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Departments of 1 Pharmacology and Physiology and 2 Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The goal of this study was to determine the role of the pontine lateral parabrachial nucleus (LPBN) in the compensatory responses to blood loss. Conscious unrestrained rats with complete, partial, or sham bilateral ibotenic acid lesions of the LPBN were subjected to a hypotensive 16-ml/kg blood withdrawal via arterial catheter. Complete lesions (LPBNx) encompassed the entire LPBN and extended into the ventrolateral parabrachial region to encroach on the Kolliker-Fuse nucleus. Partial lesions were restricted to the body of the LPBN and spared the outer rim of the external lateral subnucleus of the LPBN. In all three groups, serum corticosterone concentration and plasma renin activity increased four- to fivefold after hemorrhage (P < 0.01), and immunocytochemistry demonstrated numerous Fos-positive neurons in the hypothalamic supraoptic nucleus. However, the cardiovascular responses to hypotensive blood loss differed for complete and partial lesions. Blood pressure failed to recover in LPBNx rats and was significantly lower in LPBNx (66 ± 4 mmHg) than in rats with partial or sham lesions (98 ± 4 and 85 ± 5 mmHg, respectively) at 40 min posthemorrhage. In contrast, rats with partial lesions had a significant attenuation of the posthemorrhage bradycardia. This implies that a population of neurons within the body of the LPBN is essential for full expression of the bradycardia that accompanies hemorrhagic hypotension, whereas the ventrolateral parabrachial region is essential for normal restoration of arterial pressure after hypotensive hemorrhage.
blood pressure; heart rate; renin; corticosterone; supraoptic nucleus; Fos
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PARABRACHIAL COMPLEX OF the dorsolateral pons receives extensive projections from the nucleus of the solitary tract and adjacent area postrema and serves as the primary relay center for transfer of visceral sensory information to forebrain regions involved in autonomic regulation (11, 17, 28). Multiple lines of evidence suggest that the lateral parabrachial nucleus (LPBN) may play an integral role in cardiovascular regulation. Electrophysiological studies demonstrate that LPBN neurons are activated by cardiovascular stimuli (15, 16, 33). This has been confirmed by studies employing immunocytochemical localization of Fos protein, a marker for neuronal activation, demonstrate the presence of increased numbers of Fos-immunoreactive cell nuclei in the LPBN following hemorrhage (6) or pharmacologically induced changes in arterial pressure (12, 25, 27). Electrical or glutamate stimulation of the LPBN elicits increases in arterial pressure (5, 18) that can be blocked by guanethidine and are accompanied by increased renal sympathetic nerve activity and decreased hindlimb blood flow (19, 23). LPBN neuronal activation also can elicit tachycardia (5) and attenuate baroreflex suppression of heart rate and renal sympathetic nerve activity (10, 20). In addition, the parabrachial region is implicated in control of two vasoactive hormone systems, renin-angiotensin (13) and vasopressin (7, 14, 22), as well as in control of ACTH release (4). Thus the LPBN receives cardiovascular sensory information; can elicit sympathetic activation, tachycardia, and increased blood pressure; interacts with baroreflex control of cardiovascular function; and may influence control of vasopressin, renin, and ACTH release. Lesions of the LPBN attenuate hypertension produced either by chronic angiotensin infusion or by renal wrap (9, 21), indicating that the LPBN contributes to the pathophysiology of certain forms of hypertension. However, despite considerable evidence that the LPBN has the capacity to increase blood pressure and heart rate, a functional role of the LPBN in homeostatic cardiovascular regulation has not been previously demonstrated.
