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(Hypertension. 2004;43:329.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Tempol Lowers Blood Pressure and Sympathetic Nerve Activity But Not Vascular O₂^- in DOCA-Salt Rats

From the Department of Pharmacology and Toxicology and The Neuroscience Program, Michigan State University, East Lansing, Mich.

Correspondence to Dr Hui Xu, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824. E-mail xuhui2{at}msu.edu

	Abstract

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This study tested the hypothesis that depressor responses caused by tempol are not associated with reductions in vascular O₂^- levels in urethane-anesthetized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We compared the effects of intravenous (IV) administration of tempol, apocynin, superoxide dismutase-polyethylene glycol (PEG-SOD), and SOD on mean arterial blood pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). In DOCA-salt rats, tempol (30 to 300 µmol/kg) dose-dependently decreased RSNA, MAP, and HR. Tempol (300 µmol/kg) decreased MAP from 140±5 to 83±4 mm Hg (P<0.05). HR decreased from 435±15 to 390±12 bpm (P<0.05). RSNA was reduced by 54%±6% from baseline. However, in the same rats, tempol did not reduce dihydroethidium-induced fluorescent signals in the aorta and vena cava. Apocynin (200 µmol/kg) did not lower MAP (142±5 mm Hg versus 140±6 mm Hg) or HR (428±15 bpm versus 420±13 bpm) and apocynin did not potentiate depressor responses caused by tempol. PEG-SOD (10 000 U/kg, bolus or 5000 U/kg bolus followed by a 30-minutes infusion of 500 U/kg/min) or SOD (25 000 U/kg, bolus or 10 000 U/kg bolus followed by a 30-minutes infusion of 1000 U/kg per minute) did not alter MAP or HR. It is concluded that depressor responses and decreases in HR and RSNA caused by acute tempol treatment are caused by direct sympathetic nerve activity inhibition that is not accompanied by SOD-mimetic action in the aorta or vena cava.

Key Words: super oxide • antioxidants • blood pressure

	Introduction

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Oxidative stress is associated with human and some animal models of hypertension.^1–3 Superoxide anion (O₂^-) is produced in the vasculature of hypertensive subjects, and O₂^- increases blood pressure in part by reducing the bioavailability of nitric oxide (NO).¹ Treatments that reduce vascular O₂^- levels have potential therapeutic application in the treatment of hypertension.^4,5 However, data from studies of the effects of antioxidants in hypertensive subjects have been inconsistent. Acute treatment with ascorbic acid did not alter blood pressure in hypertensive patients⁵ or in DOCA-salt hypertensive rats.⁶ However, long-term treatment of hypertensive patients with ascorbic acid reduced systolic blood pressure.⁴ The role of endothelial-derived NO in the effects of ascorbic acid on blood pressure are not clear, because ascorbic acid-induced blood vessel dilation are endothelium-independent.^5,7

Superoxide dismutase (SOD) mimetic 4-hydroxy 2,2,6,6,-tetramethyl piperidine 1-oxyl (tempol) lowers blood pressure in normotensive and hypertensive rats.^6,8–10 It has been recently reported that acute administration of tempol to normotensive or DOCA-salt and spontaneously hypertensive rats (SHRs) causes a decrease in sympathetic nervous system activity that is not prevented by nitric oxide synthase (NOS) inhibition.^6,10,11 Long-term tempol treatment attenuates hypertension development in several animal models of hypertension, and the antihypertensive actions were proposed to be caused by an improvement of endothelium function via reduction of oxidative stress.^12–15 Recently, it has been shown that prevention by tempol of hypertension development in Dahl salt-sensitive rats or in ACTH-induced hypertension in rats is independent of an improvement in endothelium function and oxidative stress.^16,17 Thus, these findings suggest that tempol has important pharmacological actions on sympathetic function and blood pressure that may not be related to the removal of O₂^- and/or increased NO availability.

