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(Hypertension. 1999;33:1353-1358.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Superoxide Anion Production Is Increased in a Model of Genetic Hypertension

Role of the Endothelium

Susanne Kerr; M. Julia Brosnan; Martin McIntyre; John L. Reid; Anna F. Dominiczak; Carlene A. Hamilton

From the Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK.

Correspondence to Dr Carlene A. Hamilton, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK.

	Abstract

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Abstract—The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O₂^-) was examined. O₂^- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O₂^- generation was increased in male and female SHRSP (4.11±0.24 and 3.84±0.28 nmol O₂^- · min^-1 · mg^-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22±0.08 in males and 0.8±0.08 nmol O₂^- · min^-1 · mg^-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O₂^- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O₂^- generation from 3.86±0.12 to 1.35±0.08 nmol · min^-1 · mg^-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13±0.17 to 1.32±0.16 nmol · min^-1 · mg^-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O₂^- generation in SHRSP from 4.04±0.11 to 2.36±0.40 nmol · min^-1 · mg^-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O₂^- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O₂^- appear to be the endothelium and eNOS, respectively. The increase in O₂^- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.

Key Words: superoxide • endothelium • nitric oxide • rats, inbred SHR • nitric oxide synthase

	Introduction

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Endothelial dysfunction and a relative deficiency in nitric oxide (NO) may be associated with hypertension in humans^{1 2} and in some models of experimental hypertension.^{3 4} In the spontaneously hypertensive stroke-prone rat (SHRSP), a model of genetic hypertension, we have shown an attenuation of functional basal NO despite increased eNOS enzymatic activity.⁵ Although endothelial NO synthase (eNOS) enzymatic activity was greater in SHRSP than in Wistar-Kyoto rats (WKY) when examined in vitro the possibility that the actual amount of eNOS was reduced in SHRSP in vivo could not be excluded from these results. Alternatively, eNOS levels could be similar or elevated but NO availability decreased because of more rapid removal after synthesis. Superoxide anion (O₂^-) is produced in the vasculature and can scavenge NO forming peroxynitrite. Increased scavenging of NO by O₂^- could lead to a decrease in NO availability despite increased synthesis. Raised O₂^- levels have been reported recently in a number of models of endothelial dysfunction including hypertension, induced by either angiotensin infusion⁶ or aortic banding.⁷ In the majority of cases the source of excess O₂^- is uncertain, although involvement of NADH/NADPH oxidases⁸ and xanthine oxidase⁹ have been suggested.

The aim of this study was to examine the hypothesis that the decreased NO availability observed in SHRSP is due to excess O₂^-, to identify the source of this O₂^-, and to examine other molecular mechanisms involved such as the expression of the gene-encoding enzyme involved in NO generation in the endothelium (eNOS).

	Methods

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Animals
Three- to 4-month-old male and female WKY and SHRSP were obtained from the colonies established in Glasgow by brother and sister mating as previously described.⁹ Blood pressure was measured 1 week before study by tail plethysmography according to our published protocol.¹⁰

Superoxide Measurement
Animals were killed with barbiturate overdose. The abdominal aorta was removed and placed in chilled buffer. Periadventitial tissue was carefully removed and O₂^- quantified in 5-mm aortic segments with lucigenin chemiluminescence as originally described by O'Hara et al¹¹ and recently reassessed by Li and colleagues.¹²

In some experiments the endothelium was removed by rubbing. In others either N^G-nitro L-arginine methyl ester (L-NAME, 100 µmol/L), N^W-monomethyl-L-arginine (L-NMMA, 1 mmol/L), or L-arginine (1 µmol/L and 1 mmol/L) was added 30 minutes before determining O₂^- generation. Additionally, tetrahydrobiopterin (100 µmol/L), oxypurinol (10 µmol/L), or diphenyleneiodonium (DPI, 10 and 100 µmol/L) were added 30 to 60 minutes before determining O₂^- generation in some rings. Control rings from the same animal were assayed in parallel to each treatment. O₂^- generation was quantified against a standard curve of O₂^- generation by xanthine/hypoxanthine. Tissue O₂^- generation was expressed as nmol/mg wet wt per minute. Preliminary studies showed no difference in O₂^- generation between thoracic and abdominal aortas from either WKY or SHRSP.¹³ In this study abdominal aortas were taken for O₂^- measurement and thoracic aortas used to confirm the attenuation of basal NO¹⁴ in the same animals and for quantification of the mRNA of eNOS.