The goal of this study was to determine if the LPBN plays an essential role in the compensatory responses to hypovolemia. We employed a slow, graded hemorrhage that permitted evaluation of both the compensated (nonhypotensive) and decompensated (hypotensive) phases of the response to blood loss. The effect of graded hemorrhage on blood pressure, heart rate, plasma renin activity (PRA), and serum corticosterone was compared in sham-operated rats and rats with bilateral LPBN lesions produced by microinjection of the cell-selective neurotoxin ibotenic acid. These lesions were directed at the external lateral subnucleus of the LPBN in view of evidence that the majority of pressor-tachycardic LPBN neurons is localized in or near this area (5) and because lesions directed toward the external lateral subnucleus effectively attenuate angiotensin-dependent and renal-wrap hypertension (9, 21). Because the hypothalamic supraoptic nucleus (SON) is the primary source of increased plasma vasopressin levels during hemorrhage (8), we also performed immunocytochemical localization of Fos protein within the SON as an index of activation of vasopressin-containing neurons in response to hemorrhage.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed in male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 280-380 g at the time of stereotaxic surgery. The rats were housed in individual cages in the University of Rochester vivarium with a 12:12-h light-dark cycle (lights on 0600-1800) and with standard laboratory chow and tap water available ad libitum. All experimental procedures were approved by the University Committee on Animal Research.
Surgical procedures.
Surgical procedures were performed under anesthesia (25 mg/kg ip
pentobarbital sodium with 128 mg/kg chloral hydrate) using sterile
conditions. Lesioned rats received bilateral stereotaxic injections of
400-500 nl ibotenic acid (10 µg/µl in 0.10 M phosphate buffer,
pH 7.4; Research Biochemicals International, Natick, MA) directed
toward the LPBN (0.3 mm posterior to interaural line, ±2.0 mm lateral,
5.9 mm dura, 3.3 mm incisor bar). The ibotenate was
injected over a 10-min period using a 500-nl Hamilton syringe, and the
needle was then left in place for an additional 10-min period before
withdrawal. In sham-lesioned rats, the injection needle was lowered to
the same location, but no drug was administered. Femoral arterial
catheters were surgically implanted 5-7 days after stereotaxic
surgery, as previously described (32).
Experimental procedures.
Experiments were performed after at least 4 days had elapsed since
catheter implantation (
9-11 days after stereotaxic surgery). During experiments, each rat was placed in a 10-in. high, 7.5-in. inner
diameter Plexiglas cage. The catheters were connected to tubing
extensions that permitted blood to be withdrawn and arterial blood
pressure to be recorded without restraining or otherwise disturbing the
rat. The rat was adapted to the experimental conditions by being placed
in the recording cage for 1-2 h on at least 1 day before the
experiment and was permitted an additional 30-min adaptation period
between the time at which the catheter extensions were connected and
when data collection began on the morning of the experiment. Food and
water were not available while the rat was in the recording cage.
Hemorrhage protocol. All experiments began in the morning, with the first blood withdrawal performed at 1000-1130. Na heparin (150 U in 150 µl) was injected into the arterial catheter 15 min before beginning the hemorrhage procedure to prevent clotting during blood withdrawal.
During the hemorrhage procedure, blood was withdrawn from the arterial catheter at a rate of 1.6 ml/kg body wt per minute during an initial 4-min hemorrhage and three subsequent 2-min hemorrhages, each separated by an 8-min observation period during which arterial pressure was recorded. This resulted in a total blood loss of 16 ml/kg body wt over 34 min. An additional 1.2-ml blood sample was collected at 75 min after initiation of the hemorrhage procedure. This sample, and blood collected from each of the four hemorrhages, was used for renin and corticosterone determinations. Hematocrit and plasma Na concentration were determined from the blood collected during the first hemorrhage. Arterial blood pressure was recorded continuously except during the periods of blood withdrawal.Plasma renin, corticosterone, electrolyte, and hematocrit
determinations.
Blood samples for renin determinations were collected with 0.26 M EDTA
solution (30 µl/ml) and the plasma frozen at 20°C until assay.
PRA was determined by radioimmunoassay for ANG I and expressed as
nanograms ANG I formed per milliliter plasma per hour of incubation at
37°C, pH 6.5, as previously described (31). Serum
corticosterone concentration was measured by radioimmunoassay using a
commercially available kit (Immunochem double antibody corticosterone
radioimmunoassay kit; ICN Biomedicals, Costa Mesa, CA).