NAD(P)H oxidase is the major source of O₂^- in the vasculature.^2,3 Increased NAD(P)H oxidase activity mediates O₂^- production in angiotensin II (Ang II)-induced hypertension,¹⁸ SHRs,¹⁹ and DOCA-salt²⁰ hypertensive rats. In these animals, the mRNA for the NAD(P)H oxidase subunits p^22phox, gp^91phox, and nox-1 were greater than in normotensive rats. Apocynin, a NAD(P)H oxidase inhibitor, reduces O₂^- production and improves endothelium function in rat and human blood vessels^19,21,22 and attenuates DOCA-salt hypertension.¹⁹ Pretreatment with the superoxide dismutase-polyethylene glycol (PEG-SOD), a membrane-permeable SOD analog, protects against myocardium ischemia/reperfusion injury by reducing O₂^- levels.^23,24

The present studies were performed to test the hypothesis that acute treatment of DOCA-salt hypertensive rats with drugs that lower O₂^- should lower blood pressure. Furthermore, if the depressor and sympatho-inhibitory effects of tempol are mediated by reduction of O₂^-, then other treatments that reduce O₂^- should mimic the effects of tempol.

	Methods

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General Procedures
Animal use protocols were approved by the All University Committee for Animal Use and Care at Michigan State University. Male Sprague-Dawley rats (Charles River Laboratories, Portage, Mich) with an initial weight of 175 to 225 grams were used in these studies. DOCA-salt hypertension was produced using previously published methods.^6,25 Three to four weeks after uninephrectomy and DOCA pellet implantation or sham surgery, rats were anesthetized with urethane (1.2 g/kg, intraperitoneally). Heart rate (HR), mean arterial blood pressure (MAP), and renal sympathetic nerve activity (RSNA) were recorded using methods that have been described in detail previously.^6,9 Supplements of urethane were administered when required and the rats respired spontaneously.

Oxidative Fluorescent Microtopography
The thoracic aorta and vena cava were removed from DOCA-salt rats after tempol treatment (1000 µmol/kg) for 5 minutes and were cut into 30-µm-thick vertical sections using a cryostat. Dihydroethidium (1 µmol/L) was topically applied to each tissue section. Slides were incubated in a light-protected humidified chamber at 37°C for 30 minutes. PEG-SOD (500 U/mL) was applied topically on some tissue sections as a positive control. Images were obtained using a laser scanning confocal microscope (Leica Instruments, Heidleberg, Germany) as described previously.⁶

Experimental Protocol
Effects of Tempol on HR, MAP, and RSNA in DOCA-Salt and Sham Rats
After surgical preparation of the rats, 30 to 40 minutes were allowed for stabilization of all variables. The effects of tempol (30, 100, and 300 µmol/kg) on HR, MAP, and RSNA were examined after intravenous (IV) bolus administration to sham and DOCA-salt rats using an interdose interval of 30 to 60 minutes. Tempol doses were administered over a 1-minute period, and each variable was monitored for 20 minutes after tempol treatment. To study the effects of tempol on vascular O₂^- levels, the thoracic aorta and vena cava were taken from DOCA-salt rats within 5 minutes after treatment with tempol (1000 µmol/kg) or saline, because this was the time of peak effect. Vascular O₂^- levels were then measured using oxidative fluorescent microtopography.

Effects of Apocynin on MAP and HR in DOCA-Salt and Sham Rats
The effects of apocynin (200 µmol/kg) on MAP and HR were studied after IV bolus administration in sham and DOCA-salt rats. Apocynin was dissolved in 6% dimethyl sulfoxide-saline to produce a 100-mmol/L stock solution. The effects of tempol on MAP and HR with or without of apocynin were tested in another group of sham and DOCA-salt rats. In these animals, tempol (300 µmol/kg IV) was administered after 5 minutes of apocynin treatment.

Effects of PEG-SOD and SOD on HR and MAP in DOCA-Salt Rats
After recording basal MAP and HR, the effects of PEG-SOD (10 000 U/kg) or SOD (25 000 U/kg) IV administration on MAP and HR were studied in DOCA-salt rats. This dose of PEG-SOD reduces O₂^- levels and protects against cardiac ischemia/reperfusion injury in rats.^23,24 The effects of PEG-SOD (5000 U/kg bolus followed by a 30-minute infusion of 500 U/kg per minute) or SOD (10 000 U/kg bolus followed by a 30-minute infusion of 1000 U/kg per minute) on MAP and HR were studied in 4 other DOCA-salt rats.

Statistics Analysis
All data are expressed as mean±SE. The overall effects of tempol, apocynin, SOD, and PEG-SOD were evaluated using 1-way ANOVA with repeated measures. Differences between parameters before and after each treatment were evaluated using Student paired t test comparing control responses to those obtained after each treatment. P<0.05 was the level of statistical significance.

