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Department of Pharmacology and Toxicology and 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
the sympathetic nervous system in 4-hydroxy-2,2,6,6-tetramethyl
piperidinoxyl (tempol)-induced cardiovascular responses in
urethane-anesthetized, normotensive rats was evaluated. Tempol caused
dose-dependent (30-300 µmol/kg iv) decreases in renal
sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP),
and heart rate (HR). Similar responses were obtained after sinoaortic
denervation and cervical vagotomy. These responses were not blocked
following treatment with the nitric oxide synthase inhibitor
NG-nitro-L-arginine (2.6 mg · kg
1 · min1 iv for 5 min) or the 
2-adrenergic receptor antagonist idazoxan (0.3 mg/kg iv bolus). Idazoxan blocked the effects of clonidine (10 µg/kg iv) on HR, MAP, and RSNA. Hexamethonium (30 mg/kg iv) inhibited
RSNA, and tempol did not decrease RSNA after hexamethonium. The effects
of tempol on HR and MAP were reduced by hexamethonium. In conclusion,
depressor responses caused by tempol are mediated, partly, by
sympathoinhibition in urethane-anesthetized, normotensive rats. Nitric
oxide does not contribute to this response, and the sympathoinhibitory
effect of tempol is not mediated via 2-adrenergic receptors. Finally, tempol directly decreases HR, which may contribute to the MAP decrease.
sympathetic nervous system; NG-nitro-L-arginine
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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TEMPOL, A SUPEROXIDE DISMUTASE (SOD) mimetic, has been used to reduce superoxide-related tissue injury in ischemia-reperfusion protocols (4) and in inflammation assays (7). Tempol also lowers blood pressure in spontaneously hypertensive, deoxycorticosterone acetate salt, and angiotensin II-treated hypertensive rats (1, 11, 13, 14). The depressor effect depends on nitric oxide (NO) synthesis because tempol-induced responses are blocked following NO synthase (NOS) inhibition (11, 13, 14). Schnackenberg and colleagues (13) also found that tempol reduces blood pressure in normotensive rats, but they did not show that this effect was NOS dependent. Furthermore, these authors did not study changes in heart rate (HR) during the blood pressure decrease. This measurement would have been important because tempol can directly decrease HR in isolated heart preparations (4).
SOD injected into the rostral ventrolateral medulla inhibits renal
sympathetic nerve activity (RSNA) and decreases blood pressure and HR,
but the depressor response could not be completely accounted for by an
interaction with NO (23). Therefore, all of the
mechanisms mediating tempol-induced hemodynamic changes
have not been identified. The present study evaluated the role of
the sympathetic nervous system and NO availability in
tempol-induced cardiovascular responses in urethane-anesthetized
normotensive rats. These studies examined for the first time the
effects of tempol on sympathetic nerve activity. Because SOD
(23) and the 2-adrenergic receptor agonist clonidine (16) can lower blood pressure and inhibit
sympathetic nerve activity via a central mechanism, the role of
2-adrenergic receptors in mediating the effects of
tempol was also investigated. RSNA was used as a measure of sympathetic
nerve activity.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Surgical Procedures
Animal use protocols were approved by the All University Committee for Animal Use and Care at Michigan State University. Male Sprague-Dawley rats (n = 20, 300-350 g; Charles River; Portage, MI) were used. Rats were anesthetized with urethane (1.5 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 (4 mg · kg1 · h1 iv gallamine
triethiodide) during periods of data collection to maintain stable
recording conditions. The depth of anesthesia was monitored
continuously and supplement doses of urethane (25-50 mg iv) were
given as required. Depth of anesthesia was assessed as stability of HR,
blood pressure, and respiratory movement and pupil size and paw-pinch
reflexes. Before periods of paralysis, anesthesia was assessed as
described and during periods of paralysis by monitoring HR, blood
pressure, and RSNA.
A polyethylene catheter was placed into a femoral artery and two femoral veins for measurement of blood pressure and for 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 (20-22).
