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1 Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, 05508-900, Sao Paulo, Brazil; 2 Department of Pharmacology and Toxicology, Wright State University School of Medicine, Dayton, Ohio 45401; and 3 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Oxytocin (OT) has been implicated in
the cardiovascular responses to exercise, stress, and baroreflex
adjustments. Studies were conducted to determine the effect of genetic
manipulation of the OT gene on blood pressure (BP), heart rate (HR),
and autonomic/baroreflex function. OT knockout (OTKO 
/) and control
+/+ mice were prepared with chronic arterial catheters. OTKO / mice
exhibited a mild hypotension (102 ± 3 vs. 110 ± 3 mmHg).
Sympathetic and vagal tone were tested using
1-adrenergic and cholinergic blockade (atenolol and
atropine). Magnitude of sympathetic and vagal tone to the heart and
periphery was not significantly different between groups. However,
there was an upward shift of sympathetic tone to higher HR values in
OTKO / mice. This displacement combined with unchanged basal HR led
to larger responses to cholinergic blockade (+77 ± 25 vs. +5 ± 15 beats/min, OTKO / vs. control +/+ group). There was also an
increase in baroreflex gain (13.1 ± 2.5 vs. 4.1 ± 1.2 beats · min
1 · mmHg1,
OTKO / vs. control +/+ group) over a smaller BP range. Results show
that OTKO / mice are characterized by 1) hypotension,
suggesting that OT is involved in tonic BP maintenance; 2)
enhanced baroreflex gain over a small BP range, suggesting that OT
extends the functional range of arterial baroreceptor reflex; and
3) shift in autonomic balance, indicating that OT reduces
the sympathetic reserve.
heart rate; blood pressure; autonomic nervous system; peptides; genetic models; brain
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BESIDES THE CLASSIC effects of oxytocin (OT) on uterine contraction and milk ejection, a growing body of evidence suggests that OT also modulates cardiovascular function and water/electrolyte balance (12, 15, 35). It was established that OT is present in males as well as females, acts as a vasoconstrictor, is secreted in response to volume and osmotic stimuli, affects sodium excretion and consumption, and is involved in the central mediation of the cardiovascular responses to stress, hypotension, and exercise (8, 21, 25, 27-29, 42, 45).
In recent studies, we showed that endogenous OT acts as a neuromodulator in a brain stem region critical in cardiovascular coordination, the nucleus of the solitary tract-dorsovagal complex (NTS/DVC) (5, 16, 27). Combining measurement of brain stem peptides with functional responses following local OT receptor blockade, we showed that activation of oxytocinergic projections is important in the heart rate (HR) response to exercise. OT appeared to mediate the smaller tachycardiac response to exercise, characteristic of trained animals (5, 16, 27). Baroreflex gain was also affected by central OT administration, an increase after NTS/DVC injection (16), and a decrease after intracisternal injection (32). Autoradiographic binding and immunohistochemical staining methods verified the presence of the peptide and its receptor in key brain stem centers (6, 24, 26, 30, 40).
The study of peptidergic modulation of cardiovascular function has
largely depended on the use of exogenous receptor agonists and
antagonists. These experiments require injections into specific brain
regions to localize effects as well as long-term maintenance of
pharmacological blockade. The development of new animal models in which
genes are removed or added allows for investigation at a different
level. The OT knockout mouse strain (OTKO), developed by Young et al.
(46), lacks the ability to synthesize OT. This genetic
strain shows a deficit in milk ejection, changes in social behavior,
and enhancement of sodium consumption (1, 10, 34, 46, 47).
However, there is a lack of information on the cardiovascular changes
associated with this genetic modification. We developed sophisticated
methods for the conduct of cardiovascular studies in mice, allowing for
chronic, long-term measurements of blood pressure (BP) and HR (2,
23). Studies were designed to compare OTKO / with its
control +/+ group in terms of 1) baseline BP and HR,
2) baroreceptor reflex control of HR, 3)
sympathetic and parasympathetic tone to the heart, and 4)
sympathetic tone to the periphery.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Male wild-type (OT +/+, control) and OTKO / mice (~30 g) were
obtained from a colony at the University of Pittsburgh. The founders
were derived from the strain developed by Dr. W. S. Young III and
colleagues (Bethesda, MD) (46). Genotypes were determined from DNA extracted from tail using a polymerase chain reaction technique. The experimental mice (+/+ and /) were produced by breeding heterozygote (+/) parents. Although this breeding strategy is time and labor intensive, it produces animals with similar genetic
and environmental backgrounds. Animals were housed in clear cylindrical
cages (Instech Laboratories, Plymouth Meeting, PA) at 22°C, under a
12:12-h light-dark cycle (0500-1700 lights on), and with ad
libitum access to water and standard mouse chow. The Laboratory Animal
Care and Use Committee of Wright State University approved all
experimental protocols.