Reverse Transcription–Polymerase Chain Reaction for eNOS
Total RNA was extracted from homogenized thoracic aortas with the use of RNAzol B. Messenger RNA for eNOS was quantified by reverse transcription–polymerase chain reaction (RT-PCR) as described.¹⁵ Briefly, competitor RNA was transcribed in vitro from the plasmid pReNIS5, which was kindly donated by F. Soubrier (Paris, France). This plasmid contains a 64 bp fragment of polylinker inserted in the Sac II site of a rat eNOS cDNA.

Total aortic RNA (100 ng) and competitor RNA(0 to 400 fg) were reverse transcribed in the same reaction at 42°C for 45 minutes with oligo(dT)¹⁵ primer (0.5 µg/µL) and Avian Myoblastosis Virus (AMV) reverse transcriptase (10 U/µL) in the presence of RNase inhibitor (40 U/µL). PCR was carried out on a 3-µL aliquot of each RT reaction with the use of 2 primers, forward (5'-TTC CGG CTG CCA CCT GAT CCT AA-3') and reverse (5'-AAC ATG TGT CCT TGC TCG AGG CA-3') surrounding the 64 bp fragment insertion site. Each reaction contained Taq DNA polymerase (5 U/µ/L), primers (10 µmol/L each), and dNTPs (1.25 mmol/L) and was subjected to an initial denaturation at 94°C for 5 minutes, then 28 cycles of 30 seconds at 94°C, 30 seconds annealing at 62°C, and 1-minute elongation at 72°C, then completion of ongoing reactions at 62°C for 1 minute and 72°C for 10 minutes.

The products of each reaction were run on a 2% agarose gel and bands visualized by Southern blotting. The density of each band was quantified with a densitometer and a plot of long competitor density (x-axis) versus log ratio (target density/competitor density) (y-axis) constructed. When the log ratio=0, then the concentration target and competitor are equal, and this value can be read from the x-axis (Figure 1). For each sample, 10 RT-PCR reactions were run with a range of amounts of competitor RNA in 40-fg increments around the target concentration.

View larger version (32K): [in this window] [in a new window]   Figure 1. Quantification of eNOS mRNA by competitive RT-PCR. A constant amount of total RNA from rat aorta (target) was mixed with increasing amounts of internal standard mRNA (competitor), reverse transcribed, and amplified by PCR with eNOS specific primers. PCR products were run on a 2% (wt/vol) agarose gel, blotted onto nylon membrane, hybridized with an end-labeled primer as a probe, and exposed to photographic film. The density of each band was measured and the logarithm of the ratio (density of target/density of competitor) plotted against the logarithm of the known amount of competitor mRNA in each reaction. At the competition equivalence (log ratio=0), the amount of target mRNA (unknown) corresponds to the amount of competitor mRNA (known).

Western Blotting
After the rats were killed, the thoracic aorta was removed and rapidly frozen in liquid nitrogen. The proteins were extracted by homogenization using a Kinematica polytron homogenizer (Philip Harris Scientific) in boiling 250 mmol/L Tris HCl pH 6.8, 4% SDS, 10% glycerol, 0.006% biomaphenol blue, and 2% ß-mercapto ethanol. Protein (10 µg) was electrophoresed on an SDS polyacrylamide gel. The proteins were transferred onto PVDF (polyvinyl difluoride) membrane overnight. Prestained Rainbow Markers (Amersham) were used as molecular mass standards. The membranes were blocked in 5% skimmed dried milk in 10 mmol/L Tris, pH 7.5, 100 mmol/L NaCl, 0.1% Tween 20 for 1 hour at room temperature. Thereafter they were incubated with antibodies directed against human eNOS (Transduction Laboratories) according to the manufacturer's instructions. Bands were detected by use of an enhanced chemiluminescence test (Amersham) and autoradiography by exposure to x-ray film (Kodak, X-OMAT). The blots were also incubated with an antibody against -actin (Boehringer), and both sets of bands were quantified with the use of a Phospho-Imager (Molecular Dynamics).

Analysis of Data
Analysis was by unpaired t test or ANOVA as appropriate. Bonferroni correction was used when multiple comparisons were made. Results are expressed as mean±SE.

	Results

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Blood Pressure
Blood pressure was elevated in SHRSP compared with WKY and in addition was significantly higher in males than females. Systolic blood pressure (mm Hg) was as follows: male WKY 131±3 (n=21); female WKY 123±2 (n=17); male SHRSP 171±6 (n=23); female SHRSP 149±3 (n=30).