	Results

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A total 30 rats (9 sham and 21 DOCA-salt) were used for the studies. At the time of the experiments, the body weight of sham rats was 425±15 grams and 330±20 grams in DOCA-salt rats. The baseline MAP under urethane anesthesia was significantly higher in DOCA-salt rats than in sham rats (140±5 mm Hg versus 98±6 mm Hg; P<0.01), but there were no differences in HR between sham and DOCA-salt rats (420±15 bpm versus 425±16 bpm; P>0.05).

Effects of Tempol on HR, MAP, RSNA, and Vascular O₂^- Levels
Tempol (100 and 300 µmol/kg) transiently decreased HR, MAP, and RSNA in sham and DOCA-salt rats (Figure 1, 2). Peak responses occurred within 5 minutes after tempol administration. In DOCA-salt rats, tempol caused a larger decrease in MAP than in sham rats. At 300 µmol/kg, tempol reduced MAP from 140±5 mm Hg to 80±6 mm Hg and from 98±4 mm Hg to 74±4 mm Hg in DOCA-salt and sham rats (-43%±5% versus -24%±3%; P<0.01) (Figure 2). Tempol-induced decreases in HR and RSNA were similar in DOCA-salt and sham rats (Figure 2). HR decreased from 435±15 bpm to 390±12 bpm in DOCA-salt rats, and from 420±12 bpm to 383±16 bpm in sham rats. RSNA was inhibited by 50%±7% and 40±9% from baseline in DOCA-salt and sham rats, respectively (Figure 2). All parameters recovered to baseline levels within 15 minutes of tempol administration.

View larger version (31K): [in this window] [in a new window]   Figure 1. Representative recording of HR (bpm), BP (mm Hg), mean BP (mm Hg), and RSNA (mV), with integrated RSNA activity given in arbitrary units, in an anesthetized DOCA-salt rat before and after tempol treatment. Tempol reduced HR and MAP, and it inhibited RSNA.

View larger version (19K): [in this window] [in a new window]   Figure 2. Effects of tempol on HR, MAP, and RSNA in DOCA-salt and sham rats (n=5 in each group). Depressor responses were significantly increased in DOCA-salt rats, whereas decreases in HR and RSNA were not altered. All measurements were made 2 to 4 minutes after tempol administration, because this was the time of peak effect. Data are expressed as a percent change from the baseline level measured just before each tempol dose. Data are mean±SE. *Significantly different from baseline levels (P<0.05). #Significantly different from sham rats (P<0.05).

Tempol (1000 µmol/kg) did not reduce O₂^- levels in the aorta or vena cava from DOCA-salt rats compared with vessels from saline-treated DOCA-salt rats. However, in the same rats, tempol lowered blood pressure from 142±4 mm Hg to 75±3 mm Hg, and RSNA was inhibited by 60% from baseline (n=3 in each group) (Figure 3). PEG-SOD (500 U/mL) applied topically to the blood vessel sections reduced dihydroethidium fluorescence markedly in the aorta and vena cava.

View larger version (26K): [in this window] [in a new window]   Figure 3. Confocal images of dihydroethidium-treated aorta (a) and vena cava (v) tissue from representative DOCA-salt rats after IV administration with saline (I and II) or tempol 1000 µmol/kg (III and IV) for 5 minutes. Fluorescence was not reduced in the aorta and vena cava; even though tempol lowered blood pressure from 142 mm Hg to 75 mm Hg. PEG-SOD 500 U/mL applied topically (V and VI) significantly reduced fluorescence in tissue from aorta and vena cava. Sections shown were typical of 4 separate experiments.

Effects of Apocynin, SOD, and PEG-SOD on MAP and HR in DOCA-Salt Rats
At resting MAP (140±6 mm Hg), apocynin (200 µmol/kg) did not lower MAP or HR (Table). Apocynin also did not potentiate depressor responses caused by tempol, because the effects of tempol on MAP and HR were similar before and after apocynin treatment in sham and DOCA-salt rats (Figure 4).

View larger version (43K): [in this window] [in a new window]   Figure 4. Effects of apocynin on tempol-induced decreases in MAP in DOCA-salt and sham rats. Apocynin did not alter the effects of tempol on MAP. Tempol (300 µmol/kg IV) was administrated before or after apocynin (200 µmol/kg IV) for 5 minutes. All measurements were made 2 to 4 minutes after tempol administration. Data are mean±SE. *Significantly different from baseline levels (P<0.05). #Significantly different from sham rats (P<0.05).

