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Department of Physiology, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Several lines of evidence support the
existence of an oligosynaptic projection from the paraventricular
nucleus of the hypothalamus (PVN) to the kidney in the rat. We sought
to provide evidence that this neural pathway is capable of influencing
renal function in rats. Bilateral microinjections of bicuculline (Bic;
1 nmol) into the PVN decreased glomerular filtration rate (59%),
effective renal plasma flow (71%), urine flow (UV; 57%), and urinary
sodium excretion (UNaV; 54%),
accompanied by increased mean arterial pressure (17%) and heart rate
(17%). These results were not obtained when Bic was injected outside
the PVN or when vehicle (0.9% saline) was injected into the PVN.
Bilateral renal denervation (5-7 days before the experiments)
significantly reduced the renal vasoconstriction, attenuated the
antidiuresis, and abolished the antinatriuresis evoked by PVN
stimulation. On the other hand, both the antidiuresis and
antinatriuresis evoked by PVN stimulation were undiminished after
treatment with either of two vasopressin receptor antagonists ([
-mercapto-,-cyclopentamethylenepropionyl1,O-Et-Tyr2,Val4,Arg8]vasopressin,
a vasopressin V1 receptor
antagonist, or
[adamantaneacetyl1,O-Et-D-Tyr2,Val4,aminobutyryl6,Arg8,9]-vasopressin,
a V2 receptor antagonist). In
renal-denervated rats treated with the same
V2 receptor antagonist, PVN
stimulation produced highly variable increases in both UV and
UNaV, which overall were not
statistically different than zero. We conclude that the activation of
neurons in PVN evokes 1) renal
vasoconstriction accompanied by antinatriuresis, both of which are
attributable to the renal nerves, and
2) decreased water excretion, which
is mediated by the renal nerves and vasopressin
V2 receptors.
renal excretory function; vasopressin
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE PARAVENTRICULAR NUCLEUS of the hypothalamus (PVN) affects renal function via humoral, and perhaps neural, mechanisms. The involvement of PVN in humoral control of the kidney is well established, because its role in the control of the release of the antidiuretic hormone arginine vasopressin has been documented (1, 4). Several reports have provided convergent lines of evidence suggesting that PVN may also influence renal function via the renal nerves (10, 11, 23). Specifically, it has been demonstrated that a direct oligosynaptic projection arises from PVN and terminates in the kidney (23). Extracellular single-unit recordings of paraventriculo-spinal or preautonomic neurons have shown that they are responsive to input arising from high-pressure arterial baroreceptors and cardiac afferents sensitive to serotonin (10) as well as low-pressure cardiopulmonary stretch receptors (9). These properties are also exhibited by the discharge of efferent fibers of the renal nerve (2, 17). Although these reports suggest that neuronal cell bodies in PVN may be capable of influencing renal function via the renal nerves, this possibility has not been directly examined.
The present study was conducted to provide evidence that activation of neuronal cell bodies in PVN does alter renal function via the renal nerves. Previous studies have documented variable changes in arterial pressure and renal nerve discharge following direct activation, with glutamate microinjections, of neuronal cell bodies in PVN (6-8, 11, 13, 16). In this study we used bilateral microinjections (100 nl) of the GABAergic receptor antagonist bicuculline methiodide (Bic; 1 nmol) to indirectly activate neuronal cell bodies via disinhibition. This strategy appeared promising in light of studies that evoked cardiorespiratory responses and locomotion (28) when Bic was injected in sites in the hypothalamus. Furthermore, an inhibitory input to PVN arising from arterial baroreceptors utilizes GABA as a transmitter (22).
This study had two objectives: 1) to document changes in renal hemodynamic and excretory function following the stimulation of neuronal cell bodies in PVN and 2) to characterize the mechanism responsible for this response. The latter objective was focused on determining the role of vasopressin versus the renal nerves in mediating this response.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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All of the experiments described in this study conform to the Guide for the Care and Use of Laboratory Animals, published by the National Research Council (1996), and were approved by the University of North Dakota Institutional Animal Care and Use Committee.