Superoxide Levels
Superoxide levels were increased in SHRSP males and females compared with their WKY counterparts, as shown in Figure 2. In addition, a gender difference was observed in WKY rats, with males having higher levels than females. However, although overall O₂^- generation was greater in male than female SHRSP (4.11±0.24 versus 3.84±0.28 nmol O₂^- · min^-1 · mg^-1), this did not reach significance. Levels of O₂^- in another rat strain, the Sprague-Dawley, were similar to those observed in WKY 1.27±0.08 nmol · min^-1 · mg^-1 (males only).

View larger version (37K): [in this window] [in a new window]   Figure 2. Superoxide generation in rings of abdominal aorta from male and female WKY and SHRSP. O2- was measured by lucigenin chemiluminescence. Results are expressed as mean ±SEM for each group. Groups were compared with the use of ANOVA with Bonferroni correction for multiple comparisons such that P0.017 was taken as significant. n=6 to 9. Open bars indicate female animals; hatched bars, male animals.

Removal of the endothelium had no effect on O₂^- generation in either male or female WKY (Figure 3a). In contrast, in male SHRSP O₂^- was reduced from 3.86±0.12 to 1.35±0.08 and in female SHRSP from 3.58±0.15 to 1.41±0.10 nmol O₂^- · min^-1 · mg^-1. These reductions in O₂^- levels were highly significant: P<0.0001, 95% CI 2.29, 2.81, and P=0.0001, 95% CI 1.82, 2.52 for males and females, respectively.

View larger version (30K): [in this window] [in a new window]   Figure 3. a, Effect of removal of endothelium on superoxide generation in rings of abdominal aorta from male and female WKY and SHRSP. The endothelium (E) was removed by rubbing and O2- measured by lucigenin chemiluminescence. Groups were compared with the use of unpaired t tests. P<0.05 was taken as significant. Results are shown as mean±SEM. n=9 to 11. Open bars indicate intact tissue; hatched bars, endothelium removed. b, Effect of treatment with L-NAME on superoxide generation in rings of abdominal aorta from male and female WKY and SHRSP. Rings were treated with L-NAME 10-4 mol/L or buffer for 30 minutes before measuring O2- generation by lucigenin chemiluminescence. Groups were compared with the use of unpaired t tests. P<0.05 was taken as significant. Results are shown as mean±SEM. n=5 to 8. Open bars indicate control tissue; hatched bars, L-NAME treated.

Treatment with L-NAME had effects similar to removing the endothelium. In WKY, O₂^- generation was unaffected by treatment, whereas in SHRSP, levels were significantly reduced, as shown in Figure 3b. In male SHRSP, levels were 4.13±0.17 and 1.32±0.16 nmol O₂^- · min^-1 · mg^-1 for control and L-NAME–treated rings, respectively: P<0.0001, 95% CI 2.36, 2.83 and in females 3.98±0.08 and 1.38±0.06 nmol/L O₂^- · min^-1 · mg^-1, P<0.0001, 95% CI 2.36, 2.83. L-NMMA caused a similar reduction in O₂^- levels in SHRSP values, being 4.17±0.17 and 1.84±0.15 nmol/L O₂^- · min^-1 · mg^-1 in control and L-NMMA–treated rings (n=6; P=0.0003, 95% CI 1.68, 3.0).

Treatment with L-arginine had no significant effect on O₂^- generation in any group. In contrast, although 5 minutes of incubation with tetrahydrobiopterin only caused small, nonsignificant attenuation of O₂^- generation, 30 minutes of incubation with tetrahydrobiopterin significantly reduced O₂^- generation in SHRSP from 4.04±0.11 to 2.36±0.40 nmol · min^-1 · mg^-1 (P=0.0026, 95% CI 0.90, 2.45, males and females combined). No significant change in O₂^- generation was observed in WKY rats (Figure 4a). The NADH/NADPH oxidase inhibitor DPI caused a dose- and time-dependent reduction in O₂^- generation. Thirty-minute incubation with 100 µmol/L DPI resulted in a decrease in O₂^- from 4.39±0.04 to 2.68±0.12 and from 1.11±0.13 to 0.69±0.06 nmol · min^-1 · mg^-1 in SHRSP and WKY, respectively (males and females combined). When the incubation time was extended to 1 hour, O₂^- generation was reduced from 3.73±0.04 to 0.66±0.05 nmol · min^-1 · mg^-1 in SHRSP (P<0.001, 95% CI 2.96, 3.17) and from 0.98±0.10 to 0.17±0.02 in WKY (P=0.006, 95% CI 0.58, 1.04) (Figure 4b). In contrast, oxypurinol, an inhibitor of xanthine oxidase, had no effect on O₂^- generation in either SHRSP or WKY (Figure 4b).