Sinoaortic denervation and cervical vagotomy (SADV) were accomplished by cutting the cervical sympathetic trunks, the aortic depressor nerve, the superior laryngeal nerve, and vagal nerves. Carotid baroreceptors were denervated by cutting the carotid sinus nerve and stripping the area of the carotid sinus (12). After denervation, blood pressure was elevated for 30-40 min, but hemodynamics and RSNA gradually returned to predenervation levels. Completeness of SADV was confirmed by the absence of HR and RSNA responses to sodium nitroprusside (SNP)-induced decreases and phenylephrine-induced increases in blood pressure.
Data Acquisition
The arterial catheter was connected to a Statham pressure transducer (P23D; Oxnard, CA) 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 (P511, Grass Instruments) with the use of a band-pass filter (low pass, 100 Hz; high pass, 1,000 Hz). The amplified and filtered signal was displayed with a digital oscilloscope (model 1425, Gould Instruments; Cleveland, OH) and monitored by an audiospeaker (Grass Instruments). Raw nerve activity was full-wave 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 using 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 activity obtained after the death of each animal was recorded and set as a zero level of nerve activity. The zero level of activity was digitally subtracted from recordings obtained from each animal. RSNA was measured at 0, 2, 5, 10, and 20 min after each tempol treatment. RSNA was quantitated as the root mean square of nerve activity during a 1-min interval at the time points described above. Root mean square was determined using a fast Fourier transform (Clampfit 8, Axon Instruments).Experimental Protocols
After surgical preparation, 30-40 min were allowed for stabilization of all variables. Tempol, hexamethonium, SNP, idazoxan, or clonidine (Sigma; St. Louis, MO) were dissolved in saline. NG-nitro-L-arginine (L-NNA, Sigma) was dissolved in sodium phosphate buffer (pH 7.2). A volume of 0.4 ml of saline or sodium phosphate buffer injected in 1 min did not change HR, MAP, or RSNA. HR, MAP, and RSNA were monitored for 20 min after drug treatments.Effects of tempol on HR, MAP, and RSNA with or without
L-NNA.
Tempol was administered 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 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% for >2 h in the periphery and in the central nervous system
(8, 15). Beginning at 20 min after L-NNA
infusion, tempol was injected again as described above.
Effects of tempol on HR, MAP, and RSNA in SADV rats. Hemodynamic measurements were made after SADV. One hour after the effectiveness of SADV was tested, tempol was administered as described above.
Effects of tempol on HR, MAP, and RSNA after ganglion block. Tempol was injected as described above before and after hexamethonium (30 mg/kg iv). Because hexamethonium decreases MAP, it may not be possible for tempol to produce further decreases in MAP after ganglion blockade. To verify that MAP could be further decreased after ganglionic blockade, depressor responses to SNP (5 µg/kg) were examined before and after hexamethonium.
Effects of tempol on HR, MAP, and RSNA after
2-adrenergic receptor blockade.
To determine whether the responses to tempol were mediated by an
2-adrenergic receptor-dependent pathway, tempol was
given before and after idazoxan (an 2-adrenergic
receptor antagonist) treatment (0.3 mg/kg iv) (17).
Clonidine, an 2-adrenergic receptor agonist, was used to
verify the effectiveness of 2-adrenergic receptor
blockade (16).
Statistics
Data are means ± SE and n values are the number 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 using Student's paired t-test by comparing control responses to those obtained after various treatments. Group differences in baseline values were analyzed using Mann-Whitney U-tests. P < 0.05 was taken as the level of statistical significance.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 six rats. Tempol alone at 100 and 300 µmol/kg but not at 30 µmol/kg transiently decreased HR, MAP, and RSNA (Figs. 1 and 2). Peak responses occurred 2-4 min after tempol administration. L-NNA treatment increased MAP by ~20 mmHg (P < 0.05) without significantly changing HR or RSNA (Table 1). However, the effects of tempol on MAP after L-NNA treatment were not different from those obtained before L-NNA treatment (P < 0.05) (Figs. 1 and 2). By 20 min after tempol administration, all parameters returned to pretreatment levels (Fig. 1).
