, et al. Acute antihypertensive action of nitroxides in the spontaneously hypertensive rat Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R37 - R43. [Abstract] [Full Text] [PDF]

				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]

				Y. Chen, P. S. Gill, and W. J. Welch Oxygen availability limits renal NADPH-dependent superoxide production Am J Physiol Renal Physiol, October 1, 2005; 289(4): F749 - F753. [Abstract] [Full Text] [PDF]

				M. C. Blendea, D. Jacobs, C. S. Stump, S. I. McFarlane, C. Ogrin, G. Bahtyiar, S. Stas, P. Kumar, Q. Sha, C. M. Ferrario, et al. Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E353 - E359. [Abstract] [Full Text] [PDF]

				C. S. Wilcox and D. Gutterman Focus on oxidative stress in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H3 - H6. [Full Text] [PDF]

				W. J. Welch, J. Blau, H. Xie, T. Chabrashvili, and C. S. Wilcox Angiotensin-induced defects in renal oxygenation: role of oxidative stress Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H22 - H28. [Abstract] [Full Text] [PDF]

				Z. Zhang, K. Rhinehart, G. Solis, J. Pittner, W. Lee-Kwon, W. J. Welch, C. S. Wilcox, and T. L. Pallone Chronic ANG II infusion increases NO generation by rat descending vasa recta Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H29 - H36. [Abstract] [Full Text] [PDF]

				N. Kawada, K. Dennehy, G. Solis, P. Modlinger, R. Hamel, J. T. Kawada, S. Aslam, T. Moriyama, E. Imai, W. J. Welch, et al. TP receptors regulate renal hemodynamics during angiotensin II slow pressor response Am J Physiol Renal Physiol, October 1, 2004; 287(4): F753 - F759. [Abstract] [Full Text] [PDF]

				M. C. Zimmerman, E. Lazartigues, R. V. Sharma, and R. L. Davisson Hypertension Caused by Angiotensin II Infusion Involves Increased Superoxide Production in the Central Nervous System Circ. Res., July 23, 2004; 95(2): 210 - 216. [Abstract] [Full Text] [PDF]

				D. Wang, T. Chabrashvili, and C. S. Wilcox Enhanced Contractility of Renal Afferent Arterioles From Angiotensin-Infused Rabbits: Roles of Oxidative Stress, Thromboxane Prostanoid Receptors, and Endothelium Circ. Res., June 11, 2004; 94(11): 1436 - 1442. [Abstract] [Full Text] [PDF]

				A. R. Chade, J. D. Krier, M. Rodriguez-Porcel, J. F. Breen, M. A. McKusick, A. Lerman, and L. O. Lerman Comparison of acute and chronic antioxidant interventions in experimental renovascular disease Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1079 - F1086. [Abstract] [Full Text] [PDF]

				E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987. [Full Text] [PDF]

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