Published online before print September 15, 2003, doi: 10.1161/01.HYP.0000094220.06020.C8
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(Hypertension. 2003;42:945.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
In Salt-Sensitive Hypertension, Increased Superoxide Production Is Linked to Functional Upregulation of Angiotensin II
From the Nephrology and Hypertension Division, Veterans Affairs Medical Center, and the Vascular Biology Institute, University of Miami School of Medicine, Miami, Fla.
Correspondence to Leopoldo Raij, MD, Chief, Nephrology-Hypertension Section, Veterans Affairs Medical Center, 1201 NW 16 St (Room A-1009), Miami, FL 33125. E-mail LRaij{at}med.miami.edu
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Abstract |
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The balance between endothelial nitric oxide (NO) and angiotensin II (Ang II) maintains the homeostasis of the cardiovascular and renal systems. We tested the hypothesis that increased oxidant stress linked to a functional imbalance between NO and Ang II might play a central pathogenetic role in salt-sensitive (SS) hypertension. We studied Dahl SS (DS) rats during the prehypertensive (5 days) and hypertensive (12 weeks) phases of a high-salt (4% NaCl) diet. Control rats received a normal-salt (0.5% NaCl, [NS]) diet. Prehypertensive DS rats (systolic blood pressure [SBP] 138±2 mm Hg) manifested a 35% increase (P<0.05) in aortic superoxide (O2-) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214±11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O2- production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg · kg-1 · d-1) an Ang II type 1 receptor blocker (ARB), normalized O2- production. In hypertensive DS rats, the ARB decreased aortic O2- production by 71% and normalized EDR without affecting SBP (212±8 mm Hg), aortic hypertrophy, LVH, or proteinuria. Switching hypertensive DS rats to an NS diet did not affect SBP (208±8 mm Hg), LVH, aortic hypertrophy, or proteinuria and had minimal effects on O2- and EDR. Concomitant ARB administration plus a switch to an NS diet normalized SBP (138±8 mm Hg) as well as end-organ damage. Dahl salt-resistant rats fed an HS diet for 12 weeks did not show hypertension or increased O2- production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O2- synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.
Key Words: angiotensin II • endothelium • nitric oxide • oxidative stress • hypertension, sodium-dependent
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Introduction |
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Extensive studies of the relation between salt and blood pressure have established that some individuals are sensitive to dietary salt changes, whereas others are resistant.1 Epidemiologically, salt sensitivity (SS) affects
50% of hypertensive patients and 20% of normotensive patients.2 SS hypertensive patients almost uniformly have low plasma renin levels and often manifest microalbuminuria.3 SS hypertension, which is more prevalent in blacks and the elderly, has traditionally been considered a "volume-dependent hypertension," in which the role of angiotensin II (Ang II) was presumed to be irrelevant because of suppressed plasma renin.4 However, recent studies in Dahl SS (DS) rats, a well-known model of SS hypertension, have suggested that SS hypertension is accompanied by increased activation of the local renal renin-angiotensin system.5–7 On the basis of these studies, we hypothesize that functional upregulation of the renin-angiotensin system linked to a concomitant decrease in the bioactivity of nitric oxide (NO) might be an important contributor to the pathophysiology of endothelial dysfunction and end-organ injury in SS hypertension.8–10 There is an antagonistic interaction between endothelial NO and Ang II,11–13 and the balance between NO and Ang II appears crucial for maintaining homeostasis of the cardiovascular and renal systems,13 particularly for regulation of vascular tone and modulation of growth-related pathologic changes.14 The functional interaction is such that a reduction in NO bioactivity represents a proportional increment in the bioactivity of Ang II.15 Furthermore, recent studies have reported that long-term inhibition of NO synthesis actually results in upregulation of the synthesis of Ang II, as well as expression of the Ang II type 1 (AT1) receptor.16 Ang II activates NADH/NADPH oxidase in endothelial cells, vascular smooth muscle cells, adventitial fibroblasts, and glomerular mesangial cells.17–20 NADH/NADPH oxidase in turn produces superoxide anion (O2-), which avidly interacts with NO, reduces its bioactivity, and generates peroxynitrite.21–23 Elegant studies in patients with renovascular hypertension24 as well as ex vivo studies of human arteries have demonstrated that the biologic interaction between Ang II, O2-, and NO is fully operative in humans.25
The DS rat is a paradigm of low plasma renin, SS hypertension.26 We have previously shown that hypertensive DS rats downregulate endothelial NO synthase (eNOS) and develop impaired NO-mediated endothelial function, accompanied by cardiovascular and renal injury.10,27 It has been shown that levels of Ang II and angiotensinogen are increased in the kidney and heart of hypertensive DS rats.5–7 Moreover, recent studies have reported that vascular oxidative stress might be increased in hypertensive DS rats,28,29 although the mechanisms involved were not elucidated.