Animal surgery. Animals were prepared with chronic carotid arterial catheters according to the method of Li et al. (23). The catheters were formed from Micro-Renathane tubing (0.025-mm OD × 0.012-mm ID) with the end heat-stretched (about one-half the original diameter) and beveled. Mice were anesthetized with a ketamine-xylazine mixture (70:6 mg/kg im) and the catheter was inserted into the carotid artery. The external extremity of the catheter was tunneled subcutaneously to pass through a polysulfone button (model LW62; Instech Labs), surgically attached to the back muscles. The catheter was covered with a stainless steel spring, which was attached to a fluid swivel (model 375/25; Instech Labs) mounted on top of the cage. The tether and swivel system allowed the animal to move freely, while protecting the arterial catheter. The catheter was connected to a flow-through pressure transducer (model 041-500503A; Argon, Athens, TX), which was continuously infused with heparinized saline (80 U/ml, 20 µl/h syringe pump, model 220; Kd Scientific, Boston, MA). The heparinized saline infusion was required to maintain catheter patency. The animals were allowed to recover from surgery for a minimum of 3-5 days before experimentation.
Experimental protocols. The first experiment determined baseline levels of BP and HR using continuous cardiovascular measurements (3-5 days). The continuous recording method is preferable because it provides a true nonstress baseline without the complications of animal handling.
The second experiment evaluated baroreceptor reflex control of HR, determined by HR responses to pressor and depressor agents. Baroreceptor activation was produced by bolus intra-arterial injections (5-30 µl) of phenylephrine (20 µg/ml) and sodium nitroprusside (50 µg/ml). The catheter was loaded with the drug solution and the injections were made from low to high volume (5-30 µl) with a saline flush (20-30 µl) at the end of the injection series. This method avoids the complications of volume overload with repeated flushing. Subsequent injections were not made until the cardiovascular parameters had returned to preinjection levels. BP and HR measurements were made during the baseline period (immediately before injection) and during the development of the pressor or depressor responses. The third experiment determined vagal and sympathetic tone, using blockade of1- and cholinergic receptors. OTKO / and control +/+ mice were given atropine (30 µl, 2 mg/kg) or atenolol (50 µl, 4 mg/kg) via the arterial catheter. The drugs were given in a
counterbalanced design, atropine (maximal tachycardia) followed by
atenolol (maximal bradycardia) and the opposite order for the second
test (1-3 days later). Sequences were randomized between mice, and
basal and double blockade values were averaged for the two injection
sequences. Preliminary tests using acetylcholine and isoproterenol were
performed to verify the efficacy of the antagonist treatment.
Ganglionic blockade was tested using hexamethonium (10 µl, 6 mg/kg).
BP measurements after ganglionic blockade were made at the nadir of the
pressor response (20-30 s after injection). These measurements
were made at the end of the experiment (up to 2 wk after cannulation)
and the pulse pressure was lower. For this reason, only the BP data are provided.
Data collection.
The calibrated pressure transducer was connected to a computerized
data-acquisition system (model MP100WSW; BIOPAC Systems, Santa Barbara,
CA), specifically designed for cardiovascular measurements. BP was
sampled at different rates for the acute and chronic studies (500 and
100 Hz, respectively). The lower sampling rate was used for continuous
measurements because of the data-storage requirements. Data were
recorded online using a computer (XPS-D300; Dell Computer, Austin, TX)
and a removable disk storage system (Jazz Drive; Iomega, Roy, UT). Data
were processed beat to beat. Mean arterial pressure (MAP) was
calculated using the formula MAP = diastolic BP (DBP) + [systaltic BP (SBP) DBP]/3 and the instantaneous HR by the period between SBP in two consecutive beats.
![HR = <IT>P</IT>1 + <FR><NU><IT>P</IT>2</NU><DE>[1 + <IT>e</IT><SUP><IT>P</IT>3(<IT>MAP − P</IT>4)</SUP>]</DE></FR>](/content/vol284/issue6/fulltext/H2269/img001.gif)
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P2 × P3/4 and the upper plateau = P1 + HR range (P2). The
maximal tachycardic (upper plateau average HR) and bradycardic
responses (average HR lower plateau) and the MAP range
(corresponding to the interval in the x-axis between lower
and upper plateau) were also calculated (16). Parameters
of the sigmoid fitting were used to compare the OTKO / and control
+/+ groups.
