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Department of Pharmacology and Toxicology and The Neuroscience Program, Michigan State University, East Lansing, Michigan 48824
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of sympathetic
nerves and nitric oxide (NO) in tempol-induced cardiovascular responses
was evaluated in urethane-anesthetized sham and deoxycorticosterone
acetate (DOCA)-salt-treated (DOCA-salt) rats. Tempol (30-300
µmol/kg iv), a superoxide (O
sympathetic nervous system; deoxycorticosterone acetate
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SUPEROXIDE ANION
(O
We recently (30) showed that acute administration of tempol to anesthetized, normotensive rats caused a fall in sympathetic nervous system activity that was not prevented by NO synthase (NOS) inhibition. Furthermore, complete sympathoinhibition following ganglion blockade virtually eliminated the depressor response to tempol (30). These findings indicate that tempol has important pharmacological actions on sympathetic function and blood pressure, which may not be related to increased NO availability.
Responses to drugs that act by limiting O
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed using male Sprague-Dawley rats (Charles River Laboratories) that weighed 175-225 g at the beginning of the study. All protocols were approved by the Michigan State University Committee on Animal Use and Care. Until the time of experiments, rats were housed two to three per cage in a temperature- and humidity-controlled room under a 12-h/12-h light-dark cycle. Free access was allowed to standard laboratory rat chow (8640 Rodent Diet; Harlan/Teklad). Housing was in accordance with National Institutes of Health and Michigan State University care guidelines.
DOCA-Salt Hypertension
DOCA-salt hypertension was produced by using previously published methods (4, 10, 18). Rats were anesthetized using pentobarbital sodium (50 mg/kg ip). A midscapular incision was made, and a chip of silicone rubber containing 200 mg/kg DOCA was implanted subcutaneously. A right flank incision was made, and a right nephrectomy was performed. Sham-operated rats underwent uninephrectomy and were supplied with normal tap water. Rats receiving DOCA implants were provided with drinking water containing 1% NaCl-0.2% KCl throughout the 4-wk protocol. Blood pressure was measured in conscious animals by tail-cuff plethysmography 4 wk after DOCA implant.Acute Surgical Procedures
Three to four weeks after DOCA implant or sham surgery, rats were anesthetized with urethane (1.2 g/kg ip). Body temperature was maintained at 36-37°C by a heating pad. After tracheostomy, respiration was maintained by positive-pressure ventilation with room air (60 cycles/min, 3 ml cycle volume). Animals were paralyzed (gallamine triethiodide, 4 mg · kg
1 · h1 iv) during
periods of data collection. The depth of anesthesia was monitored
continuously, and supplements of urethane (25-50 mg iv) were given
when required. Depth of anesthesia was judged from the stability of
heart rate (HR), blood pressure, and respiratory movement; the size of
the pupils; and paw-pinch reflexes. Steady increases in basal HR, blood
pressure, and pupil size or paw withdrawal in response to pinching with
forceps were indicators that supplement anesthesia was required. Before
periods of paralysis, the depth of anesthesia was assessed as described
above. During periods of periods of paralysis, HR, blood pressure, and
level of renal sympathetic nerve activity (RSNA) were used to monitor
the level of anesthesia. Drug treatment-independent increases in these
parameters were indictors that supplemental anesthesia was needed.
A polyethylene catheter was placed into a femoral artery and two femoral veins for measurement of blood pressure and administration of fluids and drugs. A left flank incision was made, and a retroperitoneal dissection was used to expose the renal artery and nerves. Renal sympathetic nerves were identified, and a branch was dissected free of connective tissue and placed on a bipolar stainless steel electrode. When stable recording conditions were established, the renal nerve and electrode were covered with silicone rubber, and the rats were placed in the right lateral decubitus position (30, 31).