In the present study, we used DS rats to test the hypothesis that the vascular phenotype of SS, low-renin hypertension is one of endothelial dysfunction and functional upregulation of Ang II, accompanied by susceptibility to the development of cardiovascular and renal injury. The studies reported herein support the notion that SS might represent a vascular diathesis linked to functional upregulation of Ang II actions, accompanied by insufficient NO bioavailability. These studies also suggest that increased oxidant stress is associated with the functional imbalance between NO and Ang II.
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Methods |
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Animals and Experimental Protocols
In pilot studies, we determined that DS rats fed a high-salt (HS) diet containing 4% NaCl do not manifest an increase in systolic blood pressure (SBP) during the first 5 days but become progressively hypertensive thereafter. We studied groups of 6-week-old DS rats (Harlan, Indianapolis, Ind) during the prehypertensive (5 days) and hypertensive (12 weeks) phases of the HS diet. The prehypertensive DS rats were divided into 3 groups: HS, DS rats fed an HS diet (n=11); HS+ARB, DS rats fed an HS diet plus the AT1 receptor blocker (ARB) candesartan (10 mg · kg-1 · d-1 by gavage, n=7); and NS, DS rats fed a normal-sodium (NS) diet containing 0.5% NaCl (n=9). Rats in the hypertensive phase were divided into 5 groups: HS, DS rats fed an HS diet (n=6); HS+ARB, DS rats fed an HS diet plus candesartan (10 mg · kg-1 · d-1 by gavage, n=5); HS/NS, DS rats fed an HS diet for 6 weeks and then switched to an NS diet for 6 weeks (n=6); HS/NS+ARB, DS rats fed an HS diet for 6 weeks followed by 6 weeks of the NS diet plus candesartan (n=6); and NS, DS rats fed an NS diet throughout (n=6). SBP was measured by the tail-cuff method.27 Urine protein concentration was determined by a commercially available method (Bio-Rad).27
A separate group of Dahl salt-resistant (DR) rats were given a diet containing either 0.5% NaCl (NS, n=4) or 4% NaCl (HS, n=7) for 12 weeks. Aortic rings from DR rats were used for measuring O2- by lucigenin chemiluminescence, as described subsequently.
Detection of O2- Generation by Lucigenin Chemiluminescence
Measurement of O2- in intact aortic rings was performed by using the chemiluminescence of lucigenin, as previously described.20 Some rings were incubated with 10 µmol/L diphenylene iodonium (DPI), 10 µmol/L indomethacin, 100 µmol/L oxypurinol, 100 µmol/L Nw nitro-L-arginine (L-NAME), or 100 µmol/L tetrahydrobiopterin (BH4) to examine the potential role of NADH/NADPH oxidase, cyclooxygenase pathways, xanthine oxidase, NOS, and NOS cofactors, respectively, in the synthesis of O2-. All O2- measurements were adjusted for milligrams dry weight and expressed as counts per minute per milligram dry tissue per minute.
In Situ O2- Measurement by Confocal Fluorescence Microscopy
The oxidative fluorescent dye hydroethidine was used to evaluate in situ O2- generation.30 In brief, fresh aortic rings embedded in OCT compound were cut into 10-µm-thick sections, submerged in 2 µmol/L dihydroethidium in HEPES buffer, and incubated at 37°C for 30 minutes. At the end of this incubation period, the slides were washed with phosphate-buffered saline and kept at 4°C. Images were obtained with a Bio-Rad MRC-1024 laser scanning confocal microscope. Fluorescence was detected with a 585-nm long-pass filter and stored digitally.
Urine Isoprostane Excretion
Urinary isoprostanes were measured by an enzymatic immunoassay and by following the manufacturer’s instructions (Cayman). Results were expressed as nanograms per milligram creatinine.
Organ Chamber Experiments
Endothelial function was examined in aortic rings in an organ chamber bath, as previously described.10 Endothelium-dependent relaxation (EDR) in response to acetylcholine (Ach, 10-9 to 10-5 µmol/L) was studied in rings precontracted to 70% of maximal contraction to norepinephrine.10
Data Analysis
The data were expressed as mean±SEM. Statistical analyses were performed by ANOVA (Stat-View). Results were considered significant when P<0.05.