General surgical procedures. Male Sprague-Dawley rats, obtained from the in-house colony located in the Center for Biomedical Research at the University of North Dakota, were maintained on a 12:12-h light-dark cycle and fed standard laboratory rodent chow (PMI Feeds, St. Louis, MO) and tap water ad libitum. The rats (250-350 g) were anesthetized with Brevital (50 mg/kg ip), followed by Inactin (thiobutabarbital, 100 mg/kg ip; Research Biochemicals International). Body temperature, measured via a rectal thermistor, was maintained at 37-38°C. Polyethylene catheters were inserted into the trachea, femoral artery, femoral vein, and bladder. These were used to maintain a patent airway to facilitate spontaneous breathing, record arterial pressure, collect arterial blood samples, administer drugs, and collect urine samples. Arterial pressure was monitored with a transducer (Utah Medical Systems) attached to a transducer coupler/amplifier (Coulbourn Instruments, model S72-25). Mean arterial pressure (MAP) and heart rate (HR) were calculated and monitored online using a MacLab/8s data acquisition and analysis system.
The rats were placed in a stereotaxic instrument (Kopf). After incising the scalp, retracting the underlying soft tissue, and establishing the stereotaxic coordinates for bregma, we removed a portion (~5 mm × 10 mm) of the cranium. At the appropriate time in the protocol (see below), a micropipette filled with either Bic (10 mM in 0.9% saline containing 0.2% Chicago sky blue) or vehicle (0.9% saline containing 0.2% Chicago sky blue) was then placed either into the PVN or other sites (anatomic control group), and 75-100 nl of the Bic solution (or vehicle) was pressure-injected bilaterally using a General Valve Picospritzer. The volume injected was verified by visually monitoring the meniscus of the solution with a stereomicroscope fitted with an ocular reticle.
At the conclusion of the experiment, the rat was euthanized with an
overdose of anesthetic and saturated KCl (1.0 ml iv). The brain was
removed from the skull, placed in Formalin overnight, frozen on dry
ice, and stored in a freezer (
70°C). The brains were
sectioned (40 µm) using a cryostat, and the sections were mounted on
slides and stained with 2% neutral red. Placement of drug or vehicle
injections was verified by visually identifying, with a microscope, the
location of the deposit of Chicago sky blue.
Preparation of experimental control groups. Bilateral renal denervation was performed in rats (n = 15) anesthetized with Brevital (50 mg/kg ip), utilizing sterile surgical technique. Both kidneys were isolated via bilateral flank incisions. After the kidneys were isolated from surrounding tissue, the renal artery and vein were painted with 15% phenol (dissolved in 95% ethanol), as previously described (26, 27). Caution was used in the application of phenol to prevent any spread of the solution onto the kidney. The incisions were closed with sterile sutures and stainless steel wound clips. Procaine penicillin G was administered (75,000 IU im). The rats were used 5-7 days later for renal function experiments (described below). Kidneys were examined after the conclusion of the renal function experiments to identify possible phenol-induced renal damage or infection. None was observed in any of the animals. This procedure has been shown repeatedly to consistently lower renal tissue norepinephrine content by >95% (26, 27).
The effect of vasopressin V1 receptor blockade was examined in two groups of rats. The first group of rats (n = 5) was used to verify the efficacy of our treatment for vasopressin V1 receptor blockade. In this group, the response to a pressor dose of exogenous [Arg8]-vasopressin (Sigma no. V9879; 50 ng, 0.1 ml bolus iv) observed in the absence of vasopressin V1 receptor blockade was compared with that observed during treatment with [-mercapto-,-cyclopentamethylenepropionyl1,O-Et-Tyr2,Val4,Arg8]-vasopressin
(Sigma no. V4253; 5 nmol/kg bolus iv, followed by a continuous 60-min
infusion of 5 nmol · kg
1 · h1
iv). The dose of V1 antagonist
used has been previously shown to block the vasopressor action of
circulating vasopressin in anesthetized rats (12), and we found that
the pressor response to exogenous vasopressin administration was
completely eliminated with the vasopressin
V1 antagonist dose used in this
study (data not shown). In the second group of rats
(n = 7), we examined the effects of
vasopressin V1 receptor blockade
on the response evoked from PVN. In the latter group, the infusion of
V1 antagonist started before the
initiation of renal function measurements and continued throughout the
course of the experiments.