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Effects of Tempol on HR, MAP, and RSNA in SADV Rats
Tempol produced dose-dependent decreases in MAP, RSNA, and HR in SADV rats (n = 5) (Fig. 2). Tempol-induced changes in MAP and RSNA in SADV rats were different from control rats only at the 30 µmol/kg dose (Fig. 2). Baseline levels of each parameter before tempol injection in SADV rats did not differ from levels recorded in control rats (Table 1).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 rats. Hexamethonium (30 mg/kg iv) significantly decreased MAP and HR and completely inhibited baseline RSNA (Table 1). As shown in Fig. 2, the effects of tempol on MAP and HR were inhibited following hexamethonium treatment. 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. Before hexamethonium, SNP reduced MAP by 45 ± 5% and after hexamethonium SNP reduced MAP by 39 ± 6%; these values were not significantly different (P > 0.05). SNP-induced decreases in MAP were associated with a reflex increase in HR (6.5 ± 1.5%) that was blocked by hexamethonium.Effects of 2-Adrenoceptor Blockade on Tempol-Induced
Changes in HR, MAP, and RSNA
2-adrenergic receptor agonists on these variables
(16, 17, 20). Figure 3 shows
changes in HR, MAP, and RSNA caused by clonidine (10 µg/kg) before
and after idazoxan treatment (0.3 mg/kg iv). Clonidine caused a
transient increase followed by a decrease in MAP that was maintained
for up to 2 h. Clonidine also inhibited HR and RSNA (Fig. 3). The
effects of clonidine on MAP, HR, and RSNA were inhibited by idazoxan
pretreatment (Figs. 3 and 4). To
determine whether the depressor response caused by tempol was mediated
via an 2-adrenoceptor pathway, tempol (300 µmol/kg) was administered to rats before and after idazoxan treatment. Idazoxan
transiently decreased MAP and increased RSNA and HR, but after 10 min,
these parameters returned to baseline levels. Tempol-induced changes in
MAP, HR, and RSNA were unaffected by idazoxan pretreatment (Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The data presented here indicate that in urethane-anesthetized,
normotensive rats, acute tempol treatment causes a depressor response
that is independent of NOS activity and is associated with an
inhibition of RSNA. RSNA was used as an index of global sympathetic
nerve activity because changes in RSNA can, under some conditions, be
correlated with changes in sympathetic nerve activity in other vascular
beds (19). However, it is also recognized that responses
of the renal nerve to physiological or pathophysiological stimuli can
differ from those of sympathetic nerves supplying other vascular beds.
For example, hemorrhagic shock in anesthetized rats is associated with
a decrease in RNSA but an increase in adrenal sympathetic nerve
activity (18). Therefore, it is possible that the
symapthoinhibitory effects of tempol may be restricted to the kidney,
and further studies are needed to establish whether tempol has a more
general sympathoinhibitory effect. Finally, data from the present study
indicate that tempol-induced inhibition of RSNA is not mediated through
2-adrenergic receptors and tempol directly inhibits HR,
an effect that may contribute to the depressor response.
Superoxide anions quench NO, and therefore superoxide anions can inhibit responses mediated by endogenously released NO. As tempol chelates superoxide anions, it can potentiate NO-mediated responses. Increased oxidative stress occurs in some forms of experimental and human hypertension and antioxidants, including tempol, can lower blood pressure. For example, in spontaneously hypertensive rats and angiotensin II-infused rats, the antihypertensive action of tempol is blocked following NOS inhibition presumably because superoxide anions inactivate NO and diminish its vasodilatory action (11, 13, 14). Human subjects receiving high-dose ascorbic acid also showed reduced blood pressure levels; however, the relationship between the depressor effect of ascorbic acid and NO was not investigated (2). In the present study, tempol-induced depressor responses were unaffected by L-NNA treatment. However, L-NNA treatment was effective at inhibiting NOS as blood pressure was increased by ~20 mmHg in rats receiving L-NNA infusions. These data suggest that tempol can lower blood pressure via an NO-independent mechanism. It is unlikely that, in urethane-anesthetized normotensive rats, tempol lowers blood pressure only by causing direct vasodilation. Additional effects may include direct inhibition of sympathetic nerve activity and HR. 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.