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Results |
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Blood Pressure
DS rats fed an HS diet for 5 days did not have an increase in SBP compared with the NS controls (Table 1). In contrast, the HS diet given for 12 weeks significantly increased SBP in DS rats compared with NS controls (Table 2 and Figure 1). A few HS rats studied for 12 weeks were sacrificed by decapitation before schedule because of complications from high blood pressure, especially strokes. Neither treatment with the ARB candesartan (HS+ARB) nor a return to an NS diet (HS/NS) after 6 weeks of the HS diet resulted in a significant reduction in SBP. However, treatment with the ARB combined with removal of the HS diet (HS/NS+ARB) reduced SBP to levels even below those of control NS rats (Table 2 and Figure 1)
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Urinary Protein Excretion
An HS diet for 5 days did not result in significant proteinuria compared with the control NS group (Table 1). In contrast, an HS diet for 12 weeks resulted in a significant increase in urinary protein excretion (Table 2). In hypertensive HS rats, neither the ARB (HS+ARB) nor removal of the HS diet (HS/NS) alone significantly reduced proteinuria. However, simultaneous treatment with the ARB and removal of the HS diet (HS/NS+ARB) reduced proteinuria to levels below those of control NS rats (Table 2).
Aortic and LV Hypertrophy
An HS diet for 5 days did not have a significant effect on aortic weight or left ventricle (LV) weight–to–body weight ratio (LVW/BW; Table 1). In contrast, an HS diet for 12 weeks significantly increased aortic weight and the LVW-BW ratio (Figure 2). In hypertensive HS rats, neither a return to an NS diet (HS/NS) nor treatment with the ARB (HS+ARB) alone reduced aortic weight or the LVW-BW ratio. However, simultaneous treatment with the ARB and reinstitution of an NS diet (HS/NS+ARB) normalized both aortic weight and the LVW-BW ratio.
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Vascular O2- Production
An HS diet for 5 days significantly increased aortic O2- production by 35% compared with NS, as assessed by chemiluminescence of lucigenin (Figure 3). Treatment with the ARB (HS+ARB) prevented the increase in aortic O2-, which suggests that activation of the AT1 receptor mediated the increased O2- production in these rats (Figure 3). Furthermore, aortic rings from rats fed an HS diet for 5 days showed an increase in O2- production, as assessed by laser confocal fluorescence microscopy, compared with aortic rings from rats fed the NS diet. The increased fluorescence was evident in all vascular layers, including vascular smooth muscle, endothelial, and adventitial layers. In agreement with the studies with lucigenin, aortic rings from HS rats treated with the ARB (HS+ARB) showed a significant reduction in fluorescence (Figure 4).
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Ex vivo incubation of aortic rings with DPI significantly reduced O2- production in the aortic rings from both NS (NS, 899±89 vs NS+DPI, 644±85 counts · mg dry weight-1 · min-1; P<0.05) and prehypertensive HS (HS, 1219±65 vs HS+DPI, 632±65 counts · mg dry weight-1 · min-1; P<0.05) rats. The reduction in O2- production was less pronounced in the NS rats (28%) than in the prehypertensive HS rats (48%), suggesting that the increased NADH/NADPH oxidase activity is the source of increased O2- production in aortas from prehypertensive rats. In contrast, preincubation with indomethacin, BH4, or L-NAME did not reduce O2- production in any group of rats studied for 5 days, whether normotensive (NS) or prehypertensive (HS) (data not shown).
An HS diet for 12 weeks resulted in a 320% increase in aortic O2- production in hypertensive HS rats compared with NS rats (P<0.05). Return to an NS diet (HS/NS) resulted in a small but statistically insignificant reduction in O2- production (Figure 5A). Treatment with the ARB (HS+ARB) resulted in a 71% reduction in aortic O2- production (Figure 5A), even though it did not decrease SBP (Figure 1). In aortic rings from hypertensive HS rats studied ex vivo, preincubation with DPI, indomethacin, or L-NAME decreased O2- production by 45%, 28%, and 35%, respectively (Figure 5B). However, preincubation with the xanthine oxidase inhibitor oxypurinol had no effect on O2- production (Figure 5B), which suggests that in hypertensive HS rats, in addition to NADH/NADPH oxidase, cyclooxygenase31 and uncoupling of NOS32,33 participate in the increased generation of aortic O2-. In contrast with DS rats, in DR rats an HS diet for 12 weeks did not result in increased aortic O2- production (DR rats fed an NS diet, 903±74 counts · mg-1 · min-1 vs DR fed an HS diet, 784±149 counts · mg-1 · min-1, P=NS). Chemiluminescence of lucigenin has been validated as a sensitive and specific method to measure O2-.34 However, to further validate the O2- measurements, aortic rings from hypertensive rats were incubated with the specific O2- scavenger Tiron (10 mmol/L). Preincubation of aortic rings from HS rats with Tiron resulted in a 90% reduction of aortic O2- measurements, further establishing the specificity of chemiluminescence of lucigenin to assess aortic O2- generation (Figure 5B).
