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(Hypertension. 1996;27:591-597.)
© 1996 American Heart Association, Inc.
Articles |
Role of Area Postrema in Transgene Hypertension
From the Hypertension Center, Division of Surgical Sciences, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC, and the Max-Delbrück-Centrum für Molekulare Medizin, Berlin-Buch, Germany.
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Abstract |
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Abstract Transgenic [Tg(+)] rats carrying the mouse Ren-2d gene [(mRen-2d)27] are a newly established monogenetic form of experimental hypertension. To determine whether the area postrema contributes to the development of hypertension in mRen-2 Tg(+) rats, this circumventricular organ in the fourth ventricle was removed from 5-week-old Tg(+) rats. From weeks 4 through 9, systolic blood pressure was measured weekly by tail-cuff plethysmography in area postrema–lesioned and sham-lesioned Tg(+) rats. Although systolic blood pressure rose markedly in sham-lesioned Tg(+) rats, the increase in systolic blood pressure was significantly attenuated in area postrema–lesioned Tg(+) rats. At 9 weeks of age, a femoral artery was cannulated for the measurement of arterial pressure in awake rats. Mean arterial pressure (MAP) in area postrema–lesioned Tg(+) rats was significantly (P<.01) lower than that in sham-lesioned rats: 171±7 and 132±5 mm Hg, respectively. Baroreceptor reflex was evaluated by intravenous infusion of sodium nitroprusside. There was no significant difference in baroreceptor reflex sensitivity between the two groups. Intravenous pentolinium (5 mg/kg), used to produce sympathetic ganglionic block, caused significant decreases in MAP in both groups. However, the reduction of MAP in the sham-lesioned group was significantly (P<.05) greater than that in the area postrema–lesioned group: -73±4 and -48±6 mm Hg, respectively. The ratio of left ventricular weight to body weight in sham-lesioned Tg(+) rats was significantly larger than that of area postrema–lesioned rats. These results suggest that ablation of the area postrema markedly attenuates the development of hypertension in mRen-2d Tg(+) rats, and this attenuation may be attributed to decrease in sympathetic outflow.
Key Words: area postrema • pressor receptors • hypertrophy, left ventricular • sympathetic nervous system • transgenic rats
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Introduction |
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The area postrema in the rat is a midline circumventricular organ located at the floor of the fourth ventricle on the dorsal surface of the medulla. Circumventricular organs act as "windows" through which circulating substances gain access to the central nervous system to influence neuronal excitability, since their vascular endothelium is devoid of tight junctions. Efferent fibers from neuronal elements within the area postrema project to a number of central nervous system structures participating in the regulation of sympathetic outflow and cardiovascular function.1 2
Considerable evidence suggests that area postrema neurons regulate cardiovascular function and may tonically regulate the resting level of arterial pressure and cardiac output.1 2 Area postrema ablation in dogs3 and rats4 attenuates the increase in blood pressure observed after intravenous infusion of Ang II. Furthermore, ablation of the area postrema prevented or attenuated the development of renovascular hypertension in rats5 and dogs,6 DOCA-salt hypertension,7 and elevated blood pressure of SHRs.8
The creation of transgenic rats [(mRen-2d)27; Tg(+)] expressing one or more of the genes of the RAS created a unique opportunity to study the role of the RAS in the causation of hypertension. Introduction of the mouse mRen-2d gene into the rat genome results in a severe form of hypertension9 that is associated with high levels of brain angiotensin peptides in both homozygous10 and hemizygous animals.11 Concurrent studies demonstrated that the increased brain tissue levels of Ang II are associated with desensitization of the pressor and vasopressin responses to cerebroventricular administration of the peptide12 and normalization of blood pressure after endogenous neutralization of Ang II by injection of a selective Ang II monoclonal antibody into a lateral ventricle.13 Although both biochemical and physiological studies provided evidence for the participation of the brain RAS in the evolution of this form of genetic hypertension, the neural substrates at which the influence of the RAS acts had not yet been evaluated. In an attempt to begin the characterization of these important brain mechanisms, we have now determined the effect of removing the area postrema on the evolution of this monogenetic form of renin-dependent hypertension.