20°C until
flame photometry (IL443; Instrumentation Laboratory, Lexington, MA) for
plasma Na concentration.
Histology.
At 90 min after initiation of the hemorrhage procedure, the rat was
anesthetized (25 mg/kg pentobarbital sodium with 128 mg/kg chloral
hydrate into the arterial catheter) and perfused transcardially with
4% paraformaldehyde in 0.1 M acetate buffer, pH 6.5, followed by 4%
paraformaldehyde in 0.1 M borate buffer, pH 9.3. After perfusion, the
brain was collected, postfixed for 1-2 h in 4% paraformaldehyde (pH 9.3), soaked overnight in 20% sucrose in phosphate-buffered saline, and then stored frozen at 80°C until it was sectioned (30-µM sections) using a freezing microtome. Alternate sections of
the hypothalamus were immunocytochemically labeled for Fos protein,
with a light neutral red counterstain. Fos immunocytochemistry was
performed using rabbit affinity purified polyclonal antisera directed
against amino acid residues 3-16 of the NH2-terminal region of the Fos protein (1:40,000 dilution, Santa Cruz
Biotechnology). Alternate sections through the midbrain and brain stem
were stained with cresyl violet for lesion localization.
Statistical analysis. To evaluate the effect of LPBN ibotenate lesions, statistical comparisons of data from rats with complete lesions, partial lesions, and sham lesions were performed by multifactorial repeated-measures (RM) ANOVA across all time points. Individual comparisons were performed only when the overall ANOVA showed a significant (P < 0.05) lesion effect, blood loss effect, or lesion-by-blood loss interaction effect. Individual comparisons across time within single experimental groups, and across experimental groups for individual sampling times, were made by Dunnett's and Student-Newman-Keuls comparisons, respectively, based on the error mean square computed by single-factor ANOVA. Corticosterone data were log10 transformed to adjust for unequal variance across time. Data are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Histology of LPBN lesions.
Complete ibotenate lesions caused extensive bilateral damage to the
LPBN, as indicated by neuronal loss, microgliosis, and narrowing of the
zone bordered by the ventral spinocerebellar tract and superior
cerebellar peduncle (Fig. 1C).
All injection sites were localized to the main body of the LPBN,
defined as the region bordered dorsolaterally by the ventral
spinocerebellar tract and ventromedially by the superior cerebellar
peduncle, at the level at which the superior cerebellar peduncle
contacts the mesencephalic trigeminal tract. Complete lesions
encompassed the entire rostral-caudal extent of the external lateral
subnucleus of the LPBN and extended beyond the ventral and lateral
margins of the external lateral subnucleus to encroach on the
Kolliker-Fuse nucleus. The medial parabrachial nucleus also was
partially damaged in four of five animals.
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Basal values in LPBN-lesioned and sham-lesioned rats.
Rats with complete lesions of the LPBN did not differ from rats with
partial or sham LPBN lesions for body weight, hematocrit, or plasma Na
concentration (ANOVA, P > 0.30 for each; Table
1). Basal values for MAP, heart rate,
PRA, and plasma corticosterone concentration also did not differ
between groups (see Figs. 2 and
3).
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Response to hemorrhage. During the hemorrhage period, blood was withdrawn intermittently to a cumulative blood loss of 16 ml/kg over 34 min, as shown in Fig. 2. In all three groups of rats, MAP remained within the normotensive range after blood losses of 6 and 10 ml/kg and decreased significantly after 16-ml/kg blood loss (RM ANOVA, P < 0.001; blood loss effect). All three groups of rats also showed a significant decrease in heart rate after 16-ml/kg blood loss (RM ANOVA, P < 0.001; blood loss effect), which coincided with the hypotensive phase of the response to hemorrhage. However, there were significant effects of LPBN lesions on the MAP and heart rate responses to 16-ml/kg blood loss, which differed for complete and partial lesions (RM ANOVA lesion-by-blood loss interaction effect, P < 0.02 for MAP, P < 0.001 for heart rate; RM ANOVA lesion effect, P = 0.01 for MAP, P < 0.001 for heart rate).