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P<0.05 vs NS; #P<0.05 vs control rings, n=5 or 6.Moreover, the production of O2- in aortas from ARB-treated rats (HS+ARB, 1451±88 counts · mg dry weight-1 · min-1; Figure 5A) was similar to that in aortas from hypertensive HS rats incubated ex vivo with DPI (1371±78 counts · mg dry weight-1 · min-1; Figure 5B). These findings strongly suggest that the reduction in aortic O2- production in rats treated with the ARB is due to reduced activation of NADH/NADPH oxidase.
Urinary Isoprostane Excretion
We measured the urinary excretion of isoprostanes as an additional marker of oxidative stress in vivo. Hypertensive HS rats manifested a significant increase in urinary isoprostane excretion (HS rats, 1.45±0.34 ng/mg creatinine vs NS rats, 0.79±0.11 ng/mg creatinine, P<0.05). These findings provide further evidence of increased O2- production in HS rats.
EDR to Ach
An HS diet for 5 days did not affect EDR to Ach (Figure 6A). In contrast, hypertensive HS rats showed a significant impairment of EDR to Ach when compared with NS rats. Return to an NS diet (HS/NS) increased the maximal relaxation to Ach but did not improve ED50 to Ach (Table 2). Strikingly, treatment with the ARB (HS+ARB) normalized EDR, even though this agent did not reduce the blood pressure of hypertensive HS rats (Figure 6B).
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Discussion |
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The nitric oxide–renin-angiotensin axis plays a major role in the maintenance of cardiovascular and renal homeostasis.35–37 The countervailing interaction between NO and Ang II extends beyond the fact that NO is a vasodilator and Ang II is a vasoconstrictor.13 Indeed, NO downregulates the synthesis of Ang II as well as AT1 receptors.38 On the other hand, Ang II, at both pressor and subpressor doses, results in impaired NO-mediated EDR owing to an increase in vascular production of O2-,24,39 which reduces NO bioavailability and generates peroxynitrite.21–23 O2- originates from NADH/NADPH oxidase, an enzyme that is known to be upregulated by Ang II via activation of the AT1 receptor.40 Peroxynitrite has been shown to induce the release of Zn2+ from the zinc thiolate center of NOS, which results in NOS uncoupling32; dysfunctional NOS produces more O2- than does NO.33,41
Dahl rats constitute a paradigm of SS hypertension in humans.26 In previous studies, we demonstrated that hypertensive DS rats downregulate endothelial NOS activity and develop impaired NO-mediated endothelial function, accompanied by cardiovascular and renal injury.10,27 The glomerular injury of hypertensive DS rats is associated with increased expression of transforming growth factor-ß, a molecule that is upregulated by Ang II.42 Moreover, the concentration of angiotensinogen and Ang II is increased in the kidneys of hypertensive DS rats on an HS diet, suggesting increased activation of the local renal renin-angiotensin system.5,6 In addition, studies have reported increased vascular O2- production in hypertensive DS rats,28,29,43 although the mechanisms involved were not elucidated. In the present study, we investigated whether the increased O2- generation is linked to functional upregulation of Ang II in DS rats fed an HS diet.
Initially, we demonstrated that prehypertensive DS rats fed an HS diet for 5 days did not develop either proteinuria or LV hypertrophy. However, during this prehypertensive stage, aortic O2- production was significantly increased. Confocal microscopy revealed that the increased O2- originated from all vascular layers. Because aortic O2- production was normalized by administration of the ARB in vivo and by DPI, an inhibitor of NADPH/NADH oxidase, ex vivo, we propose that in DS rats high dietary salt induces a functional upregulation of Ang II, which results in an NADH/NADPH-dependent increase in O2- production. Obviously, during the prehypertensive stage, the increased O2- production is not of sufficient magnitude to decrease NO bioactivity and result in impaired EDR. Moreover, it is apparent that the amount of O2- produced is also not enough to generate peroxynitrite in amounts sufficient to induce a functional uncoupling of NOS, leading to increased O2- production by NOS itself.32 The failure of both BH4 and L-NAME to reduce aortic O2- production in HS rats supports the latter contention.