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Methods |
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Animals
Experiments were done in 11 hemizygous Tg(+) hypertensive rats (5 male and 6 female) carrying the mouse mRen-2d gene and bred at our institution from founder breeders [(mRen-2d)27] obtained from the German Institute for High Blood Pressure Research, Heidelberg, Germany.9 These 11 hemizygous Tg(+) rats were littermates resulting from a cross between a male homozygous Tg(+) rat and a female Sprague-Dawley rat obtained from the Zentralinstitut für Versuchstierzucht (Hannover, Germany). All breeder rats are descendants of parent stock used by Mullins et al9 to generate this model of high blood pressure.
Rats were housed in plastic cages within a room maintained at 22°C with a 12-hour dark/light cycle. Animals had free access to tap water and were fed powder chow (Agway Prolab, Agway Country Foods, Inc) providing a daily intake of 17 mEq of Na+ and 28 mEq of K+ per 100 g solid weight. Experiments were done in compliance with the policies implemented by the Animal Care and Use Committee of the Bowman Gray School of Medicine and in accordance with the guiding principles for the care and use of animals determined by the American Physiological Society.
Ablation of the Area Postrema
At 5 weeks of age, the rats
were anesthetized with
sodium pentobarbital (50 mg/kg IP) and placed in a
stereotaxic frame (David Kopf Instruments). A midline
incision was made in the dorsum of the neck to expose the foramen
magnum and the area postrema after opening the atlanto-occipital
membrane. In 5 rats (2 male and 3 female), a blunt 30-gauge needle
connected to a vacuum line was used to aspirate area postrema tissue.
In the remaining 6 rats (3 male and 3 female), the area postrema was
visualized but otherwise left untouched. These 6 rats constituted a
sham-lesion cohort. After completion of the surgical procedure,
rats were hydrated by a subcutaneous injection of 5 mL 5% dextrose in
lactated Ringer's solution. Penicillin G (30 000 U) was administered
intramuscularly.
Blood Pressure Measurements
Systolic blood pressure was
measured at least twice
weekly by tail-cuff plethysmography (Narco Biosystems or Harvard
Apparatus) beginning at 4 weeks of age and continued until
the rats were 9 weeks old. The blood pressures determined by each
system were verified to ensure comparable values for systolic
blood pressure. When rats were 9 weeks of age, they were
anesthetized with sodium pentobarbital (50 mg/kg IP, one
injection). A femoral artery and vein were cannulated for measurement
of arterial pressure and the injection of drugs,
respectively. The free ends of these catheters were exteriorized at the
back of the neck. After completion of the surgical procedure, the rats
were hydrated by a subcutaneous injection of 5 mL 5% dextrose in
lactated Ringer's solution. Penicillin G (30 000 U) was administered
intramuscularly. After a recovery period of 24 hours, resting MAP and
HR were measured in each rat. The arterial catheter was
connected to a pressure transducer (model 43-MK239, Baxter Healthcare
Co) for the measurement of arterial pressure.
Beat-by-beat changes in HR were determined by a
cardiotachometer (model 13-G4615-66, Gould Inc).
Baroreflex Sensitivity Index
The baroreflex sensitivity index
to a fall in MAP of 40 to
50 mm Hg was determined during a progressive 1-minute infusion of
sodium nitroprusside (5 to 20
µg·kg-1·min-1
diluted in 0.9% NaCl) delivered at flow rates of 0.007 to 0.028 mL/min
by a compact infusion pump (model 11, Harvard Apparatus).
Baseline values of MAP and HR were obtained during the 3-minute period
preceding each infusion.