Tempol lowered MAP, HR, and RSNA in SADV rats. This result indicates that tempol-induced decreases in RSNA, MAP, and HR do not require intact baroreceptor reflex pathways. However, after hexamethonium-treatment, the tempol-induced depressor response was reduced and the sympathoinhibitory response was completely blocked. Hexamethonium lowered MAP, and it may not have been possible for tempol to lower MAP any further. This is unlikely because SNP lowered MAP to the same degree before and after hexamethonium treatment. If tempol was acting only as a vasodilator in normotensive rats, it also should have lowered MAP to a similar degree before and after hexamethonium treatment. Therefore, inhibition of sympathetic ganglionic transmission accounts for the blockade of the tempol-induced depressor response by hexamethonium. Tempol produced a small decrease in MAP and HR after hexamethonium treatment. The residual depressor and HR responses may be due, in part, to a direct action of tempol on the heart because tempol slows HR in isolated heart preparations (4). Direct vasodilation caused by tempol could also contribute to the residual depressor response.
SOD injected directly into the rostral ventrolateral medulla of pigs
potentiates tonic inhibition of sympathetic nerve activity and
decreases RSNA, blood pressure, and HR (23). The depressor effect of SOD was most prominent in animals under oxidative stress when
superoxide levels would be high (23). The depressor and sympathoinhibitory effects of SOD were blocked by NOS inhibition, suggesting that NO inhibits central sympathetic nerve activity and that
superoxide ions inactivate endogenous NO. Tempol is a membrane-permeable SOD mimetic (5, 10) that freely crosses the blood-brain barrier after peripheral administration
(9). Therefore, it is possible that superoxide scavengers
such as SOD and tempol can lower blood pressure by causing central
sympathoinhibition. However, this central mechanism may not be
applicable to all models of hypertension (6).
L-NNA readily crosses the blood-brain barrier, and, at the
dose used in the present study, it produces a prolonged inhibition of
NOS activity (15). Because L-NNA did not alter
the depressor response caused by tempol, our data indicate that, if
tempol is acting as a central superoxide scavenger in normotensive
rats, then superoxide ions are not interacting with endogenous NO to
alter RSNA. Alternatively, there may be sufficient endogenous SOD
available to scavenge superoxide ions and therefore tempol would not be
expected to have an effect. Activation of central
2-adrenoceptors inhibits sympathetic nerve activity
(16, 20). In the present study, a potential
2-adrenergic receptor-mediated inhibition of RSNA by
tempol was investigated. However, inhibition of RSNA, HR, and MAP
caused by tempol was not affected following idazoxan treatment to block
2-adrenergic receptors. Idazoxan blocked
clonidine-induced decreases in RSNA, HR, and MAP, indicating that it
was an effective antagonist of 2-adrenergic receptors. These data indicate that the inhibition of RSNA caused by tempol is
independent of 2-adrenergic receptor activation.
In summary, this study has shown for the first time that tempol can lower blood pressure in normotensive rats via a sympathoinhibitory mechanism. In contrast to responses in hypertensive animals, the effects of tempol on RSNA, HR, and MAP are unaffected following treatment with a NOS inhibitor. Therefore, the effects of tempol on cardiovascular dynamics are complex and data obtained using this agent need to be interpreted cautiously.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants 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}pilot.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.
Received 14 March 2001; accepted in final form 14 May 2001.
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METHODS
RESULTS
DISCUSSION
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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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D. N. Mayorov, G. A. Head, and R. De Matteo Tempol Attenuates Excitatory Actions of Angiotensin II in the Rostral Ventrolateral Medulla During Emotional Stress Hypertension, July 1, 2004; 44(1): 101 - 106. [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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E. R. Gross, J. F. LaDisa Jr., D. Weihrauch, L. E. Olson, T. T. Kress, D. A. Hettrick, P. S. Pagel, D. C. Warltier, and J. R. Kersten Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1552 - H1559. [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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H. Xu, G. D. Fink, and J. J. Galligan Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H885 - H892. [Abstract] [Full Text] [PDF]
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