PEG-SOD (10 000 U/kg) or SOD (25 000 U/kg) did not change MAP or HR significantly in DOCA-salt rats (Table). SOD (5000 U/kg bolus followed by a 30-minute infusion of 500 U/kg per minute; n=4) or PEG-SOD (10,000 U/kg bolus followed by a 30-minutes infusion of 1000 U/kg per minute; n=3) did not lower MAP or change HR in DOCA–salt rats (141±4 mm Hg versus 138±5 mm Hg and 425±15 bpm versus 415±16 bpm, respectively).

	Discussion

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Superoxide anion is one of several reactive oxygen species produced in the vasculature of hypertensive animals and humans. It contributes to high blood pressure by quenching endogenous NO and reducing the levels of this vasodilator substance.^26,27 Also, O₂^- activates vasoconstrictor signaling mechanisms in vascular smooth muscle.^2,28 NAD(P)H oxidase is the principal source of O₂^- in the vasculature.^2,3 Scavenging O₂^- or inhibiting its synthesis will increase the bioavailability of NO and will reduce the activity of the signaling mechanisms activated by O₂^- to increase vascular tone. In previous studies and in the present work, we showed that acute treatment of DOCA-salt rats with tempol, an O₂^- scavenger, decreased blood pressure, HR, and RSNA. Shokoji¹⁰ have recently reported similar results in studies of SHRs. It is reasonable to suggest that tempol lowers blood pressure in these animals by reducing O₂^- levels in the vasculature, in the sympathetic nervous system, or perhaps in both tissues. However, we found that acute treatment with tempol did not reduce O₂^- in the aorta or the vena cava from DOCA-salt rats. We also found that acute treatment with apocynin, a NAD(P)H oxidase inhibitor, did not change blood pressure and did not potentiate depressor responses caused by tempol in DOCA-salt rats. Because O₂^- is a very short-lived molecule, inhibition of its synthesis by apocynin should cause a rapid decrease in O₂^- levels; therefore, blood pressure should also decrease rapidly. Finally, we found that acute treatment with SOD and PEG-SOD did not alter blood pressure in DOCA-salt rats. Both of these enzymes rapidly degrade O₂^-.^22,23,29 Acute administration of tempol produced a rapid but brief decrease in RSNA and blood pressure in anesthetized DOCA-salt and SHRs.^6,9,10 Depressor responses in hypertensive rats were greater than in sham rats,^6,10 because the sympathetic nervous system plays an important role in maintaining the elevated blood pressure in these models.³⁰ However, intracerebroventricular injection of tempol failed to alter MAP, HR, and RSNA in SHRs,¹⁰ suggesting that tempol acted peripherally to cause sympatho-inhibition. Interestingly, Shokoji et al¹⁰ recently reported that local application of tempol onto the renal sympathetic nerves caused a dose-dependent decrease in integrated RSNA without changing MAP and HR. They also showed that NOS inhibition did not alter basal RSNA or modify the tempol-induced reduction in RSNA.³¹ The data indicate that tempol directly inhibits peripheral sympathetic nerves, possibly by inhibiting sympathetic neuroeffector transmission. O₂^- reacts with NO to form peroxynitrite, thereby reducing tissue levels of NO. However, we have shown previously that the effects of acute tempol treatment on blood pressure and sympathetic nerve activity are NO-independent.^6,9,11

It should be noted that acute treatment with antioxidants, other than tempol, does not lower blood pressure. For example, ascorbic acid does not lower blood pressure in hypertensive patients⁵ or in DOCA-salt hypertensive rats.⁶ The antioxidants SOD and tiron quench, by >70%, O₂^- signals measured using lucigenin-enhanced chemiluminescence in human saphenous vein and internal mammary artery.²⁹ However, acute treatment with tiron did not alter blood pressure in normotensive or hypertensive rats.^6,32 Apo-cynin, a NAD(P)H oxidase inhibitor, dose-dependently relaxed human pre-constricted internal mammary arterial and saphenous venous rings via increased NO bioavailability, and this effect was larger than that caused by PEG-SOD.²² Our study is the first to our knowledge to examine blood pressure responses caused by acute treatment of DOCA–salt rats with apocynin and PEG-SOD. We found that acute treatment with apocynin or with PEG-SOD at a dose that blocks O₂^--induced ischemia/reperfusion injury^23,24 did not alter blood pressure or potentiate depressor responses caused by tempol in DOCA-salt rats. Taken together, these data indicate that acute treatment with antioxidants does not lower blood pressure via a reduction in O₂^- in DOCA-salt hypertension.