During the hypertensive phase, HS rats developed LV hypertrophy, aortic hypertrophy, proteinuria, and impaired EDR. Concomitantly, aortic O2- production was increased by 320%. In vivo administration of the ARB dramatically reduced O2- production and normalized NO-dependent EDR in response to Ach, although it did not control hypertension. It is known that a high-salt diet antagonizes the antihypertensive effects of angiotensin-converting enzyme inhibitors and ARBs.44,45 Switching HS rats from the HS diet to an NS diet (HS/NS rats) was not accompanied by a significant reduction in blood pressure, proteinuria, aortic and LV hypertrophy, or O2- production. Collectively, these findings strongly suggest that during the hypertensive phase, the increased O2- production as well as the endothelial dysfunction are maintained by a functional upregulation of Ang II. This contention is further supported by the studies ex vivo, which showed that DPI, an inhibitor of NADPH/NADH oxidase, reduced aortic O2- production by 45% and that indomethacin and L-NAME reduced O2- production by 28% and 35%, respectively. Remarkably, high dietary salt did not increase O2- production in DR rats. We have previously shown that DR rats fed high dietary salt do not develop hypertension or endothelial dysfunction.27
In concert, these data suggest that in DS rats, high dietary salt promotes an increase in O2- production that is linked to functional upregulation of Ang II, which over time reduces NO bioactivity, leading to endothelial dysfunction. During the hypertensive phase, 2 other contributors to O2- production are recruited, namely, cyclooxygenase and NOS. In this context, it is known that O2- upregulates cyclooxygenase-246 and that O2-, interacting with NO, generates peroxynitrite,22,23 which results in NOS uncoupling; dysfunctional NOS paradoxically produces more O2- than does NO.32,33,41 In summary, our studies suggest that during the hypertensive phase, a vicious circle is established that maintains an increase in O2- production and impaired endothelial function.
The fact that in the hypertensive phase the ARB normalized O2- production and EDR, but not hypertension or end-organ damage, clearly suggests that endothelial NO-dependent vascular relaxation is exquisitely sensitive to O2-. These findings have important mechanistic implications because they (1) demonstrate that increased O2- production is linked to Ang II and not the hemodynamic stress of blood pressure; (2) provide evidence of the beneficial effects of Ang II blockade on the endothelium, independently of blood pressure control; and (3) establish that endothelial dysfunction by itself is not sufficient to maintain hypertension in SS hypertension. In this context, we have previously shown that vitamin E–deficient DS rats fed a high-cholesterol diet have increased oxidant stress accompanied by severe endothelial dysfunction but do not develop hypertension on an NS diet.47 Similarly, CuZn superoxide dismutase–deficient mice manifest increased oxidant stress and impaired endothelial dysfunction but do not develop hypertension.48 Clinically, endothelial dysfunction is a major marker of cardiovascular morbidity.49 Our studies suggest, however, that to prevent or arrest end-organ injury, in addition to normalization of endothelial function, control of blood pressure is indispensable.
Perspectives
We used DS rats to test the hypothesis that there is an important interaction between Ang II, NO, and oxidative stress in SS hypertension. In SS hypertension, these studies unmasked a previously unrecognized participation of Ang II in the genesis of endothelial dysfunction that is linked to an increase in oxidative stress. Furthermore, in DS rats fed high dietary salt, the functional upregulation of Ang II occurred very early, even before DS rats become overtly hypertensive. In hypertensive rats, blockade of the AT1 receptor normalized endothelial function despite the fact that it did not affect blood pressure. Consequently, our demonstration of a dissociation between endothelial function and blood pressure elevation in SS hypertension underscores that blockade of the AT1 receptor confers an important, beneficial vascular effect. Our studies might have important clinical and therapeutic implications regarding the role of blood pressure and endothelial dysfunction in hypertensive end-organ disease.
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Acknowledgments |
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This work was supported by research funds from the Department of Veterans Affairs and a research grant from Astra-Zeneca. The authors thank Alice Holohean for her critical review of this manuscript and Esther Marquez for secretarial assistance.
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Footnotes |
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The first 2 authors contributed equally to this work.
Received June 17, 2003; first decision July 31, 2003; accepted August 25, 2003.
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