The effect of vasopressin V2
receptor blockade was examined in two groups of rats. The dose of
vasopressin V2 receptor
antagonist, [adamantaneacetyl1,O-Et-D-Tyr2,Val4,aminobutyryl6,Arg8,9]-vasopressin,
that we used (25 mg · ml1 · h1
iv) has been previously shown to block the tubular effects of vasopressin in anesthetized rats (12). In the first group of rats
(n = 8), we observed the effects of
vasopressin V2 receptor on the
response evoked from PVN. The infusion of
V2 antagonist started before the
initiation of renal function measurements and continued throughout the
course of the experiments. In the second group of rats
(n = 7), we observed the combined
effects of vasopressin V2 receptor
antagonist and renal denervation (rats underwent bilateral renal
denervation 5-7 days before the experiment) on the response evoked
from PVN.
Renal function measurements and experimental protocol.
Following completion of the placement of the femoral catheters, an
intravenous bolus injection of 10% inulin, containing 800 µl of 20%
p-aminohippurate (PAH) was
administered (200 µl/100 g body wt), followed by a continuous
infusion of 5% inulin in 3% BSA-0.9% saline containing PAH at a rate
of 500 µl · 100 g body
wt1 · h1.
Experimental and control groups. Three groups were examined to determine whether PVN stimulation affected renal function: an experimental group (Bic injected in PVN; n = 9), an anatomic control group (Bic injected outside PVN; n = 8), and a vehicle control group (0.9% saline injected in PVN; n = 5).
Four additional groups were examined to identify the renal mechanism(s) responsible for the PVN-induced renal response: a group whose kidneys were denervated bilaterally 5-7 days before renal function measurement and PVN stimulation (n = 8), a group treated with a continuous infusion of the vasopressin V1 receptor antagonist [-mercapto-,-cyclopentamethylenepropionyl1,O-Et-Tyr2,Val4,Arg8]-vasopressin
before and during PVN stimulation to block the vascular effect of
circulating vasopressin (n = 7), a
group treated with a continuous infusion of the vasopressin
V2 receptor antagonist [adamantaneacetyl1,O-Et-D-Tyr2,Val4,aminobutyryl6,
Arg8,9]-vasopressin
before and during PVN stimulation to block the tubular effect of
circulating vasopressin (n = 8), and a
group whose kidneys were denervated (as previously described) and
received the V2 receptor
antagonist treatment (as previously described;
n = 7).
Morphological, chemical, and statistical analysis. All injection sites were confirmed histologically. The identification of structures containing injection sites was determined using the stereotaxic atlas of Paxinos and Watson (19). Only those animals with dye deposits (injection sites) located bilaterally within the boundaries of PVN [as shown in Figs. 24-26 of the atlas of Paxinos and Watson (19)] were used for analysis of the effects of PVN or vehicle injections. Animals in which one dye spot was located unilaterally in the PVN and one dye spot was located outside the PVN were not used in any analysis. Animals in which both dye spots were located outside the PVN, but not necessarily bilaterally placed in the same structure, were included in the anatomic control group.
Plasma and urine electrolytes were measured by flame photometry. Inulin and PAH were measured in plasma and urine by the anthrone (5) and Waugh and Beal (29) methods, respectively. PAH clearance calculations were not corrected for PAH extraction. Plasma protein concentration was measured by refractometry. Preliminary statistical analysis of MAP, HR, glomerular filtration rate (GFR), PAH clearance (effective renal plasma flow, ERPF), urinary sodium excretion (UNaV), and urine flow (UV) were conducted using repeated-measures ANOVA (StatView, Abacus Concepts) to verify the stability of baseline values (urine collection periods U1-U3). This initial analysis indicated that there were no significant differences among the three baseline values (U1-U3) within each treatment group for any of the measured variables, indicating stability of our preparations; therefore these values (U1-U3) were averaged and are reported as a single baseline value for each group. A within-group analysis was conducted to determine whether stimulation of PVN produced any change in the observed parameters. This was accomplished using a mixed-model, one-way ANOVA (pre-post injection × treatment groups; StatView, Abacus Concepts) for each of the variables examined. When a significant pre-post injection × treatment group effect was observed, a subsequent analysis was performed (split by treatment group) to compare baseline values with the postinjection values observed in each treatment group during U4 (groups A-G, Table 1).