Data Acquisition
The arterial catheter was connected to a pressure transducer to measure arterial blood pressure. An electronic resistance-capacitance filter with a 0.5-s time constant was used to derive mean arterial pressure (MAP). HR was determined electronically from the blood pressure signal using a cardiotachograph (model 7P4FG, Grass Instruments; Quincy MA). RSNA was amplified (P5111, Grass Instruments) by using a band-pass filter (low pass, 100 Hz; high pass, 1,000 Hz). The amplified and filtered signal was displayed by using a digital oscilloscope (model 1425, Gould Instruments; Cleveland, OH). Nerve activity was full rectified and integrated using a polygraph integrator (model 7P10F, Grass Instruments). Analog signals for HR, MAP, and RSNA were digitized at 633 Hz (Digidata 1200, Axon Instruments; Foster City, CA) and were displayed with Clampex 8 software (Axon Instruments). Data were stored on a computer hard drive. RSNA was standardized between animals by setting resting nerve discharges as 100% and by expressing RSNA after various treatments as a percentage of the resting level. The level of electrical activity obtained after the death of each animal was recorded and set as a zero level of nerve activity. This signal was digitally subtracted from recordings obtained from each animal. RSNA was measured at 0, 2, 5, 10, and 20 min after tempol treatments. RSNA was quantitated as the root mean square of the nerve activity during a 1-min interval at the time points described above. Root mean square was determined by using a fast Fourier transformation (Clampfit 8, Axon Instruments).Experimental Protocols
After surgical preparation, 30-40 min were allowed for stabilization of all variables. Tempol, hexamethonium, sodium nitroprusside (SNP), tiron, and ascorbic acid (Sigma Chemical; St Louis, MO) were all dissolved in saline. The pH value of the ascorbic acid solution was adjusted to 7.2 using NaOH. NG-nitro-L-arginine (L-NNA, Sigma) was dissolved in sodium phosphate buffer (pH 7.2). A volume of 0.4 ml saline or sodium phosphate buffer injected over 1 min did not change HR, MAP, or RSNA. Drug doses were administered intravenously over a 1-min period, and each variable was monitored for 20 min after drug treatment.Effects of tempol on HR, MAP, and RSNA with or without
L-NNA.
Tempol was administered to sham and DOCA-salt rats in increasing
doses (30, 100, and 300 µmol/kg iv bolus) with an interdose interval
of 30 min. When HR, MAP, and RSNA recovered to control levels, the NOS
inhibitor L-NNA (13 mg/kg) was administered by infusion
(2.6 mg · kg1 · min1) for 5 min for a total L-NNA dose of 13 mg/kg. This dose of
L-NNA was chosen because it inhibits NOS activity in vivo
by >70% and for more than 2 h in the periphery and in the
central nervous system (11, 25). Twenty minutes after
L-NNA infusion, tempol was injected again as described above.
Effects of tempol on HR, MAP, and RSNA after ganglion block. Tempol was administered to sham and DOCA-salt rats before and after hexamethonium (30 mg/kg iv). As hexamethonium decreases MAP, it may not be possible for tempol to produce any further decreases in MAP after ganglion blockade. To verify that MAP could be further decreased after ganglion block, depressor responses to SNP (5 µg/kg) were examined before and after hexamethonium.
Effects of tiron and ascorbic acid on HR, MAP, and RSNA. Tiron (1 g/kg) or ascorbic acid (1 g/kg) were administrated (iv bolus) in a separate set of five DOCA-salt rats.
Oxidative Fluorescent Microtopography
The oxidative fluorescent dye dihydroethidium was used to measure O6 mol/l) with
or without tempol (0.3 mol/l) was topically applied to each tissue
section. Slides were incubated in a light-protected humidified chamber
at 37°C for 30 min. Fluorescent images were obtained with an Olympus
Fluoview laser scanning confocal microscope mounted on an Olympus
BW50WI upright microscope, equipped with krypton/argon lasers. Blood
vessels from sham and DOCA-salt rats were processed in parallel. A
488-nm argon laser line was used to excite dihydroethidium
fluorescence, which was detected with a 585-nm long-pass filter.
Unstained sections were used to obtain background images of vessels
from sham and DOCA-salt rats. Identical photomutiplier settings were
used for image acquisition from all samples. Images for publication
were prepared using Adobe Photoshop 4.0.