Statistical analysis. Values are reported as means ± SE. Differences between groups were compared by Student's t-test (basal values and parameters of logistic curve) or two-way ANOVA (groups and pre-/posttreatment values), as appropriate. Two-way ANOVA for repeated measurements was used to compare serial injections of phenylephrine and sodium nitroprusside between groups. Significance level was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BP and HR.
OTKO / mice demonstrated a mild hypotension with no change in HR
(Fig. 1). Twenty-four-hour mean MAP was
~7% lower in OTKO / mice compared with control +/+ mice
(102 ± 3 vs. 110 ± 3 mmHg, P < 0.05).
Baseline HR was not different between the groups (507 ± 18 vs.
523 ± 27 beats/min, control +/+ vs. OTKO / group).
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Vagal and sympathetic tone.
Intra-arterial injections of atropine or atenolol did not change MAP in
either group (Table 1). Cholinergic
blockade caused a marked increase in HR in OTKO / animals, with no
significant changes observed in control +/+ mice (+77 ± 25 vs.
+5 ± 15 beats/min, OTKO / vs. control +/+ mice). The HR
response to sympathetic blockade was not significantly different
between the groups (62 ± 21 vs. 124 ± 25 beats/min,
OTKO / vs. control +/+ group). Intrinsic HR, determined as the
level achieved after double adrenergic and cholinergic blockade (Fig.
2A), was significantly higher
in OTKO / than in control +/+ mice (483 ± 12 vs. 413 ± 22 beats/min, OTKO / vs. control +/+ group). Intrinsic HR values
and maximal HR changes observed following cholinergic or adrenergic
blockade are used for the calculation of sympathetic and vagal drive to the heart. As shown in Fig. 2A, sympathetic tone was high
and of similar magnitude in both groups (+146 ± 16 and +157 ± 15 beats/min over respective intrinsic HR). Vagal tone was not
significantly different between the groups (51 ± 20 vs.
12 ± 18 beats/min below intrinsic HR; Fig. 2A).
Although the groups showed a similar HR range, sympathetic drive, and
baseline HR (indicated by arrows in Fig. 2A), the OTKO /
mice operated at a lower level of sympathetic activity. The net result
is that these mice have a higher sympathetic reserve to be manipulated
during depressor challenges (Fig. 2B).
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Ganglionic blockade.
To quantify sympathetic drive to the periphery, we used ganglionic
blockade with hexamethonium (Table 1). Hexamethonium produced similar
MAP reductions in the control +/+ and OTKO / groups (decrease of
~15 mmHg). This suggests that the sympathetic drive to the vessels is
not altered in the knockout mice.
Baroreflex function.
Bolus injections of phenylephrine and sodium nitroprusside were used to
test baroreceptor reflex control of HR. Graded doses of phenylephrine
(3-26 µg/kg) increased MAP from 13 ± 2 to 40 ± 5 mmHg, whereas sodium nitroprusside (8-50 µg/kg) decreased MAP by
14 ± 2 to 39 ± 5 mmHg. This is a sufficient range of
pressures to test baroreflex function. There were no differences in the pressor or depressor responses between the groups (Fig.
3). Sigmoidal curves were fitted to HR
and MAP data obtained during the pressor/depressor challenges. Examples
of individual curves in OTKO / and control +/+ mice are shown in
Fig. 4. The average sigmoidal curves and calculated parameters for both groups are presented in Fig.
5 and Table 2, respectively.
Baroreflex function differed between OTKO
/ and control +/+ mice. There was a sharp increase in the reflex
gain in the OTKO / group (13.1 ± 2.5 vs. 4.1 ± 1.2 beats · min1 · mmHg1)
with a significant decrease in the pressure interval required to change
from maximal tachycardia to maximal bradycardia (93 ± 12 vs.
40 ± 3 mmHg, control +/+ vs. OTKO / mice, a reduction of
57%). These changes were accompanied by a nonsignificant change in the
functional range of the HR response (151 ± 33 vs. 203 ± 22 beats/min, control +/+ vs. OTKO / group) (Table 2 and Fig. 5).
However, the OTKO / group showed a significant reduction in control
HR values maintained during baroreflex testing (577 ± 12 vs.
511 ± 17 beats/min, control +/+ vs. OTKO / group; Table 2),
with no change in MAP. The smaller average HR in a similar reflex HR
range explains why the OTKO / group shows a difference in maximal
bradycardia (51 ± 9 vs. 102 ± 21 beats/min, OTKO /
vs. control +/+ group, P < 0.05; Fig.