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Renal response to PVN stimulation. Statistical analysis (mixed-model one-way ANOVA; pre-post injection × treatment groups) of each of the variables yielded main effects F values that exceeded the critical level for both a treatment groups effect and a pre-post injection × treatment groups effect. Therefore, subsequent pre-post injection analysis (repeated-measures ANOVA) was conducted for each treatment group to determine their respective P values. The results are summarized in Table 1. The greatest magnitude in the pre-post injection changes consistently occurred during U4; therefore only those data are shown and only those data are used in the analyses.
As shown in Table 1 (group A) and Fig. 1, stimulation of PVN with Bic evoked significant reductions in GFR, ERPF, and UV, accompanied by a marked decrease in UNaV (P = 0.0515). The distribution of injection sites in PVN is shown in Fig. 2. Twelve of the eighteen injection sites in PVN included at least a portion of the dorsal cap of the PVN (Fig. 2).
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Mechanisms responsible for the renal response to PVN stimulation. A comparison of baseline values (factorial ANOVA) indicated that the baseline values of GFR, ERPF, UV, and UNaV were significantly different among the treatment groups. Therefore, the values observed during urine collection period U4 were normalized as percent change from baseline for the purposes of comparing the effects of renal denervation (Table 2, group D) or vasopressin receptor blockade (Table 2, groups E and F) on the response to PVN stimulation observed in the intact, untreated group (Table 2, group A). The statistical analysis of the normalized responses yielded F values for treatment groups effects that exceeded the critical level for each parameter examined (i.e., MAP, HR, GFR, ERPF, UV, and UNaV); therefore, a post hoc analysis was performed to identify specific between-group differences that were significant. The results are summarized in Table 2. Neither GFR nor ERPF was examined in the group treated with vasopressin V2 receptor antagonist because it was unlikely that this treatment would affect either of these variables.
Bilateral denervation of the kidneys, performed 5-7 days before the renal function experiments, reduced the magnitude of the response to PVN stimulation. As shown in Fig. 3, both the renal hemodynamic and excretory components of the response to PVN stimulation were markedly diminished. Although the antinatriuretic component was largely absent in the denervated animals, the large variability in this parameter (see Table 1, groups A and D) prevented a statistically significant alteration in this component (P < 0.08 vs. intact) of the response (Fig. 3, bottom). However, the 95% confidence interval indicated that the small change in UNaV seen in the denervated animals was not significantly different from zero.
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-mercapto-,-cyclopentamethylenepropionyl1,
O-Et-Tyr2,Val4,Arg8]-vasopressin
(Fig. 4 and Table 2, group
E), nor the V2
antagonist, [adamantaneacetyl1,
O-Et-D-Tyr2,Val4,aminobutyryl6,
Arg8,9]-vasopressin (Fig.
5 and Table 2, group
F), diminished the response to PVN stimulation in
animals with intact renal nerves.
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Systemic cardiovascular response to PVN stimulation. The baseline and postinjection (U4) values for all treatment groups are summarized in Table 1. Stimulation of the PVN with Bic (Table 1, group A) produced significant increases in MAP and HR. The values shown in Table 1 were the average of each or these variables over the 20-min urine collection period. The peak MAP was 176 ± 7 mmHg and the peak HR was 494 ± 11 beats/min. These systemic cardiovascular responses were not reproduced when Bic was injected outside the PVN (Table 2, groups A and B) or when its vehicle was injected into the PVN (Table 2, groups A and C). The 95% confidence intervals for both MAP and HR indicated that the modest changes observed were not significantly different from zero in either the anatomic or the vehicle control group.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effects of PVN stimulation on renal function. The results of this study demonstrate that changes in renal function occur following the activation of neuronal cell bodies in the PVN. These consist of a marked renal vasoconstriction and antinatriuresis, mediated by the renal nerves, and antidiuresis, mediated by the renal nerves and vasopressin V2 receptors. Thus it is possible that the PVN serves an important function in mediating adjustments in renal function via the renal nerves, just as it is known to do via both direct and indirect humoral mechanisms.