Statistics Analysis
All data are expressed as means ± SE, and n values are the numbers of animals from which the data were obtained. The overall effects of tempol were evaluated using one-way analysis of variance with repeated measures. Differences among levels of MAP, HR, and RSNA before and after tempol were evaluated by using Student's paired t-test comparing control responses to those obtained after each treatment. Group differences in baseline values were analyzed using Mann-Whitney U-tests. P < 0.05 was set as the level of statistical significance.| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A total 26 rats (10 sham and 16 DOCA-salt) were used for the in
vivo studies. At the time of the experiments, the body weight of sham
rats was 420 ± 13 g and 320 ± 15 g in DOCA-salt
rats. As shown in Table 1, the baseline
MAP was significantly higher in DOCA-salt rats, but there were no
differences in HR between sham and DOCA-salt rats.
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A total of 10 rats (5 sham and 5 DOCA-salt) were used for the studies
of O
Effects of Tempol on HR, MAP, and RSNA With or Without L-NNA Treatment
The effects of tempol on MAP, HR, and RSNA before and after L-NNA treatment were studied in five sham and six DOCA-salt rats. In sham rats, tempol (100 and 300 µmol/kg) transiently decreased HR, MAP, and RSNA (Fig. 2). Peak responses occurred 2-4 min after tempol administration. In DOCA-salt rats, tempol caused a larger decrease in MAP than in sham rats, but tempol-induced changes in HR and RSNA were similar in sham and DOCA-salt rats (Figs. 1 and 2). L-NNA treatment increased MAP by 20 mmHg in sham rats and 50 mmHg in DOCA-salt rats (P < 0.05), without changing HR or RSNA (Table 1). In sham rats, the effects of tempol on MAP after L-NNA treatment were not different from those obtained before L-NNA pretreatment (P > 0.05) (Fig. 2). However, in DOCA-salt rats, depressor responses caused by tempol were significantly reduced following L-NNA. The effects of tempol on HR and RSNA in sham and DOCA-salt rats were not different from those of L-NNA pretreatment.
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Effects of Hexamethonium on Tempol-Induced Changes in HR, MAP, and RSNA
The effects of tempol before and after hexamethonium treatment were studied in five sham rats and five DOCA-salt rats. Hexamethonium (30 mg/kg iv) decreased MAP and HR and completely inhibited RSNA (Table 1). As shown in Figs. 3 and 4, the effects of tempol on MAP and HR sham and DOCA-salt rats were blocked in rats treated with hexamethonium. Tempol produced a small decrease in HR in sham and DOCA-salt rats treated with hexamethonium (Fig. 4). To determine whether hexamethonium-induced blockade of the depressor response caused by tempol was due to a decreased baseline MAP level, SNP (5 µg/kg), a direct-acting vasodilator, was administered before and after hexamethonium treatment. In sham rats, SNP reduced MAP before hexamethonium by 45 ± 5% and after hexamethonium by 40 ± 5% (P > 0.05). In DOCA-salt rats, the baseline MAP was lower than that in sham rats after hexamethonium treatment (68 ± 3 vs. 78 ± 3 mmHg, P < 0.05; Table 1, Fig. 4). In DOCA-salt rats, SNP reduced MAP by 60 ± 6% and 41 ± 2% before and after hexamethonium, respectively (P < 0.05).
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Effects of Tiron and Ascorbic Acid on HR, MAP, and RSNA in DOCA-Salt Rats
The effects of tiron and ascorbic acid on MAP, HR, and RSNA were studied in five DOCA-salt rats. As shown in Fig. 5, tempol (300 µmol/kg) decreased MAP, HR, and RSNA, but tiron (1.0 g/kg) and ascorbic acid (1.0 g/kg) did not alter RSNA, MAP, or HR.