Assessment of baroreflex sensitivity was determined from pairs of values for HR and MAP corresponding to 5 mm Hg decrements of MAP. Baroreceptor reflex sensitivity was estimated in each rat by fitting a least-squares regression line to the relation between changes in MAP and HR produced by infusion of sodium nitroprusside.14 The slope of the line for this relation expressed in beats per minute per millimeter mercury has been shown to provide an accurate estimate of baroreceptor reflex sensitivity.15
Effects of Sympathetic Blockade and Ang II Type 1 Receptor
Antagonist
Sympathetic ganglionic neurotransmission was blocked with
pentolinium (5 mg/kg IV; Sigma Chemical Co) at a dose shown by us to
abolish the electroneurographic activity from renal sympathetic nerves
for more than 1 hour.16 Ten minutes after injection of
pentolinium, we assessed the contribution of Ang II to the prevailing
level of blood pressure by intravenous administration of
the AT1 receptor antagonist CV-11974 (0.05
mg/kg; Takeda Chemical Industries).17 In preliminary
experiments we determined that this dose of CV-11974 prevented the
pressor response produced by intravenous injection of Ang
II (25 ng/kg).
Histology
At the completion of each experiment, rats were
anesthetized with sodium pentobarbital (50 mg/kg IV). The
animals were prepared for transcardial perfusion and then euthanatized
with a lethal dose of the barbiturate (total cumulative dose, 100
mg/kg). Animals were then perfused transcardially with 150 mL 0.9%
NaCl followed by 150 mL 10% phosphate-buffered formaldehyde
solution. The brain was removed and stored in 10%
phosphate-buffered formaldehyde solution. The medulla oblongata was
cut into 40-µm serial coronal frozen sections that were stained with
thionin. Sections were examined by light microscopy to assess the
location and extent of lesion. Anatomic structures were related to the
atlas of Paxinos and Watson.18 The heart was removed and
the left ventricle weighed. Left ventricular mass was
expressed as the ratio of left ventricular mass
(milligrams) divided by body weight (grams).
Statistics
All values are expressed as mean±SEM. To
determine the
effect of the area postrema lesion on the development of hypertension,
a two-way ANOVA with repeated measures was performed. A one-way
ANOVA, followed by Duncan's multiple range test, was performed to
determine which values of systolic blood pressure differed
statistically from the prelesion control values.14 The
data were also evaluated by unpaired t test (for comparisons
of sham- and area postrema–lesioned groups) and paired
t test (before and after intravenous injections
of pentolinium and CV-11974).14 A value of
P<.05 was required to achieve statistical
significance.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Weekly assessment of tail-cuff pressure documented that blood pressure rose significantly in sham-lesioned Tg(+) rats. However, the rapid elevation in blood pressure observed in sham-lesioned Tg(+) rats was attenuated if the area postrema was ablated when rats were 5 weeks old (Fig 1
). In the group
of area postrema–lesioned Tg(+) rats, systolic blood
pressure increased from 162±9 to 214±26 mm Hg between the ages
of
weeks 5 and 9. In contrast, the systolic pressure of the
sham-lesioned group averaged 154±5 mm Hg at 5 weeks of age and
increased to 294±6 mm Hg when the rats were 9 weeks old. Two-way
ANOVA with repeated measures showed that there was a significant
difference between groups [F(1,9)=219.8, P<.001].
Furthermore, this analysis revealed a significant interaction
between group and age of the rats [F(5,45)=8.63,
P<.001].
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Four weeks after either lesion of the area postrema or sham surgery,
rats were instrumented with an indwelling catheter for the direct
measurement of arterial pressure. Twenty-four hours
later, a representative value of MAP for awake rats in
a resting state was determined from a 15-minute segment of the blood
pressure recording after the rats had acclimated to the
laboratory environment. These measurements showed that area
postrema–lesioned Tg(+) rats had a significantly lower
(P<.01) MAP than sham-lesioned Tg(+) rats
(Table). In addition, area postrema–lesioned Tg(+)
rats showed significantly (P<.05) lower values of HR than
sham-lesioned Tg(+) rats (Table).
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Baroreceptor Reflex After Area Postrema Lesions
The effect of
area postrema ablation on the integrity of the
baroreflex terminal fields at the level of the first synapse in the
neighboring NTS was evaluated from measurements of the reflex
tachycardia produced by intravenous injection
of sodium nitroprusside. The Table
shows that baroreflex
sensitivity
did not differ (P=.30) between area postrema–lesioned
and sham-lesioned groups of Tg(+) rats. The lack of impairment of
baroreflex tachycardia suggests that removal of the area
postrema did not encroach on the surrounding tissue, where baroreceptor
afferent fibers establish the first central synapse.