The results of our study confirm evidence provided by previous reports by Porter and Brody (20, 21) that PVN stimulation produces renal vasoconstriction. However, the previous reports are based almost entirely on responses evoked by electrical stimulation of the PVN and therefore may have reflected the results of the activation of axonal fibers passing near the stimulation sites. This potential problem was addressed informally in one of the studies by showing that kainic acid microinjection into the PVN was also capable of evoking renal vasoconstriction in several rats (21), lending support to their supposition that neuronal cell bodies were responsible for the effects they observed. However, kainic acid, a neurotoxin, may have either induced depolarization blockade of the intended target neurons or damaged neuronal cell bodies or axons, obscuring the response of interest. Although these problems have been documented for kainic acid, similar problems have not been associated with the use of Bic. Therefore, our results provide unequivocal evidence of a renal vasopressor mechanism that is mediated by the renal nerves and originates from neuronal cell bodies in the PVN. To our knowledge only two previous studies examined the effects of PVN stimulation on renal excretory function, and neither of these provided unequivocal evidence that the responses observed were the result of the stimulation of neuronal cell bodies. One of the studies, reported by Haywood's laboratory, indicated that low-level electrical stimulation of PVN produced antinatriuresis and antidiuresis (18). The other study, conducted by Jin and Rockhold (5a), demonstrated that the microinjection of kainic acid in PVN evoked both diuresis and natriuresis, without any concomitant alterations in GFR or ERPF. Our results do not confirm those of Jin and Rockhold, and it seems likely that the different outcomes reflect the different effects of Bic and kainic acid on the neurons in PVN. Because there is no evidence that Bic has deleterious effects on neurons and because the systemic cardiovascular and renal hemodynamic effects of PVN stimulation in our study are confirmed by the reports of Haywood's laboratory and Porter and Brody (18, 20, 21), it appears safe to conclude that the activation (i.e., disinhibition) of neuronal cell bodies in PVN results in profound reductions in renal hemodynamics, water excretion, and sodium excretion. Thus our results expand on those from the laboratories of Haywood (18) and Porter and Brody (20, 21) by demonstrating that the application of a chemical agent that activates neuronal cell bodies in PVN produces changes in renal handling of sodium that are mediated by the renal nerves.Anatomic specificity of the renal response. The anatomic control sites included areas that were adjacent to PVN and located dorsal, anterior, and posterior to PVN. We did not obtain any sites lateral to PVN, but it seems unlikely that this area accounts for the response we observed in light of reports that the stimulation of this area produces both diuresis and natriuresis, which are mediated by a humoral mechanism (25) and not by the renal nerves (24).
Mechanisms responsible for the renal response to PVN stimulation. It seemed probable that the stimulation of PVN would, by activation of the magnocellular neurosecretory neurons, evoke an increase in the circulating level of vasopressin (1, 4). Therefore, we used vasopressin antagonists to prevent either the vasopressor or diuretic effects of vasopressin to determine whether these contributed to, or accounted entirely for, the response. We found that treatment with a vasopressin V1 receptor antagonist did not diminish the renal hemodynamic response to PVN stimulation (Fig. 4 and Table 2, group E). We also found that vasopressin V2 receptor blockade alone did not abolish the renal excretory response to PVN stimulation; however, it seemed likely that such an effect might be the result of a reduced load of filtered sodium in the renal tubules. Therefore, we tested the effect of V2 blockade in denervated rats, which lack the renal hemodynamic component of the response, to determine whether a tubular effect of vasopressin was contributing to response evoked by PVN stimulation. In animals with both renal denervation and V2 receptor blockade (Table 1, group G), both the antidiuresis and antinatriuresis seen in the intact untreated group (Fig. 5 and Table 1, group A) were eliminated (Fig. 5).