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Vascular O
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Increased oxidative stress occurs in some forms of experimental
and human hypertension, and antioxidants, including tempol, can lower
blood pressure. Tempol scavenges O
As shown previously, acute administration of tempol to anesthetized
rats causes sympathoinhibition (30). After hexamethonium treatment to block ganglionic transmission, tempol-induced depressor responses were almost eliminated, and the sympathoinhibitory effect was
completely blocked in sham and DOCA-salt rats. However, hexamethonium itself lowered MAP, and this effect was more pronounced in DOCA-salt rats. Therefore, it may not have been possible for tempol to lower MAP
any further in the hexamethonium-treated rats. This issue was
addressed by showing that the mixed arterial-venous dilator SNP lowered
MAP in sham and DOCA-salt rats to the same degree before and after
hexamethonium treatment, indicating that further decreases in MAP were
possible. These data indicate that if tempol acted exclusively as a
direct vasodilator like SNP, tempol could have lowered blood pressure
before and after hexamethonium treatment. Therefore, we conclude that
the majority of the antihypertensive effect of tempol in anesthetized
sham and DOCA-salt rats is due to sympathoinhibition rather than a
direct action on vascular smooth muscle. Superoxide dismutase (SOD)
injected directly into rostral ventrolateral medulla of pigs
potentiates endogenous NO-mediated tonic inhibition of sympathetic
nerve activity, and centrally administered SOD causes a decrease in MAP
and HR (32). The depressor effect of SOD is most prominent
in animals under oxidative stress when O
The data discussed above indicate that the sympathoinhibitory effect of
tempol was NO independent. However, a component of the tempol-induced
depressor response in DOCA-salt, but not sham, rats was blocked by
L-NNA. This result suggests that tempol lowers blood
pressure in DOCA-salt rats, in part, by scavenging O
Our previous work in normotensive rats showed that the inhibitory effects of tempol on MAP, HR, and RSNA were not blocked by sinoaortic denervation and vagotomy (30). Therefore, the depressor effect of tempol in normotensive rats is independent of the baroreceptor reflex. The baroreceptor reflex is impaired in established DOCA-salt hypertension (15), and it would be expected that the depressor effects of tempol would be potentiated in DOCA-salt rats. However, HR and RSNA responses caused by tempol were identical in sham and DOCA-salt rats. If baroreceptor reflex impairment accounted for the additional tempol-induced depressor response in DOCA-salt rats, then HR and RSNA responses should also have been altered in these animals. We conclude that changes in baroreceptor reflex function do not account for the additional depressor response caused by tempol in DOCA-salt rats.
Hypertensive human subjects chronically receiving high-dose ascorbic
acid showed reduced blood pressure levels, but the mechanism of this
therapeutic effect is unclear (3). Ascorbic acid improves endothelium-dependent vasodilation in essential hypertension
(24) and heart failure (7). In high
concentrations, ascorbic acid dilates human hand veins, an effect that
is independent of NOS activity (5). Tiron is an
antioxidant that reverses impaired regulation of blood pressure by NO
during the development of cardiomyopathy in hamsters, but tiron alone
does not lower blood pressure (6). In the present study,
acute treatment with high-dose ascorbic acid or tiron did not lower
blood pressure in DOCA-salt rats. It is possible that acute treatment
with these antioxidants is insufficient to lower O
It is important to note that these data were obtained in anesthetized rats and that hemodynamic control mechanisms are altered under anesthesia. The proposed direct sympathoinhibitory effect of tempol needs to be confirmed in studies done in conscious animals. RSNA was used as a measure of global sympathetic nerve activity because changes in RSNA not only predict changes in the renal release of norepinephrine but are also correlated with changes in nerve activity in other vascular beds (27, 28). Although sympathetic nerves supplying different vascular beds have different steady-state responses to pathophysiological stimuli, such as hemorrhage-induced hypotension (26), changes in sympathetic nerve activity occurring within 10 min of hemorrhage are uniform across a number beds (9), Because this is the time frame for tempol-induced depressor responses seen in previous (30) and present studies, measurement of RSNA is likely to represent overall sympathetic nerve activity in this setting.