The magnitude of decrease in blood pressure or heart rate after 16-ml/kg blood loss did not differ between rats with complete bilateral LPBN lesions and rats with sham lesions. However, rats with complete LPBN lesions failed to restore MAP and heart rate normally after blood loss (Fig. 2). In both sham-lesion rats and rats with partial lesions, MAP reached its minimum level within 10 min after completion of the 16-ml/kg blood withdrawal procedure and then gradually rose toward basal levels. In contrast, the MAP of rats with complete LPBN lesions showed very little recovery. By the end of the 40-min posthemorrhage recovery period (75 min after initiation of the hemorrhage procedure), MAP was 66 ± 4 mmHg in rats with complete LPBN lesions, compared with 85 ± 5 mmHg (P < 0.05) and 98 ± 4 mmHg (P < 0.05) for sham-operated and partial-lesion rats, respectively. Heart rate was also significantly lower at the end of the posthemorrhage recovery period in rats with complete LPBN lesions than in those with sham or partial lesions. In contrast to complete LPBN lesions, partial LPBN lesions attenuated the bradycardic and hypotensive responses to hemorrhage (Fig. 2). The minimum heart rate achieved after 16-ml/kg blood loss was significantly higher in rats with partial LPBN lesions (251 ± 13 beats/min) than in rats with complete bilateral LPBN lesions or sham lesions (175 ± 14 and 185 ± 13 beats/min, respectively; P < 0.01). This difference persisted for the duration of the posthemorrhage recovery period, such that the heart rate of the partial-lesion group had returned to basal levels by the end of the recovery period (351 ± 20 beats/min at +75 min), whereas heart rate remained significantly below basal levels in the complete LPBN lesion and sham-lesion groups (227 ± 13 and 286 ± 20 beats/min, respectively). The minimum MAP achieved after 16-ml/kg blood loss was also higher in rats with partial LPBN lesions (47 ± 2 mmHg) than in rats with complete bilateral LPBN lesions or sham lesions (39 ± 2 and 40 ± 2 mmHg, respectively; P < 0.05). PRA was significantly increased after 6-ml/kg blood loss, before the development of hypotension, and rose further after 10- to 16-ml/kg blood loss (RM ANOVA, P < 0.001; blood loss effect; Fig. 3). Serum corticosterone levels increased following 13-ml/kg blood loss and continued to rise during the posthemorrhage recovery period (RM ANOVA, P < 0.001; blood loss effect). The effect of blood loss on PRA and corticosterone did not differ between rats with sham, partial, and complete LPBN lesions (RM ANOVA, P > 0.25; lesion and lesion-by-blood loss interaction effects).Hypothalamic Fos immunoreactivity.
Immunocytochemical localization of Fos protein demonstrated numerous
Fos-positive neurons in the hypothalamic SON following hemorrhage.
These were localized primarily to the ventral portion of the nucleus,
where nearly all neurons demonstrated Fos-positive cell nuclei (Fig.
4). The number of Fos-positive neurons in
the SON did not differ between rats with sham, complete, and partial lesions [180 ± 32 (n = 7), 139 ± 21 (n = 4), and 172 ± 42 (n = 4)
Fos-positive cell nuclei per section, respectively; ANOVA, P = 0.70]. Numerous Fos-positive neurons were also observed
in the paraventricular hypothalamic nucleus (PVH) in all three groups. In contrast, only occasional Fos-positive cell nuclei were observed in
the SON or paraventricular nucleus of brain sections from intact nonhemorrhaged rats processed in parallel with sections from
hemorrhaged rats.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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There are two phases in the acute response to a progressive hemorrhage, which are dependent on the volume of blood lost. During the initial phase, MAP is maintained at normotensive levels (nonhypotensive hemorrhage) despite the decrease in blood volume. Arterial pressure is maintained during this phase in large part by peripheral vasoconstriction initiated by sympathetic activation. The second phase (hypotensive hemorrhage) ensues when blood loss reaches a critical volume and blood pressure falls abruptly. This phase is accompanied by decreased sympathetic drive to the peripheral vasculature and a vagal bradycardia (29). Blood pressure recovery following a hypotensive hemorrhage is paralleled by the gradual reversal of bradycardia and restoration of sympathetic tone to the vasculature and is aided by the presence of high circulating levels of the vasoconstrictor hormones angiotensin and vasopressin (29). In this study, ibotenate lesions of the LPBN area did not affect the ability to maintain normotensive arterial blood pressure during the initial phase of blood loss or the volume of blood that could be withdrawn before a significant decrease in pressure occurred. Thus the LPBN does not play an essential role in the immediate compensatory responses to a small-volume blood loss. In contrast, complete LPBN lesions significantly altered blood pressure and heart rate recovery following hypotensive hemorrhage, whereas partial lesions reduced the magnitude of hemorrhage-induced bradycardia.