6) and a potentiation of reflex
tachycardia (+152 ± 20 vs. +49 ± 14 beats/min, OTKO /
vs. control +/+ mice, P < 0.05; Fig. 6). Facilitation
of the tachycardia response in OTKO / mice is in accordance with
the higher sympathetic reserve observed in this group (Fig. 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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With the use of the OT-deficient model, we uncovered important new
findings on OT's role in BP and baroreflex/autonomic balance. The data
provide the first experimental evidence for a role of endogenous OT in
the maintenance of tonic BP, because OTKO / mice showed a small but
consistent hypotension. Alterations in baroreflex function were noted
in mice lacking OT, seen as an increase in the gain of the baroreflex
curve and an alteration in the operating pressure range. Finally, there
was a change in autonomic balance to the heart with a greater response
to cholinergic blockade and an indication of higher sympathetic reserve.
There is much evidence to show that brain peptides regulate BP and autonomic balance. For the highly complementary peptides vasopressin and OT, there are effects on BP, HR, and baroreflex activity (11, 31-33, 36, 44). There are differences, which are dependent on the route of administration (central or peripheral), the time frame (short or long term), and the animal species. For example, intracisternal OT injection produced no change in BP or HR, but it altered baroreflex sensitivity (32, 33). Injection of OT into the rostral brain stem produced a rise in BP and HR as did peripheral administration (26, 31, 33). To further investigate the impact of the peptides, investigators tested the effect of peptide antagonists, antisense oligonucleotides, and specific brain lesions on physiological function. We reported that both neurotoxin brain lesions and centrally injected OT antisense oligonucleotides attenuated the tachycardic responses to stress (8, 29). A specific OT antagonist altered exercise tachycardia as well as baroreflex function (5, 16). The antagonist actions were opposite to the peptide's effects, suggesting a specificity of the response.
As an extension of these pharmacological studies, we proceeded to use the OT gene deletion model (46). The objective was to examine cardiovascular regulation in the absence of the peptide, with the rationale that the physiological findings would provide information on function. The advantage of the knockout model is that the compound of interest, in this case OT, is absent from all tissues at all times, from uterine development into adulthood. Studies are not dependent on the efficacy of drugs or on changing plasma/tissue levels. However, the genetic model, at the same time, raises questions related to possible developmental and/or compensatory effects of the peptide removal.
Initial studies asked the question as to whether basal BP and HR are
altered in OTKO / mice. Methods established in the laboratory allow
for the long-term measurement of cardiovascular parameters in
conscious, nonstressed mice (2, 23). This is critical for
the measurement of basal levels since handling, noise, or other
environmental stimuli can affect BP and HR. Results demonstrated a
small, but consistent, hypotension in OT-deficient mice, supporting a
role for OT in BP maintenance. This effect was observed only in the
chronic monitoring study and not in the acute paradigms. This
demonstrates the requirement for continual measurements (extensive data
pool) to reveal small pressure differences (a 7% reduction). The
results were verified in a subsequent study (3) that
showed reductions in day and night BP and HR as well as an increase in stress-induced pressor responses.
There is much information on the effect of exogenous OT on
cardiovascular parameters. Many studies use acute injection protocols with tail-cuff BP monitoring. Peripheral injection of OT produced both
increases and decreases in BP (31, 33). The increase was
short lived, whereas the depressor response lasted for hours or days.
When injected directly into the brain stem, OT produced a marked
increase in BP (>30 mmHg) (26). There are also numerous studies, which show a relationship between blood volume, pressor status, and OT secretion. Hypotension and hypovolemia activate OT
neurons and increase peptide secretion (20, 21, 28, 39). Because OT is natriuretic, one might predict sodium retention and
volume expansion in the peptide-deficient condition (17, 45). However, there are no long-term changes in vascular
volume/osmolar status and no alterations in sodium balance
(13). The OTKO / mice do show an enhanced sodium
appetite, suggesting some subtle sensory or balance change.
OT-deficient mice consume fivefold more salt solution under
need-free conditions and sevenfold more following overnight fluid
deprivation (1, 34). OT replacement produced a marked
reduction in saline intake along with a reduction in salt excretion
(13).
A direct link between the OT system and hypotension cannot be established with surety. Certainly, OT's removal and the consequent lack of peptidergic signaling produce a cascade of changes. This could involve brain stem transmission and modulation of sympathetic and parasympathetic outflow. Afferent renal and brain pathways may also be altered in the knockout mice. OT antagonists attenuated the natriuresis following unilateral nephrectomy (19) and hypotension-induced renin, vasopressin, and HR responses (18). These results suggest that OT (besides its direct peripheral effects) is involved in the afferent signaling of the acute renal responses. The functional consequence resulting from the interaction between afferent × efferent OT effects on cardiovascular control remains to be determined.