View larger version (40K): [in this window] [in a new window]   Figure 4. a, Effect of treatment with tetrahydrobiopterin (BH4, 100 µmol/L) on superoxide generation in rings of abdominal aorta from WKY and SHRSP (males and females combined). Rings were treated with BH4 for 5 or 30 minutes before measuring O2- generation by lucigenin chemiluminescence. Groups were compared with the use of ANOVA. P<0.02 was taken as significant. Results are shown as mean±SEM. n=5 for WKY and 6 for SHRSP. b, Effect of treatment with oxypurinol or DPI on superoxide generation in rings of abdominal aorta from WKY and SHRSP (males and females combined). Rings were treated with oxypurinol (10 µmol/L) for 30 minutes or DPI (100 µmol/L) for 60 minutes before measuring O2- generation by lucigenin chemiluminescence. Groups were compared with the use of ANOVA. P<0.02 was taken as significant. Results are shown as mean±SEM. n=5 WKY; n=6 SHRSP.

Expression of eNOS in Thoracic Aorta
As shown in Figure 5a, eNOS mRNA expression (fg/100 ng ±SEM) was significantly greater in SHRSP (308±49) compared with WKY (84.9±14) (95% CI: 107, 339; P=0.002). Within the SHRSP, eNOS mRNA expression was significantly greater in males (417±43) compared with females (170±12) (95% CI: 123, 371; P=0.005), and within the WKY there was a tendency for greater eNOS expression in males (113±17) compared with females (49.2±3.8) 95% CI: 16, 112; (P=0.02), but this failed to achieve statistical significance when corrected for triple comparisons.

View larger version (37K): [in this window] [in a new window]   Figure 5. a, eNOS mRNA levels in thoracic aorta (±SEM) measured by competitive RT-PCR in WKY and SHRSP females (open bars) and males (hatched bars). P<0.017 is statistically significant. b, Representative Western blot showing eNOS protein in thoracic aorta from WKY and SHRSP males. -actin was used as loading control.

Western Blotting for eNOS
Comparison of the amount of NO synthase protein between WKY and SHRSP males is shown in Figure 5b. The aortas from SHRSP were found to have significantly higher levels than the aortas from the WKY. The ratios of eNOS to -actin in SHRSP and WKY were 5.24±0.43 and 3.06±0.22, respectively (P=0.02, 95% CI 0.638, 3.722; n=4).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study we have shown both increased eNOS mRNA expression and increased O₂^- production in SHRSP compared with WKY. Moreover, in this model of genetic hypertension we have identified the cellular and enzyme sources of the O₂^- excess as the endothelial cells and eNOS, respectively. Despite the increase in expression of mRNA for eNOS and the increased enzymatic activity of eNOS previously demonstrated by ourselves,⁵ NO availability has been shown to be reduced. This was manifest in a decrease in basal but not agonist-stimulated NO-mediated responses.⁵ Thus it appears that the excess O₂^- generation more than balances the increase in NO production leading to a net decrease in functional NO availability. Enhanced eNOS expression together with increased O₂^- generation has also been reported in Sprague-Dawley rats made hypertensive by aortic banding.⁷ It is tempting to speculate that the enhanced eNOS expression is a compensatory mechanism related to the increase in O₂^- generation. However, an inverse relation between eNOS expression and O₂^- generation is not always observed. In studies in mature 16-month animals, Bauersachs et al¹⁶ found no increase in eNOS expression in SHR thoracic aorta despite an increased O₂^- generation.