Blood pressure recovery following hypotensive hemorrhage was significantly attenuated by complete bilateral lesions of the LPBN area, but not by partial LPBN lesions. Lesions classified as "partial" caused less extensive neuronal loss within the main body of the LPBN than complete lesions and spared the outer rim of the external lateral subnucleus. Lesions classified as "complete" differed from partial lesions in that they encompassed the entire bilateral rostral-caudal extent of the external lateral subnucleus and extended beyond the ventrolateral margin of the LPBN to encroach on the Kolliker-Fuse nucleus. As shown by Chamberlin and Saper (5), stimulation of discrete regions within the parabrachial complex elicits prominent hypertensive and tachycardic responses that are localized to the ventrolateral aspect, in a region that encompasses the outer rim of the external lateral subnucleus of the LPBN and extends ventrally toward the dorsal Kolliker-Fuse nucleus (5). The short latency and large magnitude (up to 70 mmHg) of the increase in arterial pressure suggest that this effect is mediated by intense sympathetic activation. A recent study by Len and Chan (20) further demonstrates that stimulation of the ventrolateral aspect of the parabrachial complex inhibits baroreflex-mediated bradycardia (decreased heart rate in response to phenylephrine-induced elevations in arterial pressure). The pressor-tachycardic region described by Chamberlin and Saper (5) coincides with the region shown to inhibit baroreflex-mediated bradycardia (20) and with the region destroyed by complete lesions, but not by partial lesions, in the present study. Taken together, this evidence implies that, following a hypotensive hemorrhage, blood pressure recovery is dependent on activation of a neuronal population, localized within the ventrolateral parabrachial region, which inhibits vagal cardiac efferent activity and/or restores sympathetic drive to the heart and vasculature.
In contrast, partial LPBN lesions significantly attenuated both the magnitude and duration of the bradycardic response to hypotensive hemorrhage and also reduced the magnitude of decrease in arterial pressure. Glutamate or electrical stimulation of the dorsolateral subnucleus region of the LPBN evokes a suppression of both heart rate and arterial pressure (5). This region was damaged by partial LPBN lesions in the present study. Thus the bradycardic response to hypotensive hemorrhage may have been attenuated in rats with partial lesions as a consequence of loss of this neuronal population. The neuroanatomic circuitry underlying the bradycardic response to hypotensive hemorrhage is not known (29, 30). The present data imply that neurons within the LPBN are essential for full expression of the bradycardic response to hypotensive blood loss.
It appears paradoxical that, whereas all regions damaged by partial lesions were also damaged by complete lesions, the bradycardic response to hypotensive hemorrhage was attenuated only by partial lesions and persisted in rats with complete lesions. This may reflect the simultaneous loss, in rats with complete lesions, of two neuronal populations with opposing effects on autonomic control of heart rate; for example, reduced vagal cardiac efferent activation due to loss of neurons within the main body of the LPBN may have been counterbalanced by diminution of sympathetic cardiac drive due to loss of neurons within the ventrolateral parabrachial region.