Although we did not determine that renal denervation depleted renal catecholamines in our animals, the procedure we used was shown to consistently result in depletion of renal tissue norepinephrine to <5% of normal levels in previous studies from this laboratory (26, 27). Although we did not compare statistically the baseline values among the different treatment groups, a brief discussion of the obvious differences in baseline values is worthwhile. The animals that underwent renal denervation displayed much higher baseline values of UV (400%) and UNaV (1,000%) than those animals with intact renal nerves (Table 1, groups D and A). These differences are commonly observed following renal denervation. The animals that underwent vasopressin V1 receptor blockade exhibited elevated baseline values of UV (900%) and UNaV (400%) compared with untreated animals (Table 1, groups E and A). These differences are probably attributable, at least in large measure, to the renal vasodilation (ERPF was 25% higher) and the pronounced increase in GFR (40% higher) that occurred during V1 receptor blockade. The elevated baseline levels of UV (600%) and UNaV (68%) observed in the vasopressin V2 receptor blockade group (Table 1, groups F and A) are probably attributable to reduced reabsorption of free water in the collecting ducts, which would be expected to occur if V2 receptors were blocked. As mentioned above, circulating vasopressin levels have been shown to be very high in anesthetized animals undergoing surgery, and therefore the effects of vasopressin in the untreated group (Table 1, group A) would be maximal. Thus one would expect the effects of vasopressin V1 or V2 receptor blockade to be substantial, as we have observed.Systemic cardiovascular response to PVN stimulation. Our results confirm previous reports that have documented that stimulation of PVN produces a pressor response (13-16, 18, 20, 21), and tachycardia (13-16), both of which have been shown to be dependent on ganglionic transmission (14, 16, 20). Because the present study was primarily intended to examine the influence of PVN on renal function, experiments were not included to examine the mechanism responsible for the systemic cardiovascular components of the response.
Perspectives
This study demonstrates that neuronal cell bodies in PVN are capable of influencing renal function via the renal nerves. It does not, however, provide evidence that this neural pathway arising in PVN is actually involved in the moment-to-moment regulation of renal function, nor does it provide definitive evidence that the paraventriculo-spinal pathway is entirely responsible for the response that we observed. We plan on conducting further studies, to parallel some of those conducted on the function of the renal nerves by DiBona and Kopp (2, 3), to obtain evidence that the PVN is capable of producing all of the renal effects that have been documented for the renal nerves (e.g., changes in tubular sodium reabsorption, renin release). Additional studies are also planned to determine whether other central nervous system cell groups that project oligosynaptically to the kidney are involved in mediating the responses observed in the present study.| |
ACKNOWLEDGEMENTS |
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The authors are indebted to Hua Tu, Karilyn Avery, and Brian Walter for their assistance in conducting the experiments, and to Dr. Ross Crosby (Neuropsychiatric Research Institute, Fargo, ND) for his assistance with the statistical analysis.
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FOOTNOTES |
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This study was supported by grants-in-aid from the American Heart Association, Dakota Affiliate (9607081S), and the North Dakota Experimental Program to Stimulate Competitive Research (EPSCoR OSR-9452892) to J. R. Haselton. R. C. Vari was supported by the American Heart Association, Dakota Affiliate (9507790S). K. Avery was supported by the Howard Hughes Undergraduate Research Apprenticeship Program, and B. Walter was supported by a summer Research Experience for Undergraduates (REU) award through North Dakota EPSCoR.
Address for reprint requests: J. R. Haselton, Dept. of Physiology, UND School of Medicine & Health Sciences, PO Box 9037, Grand Forks, ND 58202-9037.
Received 19 September 1997; accepted in final form 13 July 1998.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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% from baseline), following the
injection of bicuculline or vehicle in the brain in the experimental
and control groups
P < 0.01 vs. baseline.
P < 0.001 vs. baseline.
§ P < 0.0001 vs.
baseline.