The studies described here using L-NAME and L-NMMA suggest that in the SHRSP O₂^- is generated by eNOS. There are other reports of NOS producing O₂^-. Purified rat nNOS has been shown to produce O₂^- in a reaction that is inhibited by L-NAME but not L-NMMA.¹⁷ Heinzel et al¹⁸ showed that purified nNOS can produce hydrogen peroxide under conditions of low L-arginine concentrations. Xia et al¹⁹ confirmed this finding in intact human kidney cells stably transfected with the rat nNOS gene. Huk and colleagues²⁰ suggest that O₂^- may be generated from eNOS during reperfusion after ischemia. In these studies in rabbit hind limb, administration of L-arginine before ischemia reperfusion reduced the subsequent release of O₂^-. Despite the suggestion that eNOS production of O₂^- may be related to low levels of L-arginine, the addition of exogenous L-arginine had no effect on O₂^- generation in either SHRSP or WKY in our studies. Suboptimal concentrations of tetrahydrobiopterin may also favor eNOS catalyzed production of O₂^-.²¹ Recently, Cosentino and colleagues²² have shown tetrahydrobiopterin to attenuate the O₂^- generation, which occurred in response to the calcium ionophore A23187 in aortas from young (4-week) SHR. We also saw an attenuation of O₂^- production in vessels from SHRSP that were incubated with tetrahydrobiopterin, suggesting a critical role for tetrahydrobiopterin in regulating eNOS. The exact mechanism whereby eNOS generates O₂^- is uncertain. However, molecular cloning of NO synthase revealed close amino acid sequence homology between NO synthase and cytochrome P₄₅₀ reductase, a known cellular source of O₂^-.²³

In hypertension caused by aortic banding, increased O₂^- production is reported to be an early event that reached a maximum within 2 weeks of surgery.⁷ In that study O₂^- production was not inhibited by L-NAME, and the source of the excess O₂^- was not identified. Increased O₂^- production has also been observed in angiotensin II–mediated hypertension. In this model of hypertension L-NMMA had no effect on O₂^- generation and the source of the excess O₂^- appeared to be membrane bound vascular NADH/NADPH oxidases.⁸

In our animals the major source of vascular smooth muscle O₂^- appeared to be NADH/NADPH oxidases, as illustrated by the attenuation of O₂^- generation in the presence of DPI. NADPH is a cofactor for eNOS. Thus the proportionally greater reduction in O₂^- generation in SHRSP compared with WKY is likely to be due to inhibition of O₂^- production by eNOS, in addition to inhibition of NADH/NADPH oxidases in vascular smooth muscle in SHRSP. Oxypurinol had no effect on O₂^- generation in either SHRSP or WKY, suggesting that the xanthine oxidase pathway did not contribute to O₂^- in these animals. O₂^- generation was not completely abolished in the tissues incubated with 100 µmol/L DPI for 1 hour. The effects of DPI were dose and time dependent. It is possible that complete inhibition of NADH/NADPH oxidase was not achieved. Alternatively, there are a number of other potential sources of O₂^- including aldehyde oxidase, dihydro-orotic dehydrogenases, flavin dehydrogenases, peroxidases, and auto-oxidation compounds such as catecholamines.²⁴

In WKY animals we observed a significant gender effect on O₂^- levels, O₂^- being greater in males than females. This would be consistent with the higher blood pressure in males. Brandes and Mugge²⁵ also found that levels of O₂^- were higher in male than female Wistar rats. In the SHRSP O₂^- levels tended to be higher in the males than the females, but this difference was not significant. It is probable that any gender effect was overwhelmed by the much larger hypertensive effect. One explanation for the gender effect would be that the higher levels of estrogen in the females resulted in increased scavenging of O₂^-. Arnal et al²⁶ have shown the synthetic estrogen ethynyl estradiol to increase release of bioactive NO by inhibiting superoxide anion production in cultured bovine endothelial cells, whereas Kleinert et al²⁷ have shown increased transcription of human eNOS gene on treatment with estrogens in culture.

In summary, we have shown O₂^- generation to be increased in SHRSP. The tissue and enzymatic sources of this excess O₂^- appear to be the endothelium and eNOS, respectively. The increase in O₂^- generation in SHRSP could contribute to the decreased availability of basal NO observed in this model of genetic hypertension.

Our findings reconcile previous controversies that surrounded molecular and functional analysis of endothelial function in the SHRSP and related models of genetic hypertension. Despite an excessive production of the eNOS mRNA combined with the increased eNOS protein levels, there is NO-dependent endothelial dysfunction that is best explained by an excess of O₂^- generated by the eNOS enzyme within the endothelial cells.

	Acknowledgments

 
This work was supported by the British Heart Foundation grants PG 97077 and RG97009, Scottish Hospital Endowment Research Trust Fellowship (MM) and Chest Heart and Stroke (Scotland); grant R98/3.

Received December 29, 1998; first decision January 13, 1999; accepted February 15, 1999.

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