Previous studies suggested a role for OT in the regulation of
baroreflex function (16, 27, 32), an idea supported by our
findings in the OTKO / model. There was a dramatic increase in the
gain of the reflex (greater than 3-fold) as well as a decrease in the
operating pressure range of the baroreflex function. There was a
noticeable decrease in the bradycardia phase, suggesting that OT
facilitates reflex reduction in HR. OT also appears to decrease the
sensitivity of the reflex at the midpoint of the curve (around baseline
values) and extends the pressure interval from maximal bradycardia to
maximal tachycardia. Immunohistochemical staining and
retrograde/anterograde tracing methods have shown dense oxytocinergic
projections from hypothalamic centers to integrative cardiovascular
areas in the brain stem (7, 26, 30, 38). Administration of
both peptide and antagonist into discrete areas of the dorsal brain
stem or spinal cord altered local neuronal activity (9, 11,
43). Injections of OT had divergent effects on reflex
bradycardia, enhancement after intravenous injection, and a depression
after intracisternal administration (32, 37). Our recent
studies indicate that oxytocinergic projections from hypothalamus to
NTS/DVC facilitate the slow down of the heart under various conditions
(5, 16, 27). The present results confirm and extend this
observation, showing that deletion of the OT gene and its peptide
blunts the bradycardic but also facilitates the tachycardic response to
depressor challenges. This may be partially explained by the set point
for basal HR in OTKO / mice that is in the middle of the
sympathetic range. This means that HR operates at a lower level,
resulting in a higher sympathetic reserve to the heart. This reserve is
noticeable when animals are tested with hypotensive challenges. The
larger HR increase in the OTKO / group after parasympathetic
blockade is likely the result of a downward displacement of basal HR
relative to the maximal sympathetic response, rather than increased
cholinergic drive. It should be stressed that the slightly high vagal
tone at rest and the high intrinsic HR in the / group could also contribute to the downward displacement of baseline HR. Changes in
tachycardic response were not observed in rats following OT receptor
blockade restricted to the NTS/DCV (16), indicating a more
generalized action of OT in the central adjustment of HR. The full
anatomic map for central oxytocinergic control of cardiovascular function is not established; however, pieces of the puzzle indicate participation of the hypothalamic paraventricular nucleus (site of
peptide biosynthesis) (8, 29), NTS/DVC brain stem
integrative centers (5, 11, 16, 36), and the spinal cord
(19, 41, 43).
The animals lacking OT show an increase in reflex gain over a smaller
MAP interval. The assumption is that if OT's removal mediates this
action directly, then central OT decreases gain while increasing the
operational range of the reflex. Blunting of baroreceptor reflex
control of HR has been described as a characteristic response of
hypertensives with high sympathetic tone (4). However, both control and OTKO / mice exhibited a high sympathetic tone as
demonstrated by the BP responses to 1-adrenergic and
ganglionic blockade. Therefore, it appears that OT can modify reflex
sensitivity, independent of the magnitude of sympathetic tone. Previous
results showed that OT administration into the NTS/DVC modified reflex control of HR without changing the magnitude of sympathoexcitatory response to baroreceptor stimulation (16). In addition,
our data indicate that OT is involved in setting the intrinsic HR, determining when present a low intrinsic value. Previous studies described OT-induced bradycardia as a central (5, 16) or peripheral effect (15, 33, 37). Although we have no
information on a direct OT effect on intrinsic HR, this new observation
is in accordance with the demonstration of OT receptor mRNA expression in the cardiac atria and ventricles (14) and the
demonstration of OT synthesis in the heart, with the highest
concentration found in the right atria (15).
In conclusion, this study presents the results of a comprehensive investigation of cardiovascular function in conscious mice lacking the OT gene. Differences were noted in basal BP, baroreflex function, and autonomic balance, supporting the idea that the OT secretory system is important in the regulation of cardiovascular function.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institutes of Health Grant HL-43178 and HD-37268, Fundação de Amparo a Pesquisa do Estado de São Paolo Gant 99/08012-9, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Grant 465209/00-9. L. C. Michelini is a research fellow from CNPq (300320/89-2).
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Morris, Dept. of Pharmacology and Toxicology, Wright State Univ., School of Medicine, Dayton, OH 45401 (E-mail: Mariana.Morris{at}Wright.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.
First published January 16, 2003;10.1152/ajpheart.00774.2002
Received 4 September 2002; accepted in final form 9 January 2003.
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DISCUSSION
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