Blood pressure recovery following hemorrhage is dependent not only on restoration of sympathetic activity to the heart and vasculature, but also on peripheral vasoconstriction initiated by the elevated circulating levels of renin-angiotensin and vasopressin. Renin secretion rate increases during nonhypotensive hemorrhage as a consequence of sympathetic activation (1) and increases further during hypotensive hemorrhage in response to decreased renal perfusion pressure and increased circulating levels of catecholamines released by the adrenal medulla (29). Because renin release is partially controlled by the renal sympathetic nerves, the observation that activation of LPBN neurons can increase renal sympathetic nerve activity (23) indicates that the LPBN has the capacity to stimulate renin release. In the present study, however, ibotenate lesions of the LPBN area did not alter basal PRA or the magnitude of increase in PRA during either the normotensive or hypotensive phase of hemorrhage. Thus LPBN neurons are not essential for control of renin release either in the basal state or during blood loss. Furthermore, the attenuated blood pressure recovery observed in rats with complete LPBN lesions cannot be attributed to attenuation of the renin response to blood loss.
Although a role for the LPBN in control of vasopressin release has not yet been firmly established, there is evidence that neurons or fibers of passage within the ventrolateral LPBN region may inhibit the vasopressin response to decreased arterial pressure (22), whereas neurons in the region of the dorsolateral subnucleus may play an essential role in mediating the vasopressin response to decreased blood volume (14). The primary source of increased plasma vasopressin levels during hemorrhage is the hypothalamic SON (8). In the present study, neuronal activation of the SON was assessed by immunocytochemical localization of Fos, the protein product of the protooncogene c-fos. Hemorrhage is a potent stimulus for SON neuronal Fos expression (2, 26). There were numerous Fos-positive neurons in the SON of both sham-lesioned and lesioned animals, suggesting that neurons within the LPBN area are not necessary for hemorrhage-induced activation of vasopressin neurons. It should be noted, however, that although the number of SON neurons activated by blood loss appeared to be unaffected by LPBN lesion, it cannot necessarily be assumed that the amount of vasopressin released into the circulation was also unaffected.
Plasma glucocorticoid levels also increase during blood loss. This effect requires activation of neurons within the parvicellular that synthesize corticotrophin-releasing hormone, the initiating factor in the hypothalalamic-pituitary-adrenocortical axis (3). The LPBN serves as a major relay station for brain stem autonomic projections to the hypothalamus, including the parvicellular PVH (17, 28), and thus may potentially modulate the glucocorticoid response to blood loss. However, the plasma corticosterone response to hemorrhage was unaffected by ibotenate lesions of the LPBN.
In conclusion, the LPBN is not required for the initial maintenance of arterial pressure during hemorrhage or for hemorrhage-induced increases in PRA and serum corticosterone concentration. However, the parabrachial complex is essential both for full expression of the bradycardia that typically accompanies the initial hypotensive response to blood loss and for a normal rate of blood pressure recovery following blood loss. The neuronal population required for the bradycardic response to hemorrhage appears to be located within the main body of the LPBN. The neuronal population required for restoration of arterial pressure likely resides within the outer rim of the external lateral subnucleus and/or in adjacent neurons within the ventrolateral parabrachial region.
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ACKNOWLEDGEMENTS |
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We thank D. Mickelsen for technical assistance and Dr. J. Olschowka for assistance with image analysis.
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FOOTNOTES |
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This work was supported by American Heart Association Research Grants-in-Aid 9300794 (National Center) and 9850192T (New York State Affiliate).
Address for reprint requests and other correspondence: M. L. Blair, Dept. of Pharmacology and Physiology, Box 711, School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642 (E-Mail: Martha_Blair{at}URMC.Rochester.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 18 February 2000; accepted in final form 15 December 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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, dashed line; n = 9), rats with
complete bilateral lesions of the LPBN region (LPBNx; 
,
solid line; n = 5), and rats with partial lesions
(
, solid line; n = 5). Rats with
partial lesions had an attenuated decrease in HR, whereas rats with
complete LPBN lesions failed to restore MAP normally.
*P < 0.05 vs. sham; +P < 0.05 vs. partial lesion; &P < 0.05 vs.
time 0 for LPBNx and sham lesion at +35-75 min and for
partial lesion at +35-60 min.