O₂^- is elevated in the aorta, vena cava, and mesenteric artery and vein from DOCA-salt rats compared to that in sham rats.^6,27,33 We found that acute treatment with tempol did not reduce O₂^- from aorta and vena cava in DOCA-salt rats, even though tempol lowered blood pressure and RSNA by 50%. However, the effects of tempol on blood pressure are extremely short, because tempol has a half-life time of 1 minute and it becomes undetectable within 6 minutes after administration in vivo.³⁴ Therefore, our failure to detect a tempol-induced reduction of O₂^- in the aorta and vena cava might be attributed to tempol’s short duration of action.

PEG-SOD applied topically reduced O₂^- levels in aorta and vena cava from DOCA-salt rats, indicating that O₂^- in aorta and vena cava can be reduced by this antioxidant. Furthermore, SOD and PEG-SOD increase NO bioavailability in human preconstricted internal mammary arterial and saphenous venous rings²² and afferent arteriolar in vitro.³⁵ Therefore, we used continuous intravenous infusions of SOD and PEG-SOD to determine if these antioxidants would lower blood pressure in DOCA-salt rats, because we expected that the duration of action of these enzymes might be longer than that of tempol. However, we found that prolonged treatment with SOD and PEG-SOD did not change blood pressure, HR, or RSNA in DOCA-salt of sham rats. PEG-SOD is a large molecule, and 30-minute infusion may be insufficient to allow enough of the enzyme to penetrate to interstitial sites and to quench O₂^-. Longer PEG-SOD treatments may be needed to reveal a depressor response and a reduction in O₂^- levels in the vasculature and/or in sympathetic ganglia.

Long-term tempol and apocynin administration prevents Ang-II-induced,¹² DOCA-salt,^13,20 ACTH-induced,¹⁷ endothelin-induced,³⁶ and Dahl salt-sensitive hypertension.^15,16 Apocynin attenuates hypertension by reducing NAD(P)H oxidase-derived O₂^- in DOCA-salt rats.²⁰ NAD(P)H oxidase inhibition improves endothelial function, reduces O₂^- production, and increases eNOS activity and NO generation in human and rat blood vessels.^19,22 In SHR and Ang II-infused rats, the antihypertensive action of tempol is blocked after NOS inhibition.^8,37 Treatment with tempol reduces oxidative stress and improves endothelium function.^14,15,36 Interestingly, tempol attenuates ACTH-induced hypertension but does not reduce the ACTH-induced increases in plasma F(2)-isoprostanes (a marker of oxidative stress).¹⁷ In addition, L-NAME does not attenuate tempol-induced depressor responses in Dahl salt-sensitive hypertensive rats.¹⁶ These results suggest that tempol effects on ACTH-induced and Dahl salt-sensitive hypertension are independent of oxidative stress and endothelium function. Thus, all of the mechanisms for the antihypertensive effects of tempol have not been established.

Perspectives
Oxidative stress is prominent in human hypertension, and antioxidants have potential therapeutic applications for the treatment of hypertension and associated pathologies. Tempol, a drug that can scavenge O₂^-, lowers blood pressure after acute treatment of hypertensive rats, but this effect is not shared by other drugs (apocynin, SOD) known to reduce O₂^- levels in the vasculature. Tempol inhibits sympathetic nerve activity, suggesting that the antihypertensive effects of tempol may be mediated by direct inhibition of sympathetic input to the cardiovascular system. The mechanism by which tempol inhibits sympathetic neurons is not known. Our data also indicate that long-term treatment with antioxidant drugs will be required to reduce blood pressure in hypertensive subjects. Finally, the effects of O₂^- on the mechanisms controlling vascular tone must persist in the absence of elevated levels of O₂^-, because blood pressure did not decrease during acute treatment with apocynin, PEG-SOD, or SOD, which should produce at least a transient decrease in local O₂^-.

	Acknowledgments

 
This work was supported by National Heart, Lung, and Blood Institute grant numbers HL-63973, HL-24111, and PO1 HL70687. Dr. Hui Xu is supported by a postdoctoral fellowship grant from American Heart Association Midwest Affiliate (0325510Z).

Received September 30, 2003; first decision November 6, 2003; accepted November 26, 2003.

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