To summarize and conclude, these studies show for the first time that
tempol can lower blood pressure in DOCA-salt rats via a
sympathoinhibitory mechanism, which is NO independent. The
NO-independent sympathoinhibitory effect could require central nervous
system mechanisms and/or an interactions between tempol and sympathetic postganglionic nerves. In DOCA-salt rats, tempol has an additional NO-dependent depressor action that occurs at the level of the vasculature. This additional mechanism is likely due to an increased NO
availability provided by the O
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute HL-63973 and HL-24111.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. J. Galligan, Dept. of Pharmacology and Toxicology, Michigan State Univ., East Lansing, MI 48824 (E-mail: galliga1{at}msu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 16, 2002;10.1152/ajpheart.00134.2002
Received 21 February 2002; accepted in final form 8 May 2002.
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METHODS
RESULTS
DISCUSSION
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A. Paliege, A. Parsumathy, D. Mizel, T. Yang, J. Schnermann, and S. Bachmann Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R694 - R700. [Abstract] [Full Text] [PDF]
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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]
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Y. E. Lau, J. J. Galligan, D. L. Kreulen, and G. D. Fink Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R90 - R95. [Abstract] [Full Text] [PDF]
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 L. T. de Richelieu, C. M. Sorensen, N.-H. Holstein-Rathlou, and M. Salomonsson NO-independent mechanism mediates tempol-induced renal vasodilation in SHR Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1227 - F1234. [Abstract] [Full Text] [PDF]
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H. Xu, X. Bian, S. W. Watts, and A. Hlavacova Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats Hypertension, November 1, 2005; 46(5): 1154 - 1162. [Abstract] [Full Text] [PDF]
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C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]
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L. Gao, W. Wang, Y.-L. Li, H. D. Schultz, D. Liu, K. G. Cornish, and I. H. Zucker Sympathoexcitation by central ANG II: Roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2271 - H2279. [Abstract] [Full Text] [PDF]
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N. Lu, B. G. Helwig, R. J. Fels, S. Parimi, and M. J. Kenney Central Tempol alters basal sympathetic nerve discharge and attenuates sympathetic excitation to central ANG II Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2626 - H2633. [Abstract] [Full Text] [PDF]
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T. Shokoji, Y. Fujisawa, S. Kimura, M. Rahman, H. Kiyomoto, K. Matsubara, K. Moriwaki, Y. Aki, A. Miyatake, M. Kohno, et al. Effects of Local Administrations of Tempol and Diethyldithio-Carbamic on Peripheral Nerve Activity Hypertension, August 1, 2004; 44(2): 236 - 243. [Abstract] [Full Text] [PDF]
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 H. A. Koomans, P. J. Blankestijn, and J. A. Joles Sympathetic Hyperactivity in Chronic Renal Failure: A Wake-up Call J. Am. Soc. Nephrol., March 1, 2004; 15(3): 524 - 537. [Abstract] [Full Text] [PDF]
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H. Xu, G. D. Fink, and J. J. Galligan Tempol Lowers Blood Pressure and Sympathetic Nerve Activity But Not Vascular O2- in DOCA-Salt Rats Hypertension, February 1, 2004; 43(2): 329 - 334. [Abstract] [Full Text] [PDF]
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L. Li, S. W. Watts, A. K. Banes, J. J. Galligan, G. D. Fink, and A. F. Chen NADPH Oxidase-Derived Superoxide Augments Endothelin-1-Induced Venoconstriction in Mineralocorticoid Hypertension Hypertension, September 1, 2003; 42(3): 316 - 321. [Abstract] [Full Text] [PDF]
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T. Shokoji, A. Nishiyama, Y. Fujisawa, H. Hitomi, H. Kiyomoto, N. Takahashi, S. Kimura, M. Kohno, and Y. Abe Renal Sympathetic Nerve Responses to Tempol in Spontaneously Hypertensive Rats Hypertension, February 1, 2003; 41(2): 266 - 273. [Abstract] [Full Text] [PDF]
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Significantly
different from tempol-induced responses in sham rats.