Effects of Sympathetic Blockade and AT1
Receptor Antagonism
Fig 2 shows the effect of
sympathetic ganglionic
blockade and AT1 receptor blockade on MAP in both groups.
Baseline MAP in sham-lesioned Tg(+) rats was significantly higher
than that in area postrema–lesioned rats (Table). The
depressor
response produced by ganglionic blockade was significantly
(P<.05) greater in the sham-lesioned group
(-73±4 mm Hg) than in the area postrema–lesioned group
(-48±6 mm Hg). Thus, MAP after ganglionic blockade did not
differ (P=.19) between the sham-lesioned group (97±7 mm
Hg) and the area postrema–lesioned group (85±2 mm Hg). Subsequent
blockade of AT1 receptors (CV-11974, 0.05 mg/kg IV)
produced similar reductions in MAP in the sham-lesioned and area
postrema–lesioned groups (-18±3 and -10±4 mm
Hg,
respectively).
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Left Ventricular and Body Weight Changes
Fig 3
shows the ratio of left
ventricular weight to body weight for sham-lesioned and
area postrema–lesioned rats. This ratio was significantly greater
in sham-lesioned than in area postrema–lesioned rats,
averaging 3.22±0.08 and 2.72±0.08 mg/g, respectively
(P<.01). Fig 4 illustrates the rate at which
sham-lesioned and area postrema–lesioned rats gained weight
before and after area postrema or sham lesion. Tg(+) rats with sham
lesion had a growth curve that was unabated by the surgical procedure
at 5 weeks of age. However, area postrema lesions caused growth to be
arrested for 2 weeks, after which time these rats resumed growth in
parallel to that of the sham-lesioned group.
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Histology
Histological assessment of the brain stems
from rats subjected to area postrema lesion revealed that essentially
all area postrema tissue had been removed. In addition, we found that
the ablation procedure also damaged the subjacent tissue of the
commissural NTS and the border zone between the area postrema and the
medial NTS. Conversely, the lesion did not encroach on the adjacent
structures of the medial and lateral NTS, the nucleus intercalatus, the
solitary tracts, the dorsal motor nucleus of the vagus, and the
hypoglossal nucleus. Fig 5 illustrates photomicrographs
of the caudal medulla slightly rostral and caudal to the obex of a
representative rat with complete area postrema lesion
(Fig 5A and 5C) and the normal appearance of
tissue of a
sham-lesioned rat (Fig 5B and 5D).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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These experiments provide new evidence for an important role of the area postrema in the modulation of a form of hypertension that is produced by overexpression of a renin gene in the rat. The effectiveness of the procedure during the early developing stage of hypertension suggests the engagement of central mechanisms of blood pressure regulation during the evolutionary phase of the hypertensive process. These new experiments give further credibility to previous work done by us2 19 and others4 7 8 20 regarding the apparent essentiality of central mechanisms within the caudal brain stem in the initiation of the hypertensive process. Whereas earlier studies questioned the role of caudal brain stem mechanisms in the evolution of hypertension in the rat,21 the demonstration that hypertension is arrested when the lesion is applied to young rats now explains the apparent failure of others to unmask the role of the area postrema pathway in the expression of experimental hypertension. The results of pharmacological inhibition of the sympathetic nervous system suggest that the area postrema has a direct influence on cardiac and vasoconstrictor discharges contributing to the development of hypertension, whereas the associated effect of the lesion on body weight further implicates the area postrema as an essential component of the mechanisms that contribute to growth, development, and presumably maturation of sympathetic control mechanisms.
Mullins et al9 originally reported that incorporation of the mouse submandibulary renin gene (mRen-2d) into the genome of the rat resulted in a line that developed an age-dependent form of hypertension. The mRen-2d Tg(+) rat is characterized by enhanced expression of renin mRNA in a number of tissues, including the brain.22 23 24 25 One consequence of the enhanced expression of renin mRNA in the brain of Tg(+) rats is substantially elevated tissue levels of Ang II and Ang-[1-7] in the hypothalamus and augmented tissue levels of Ang II in the medulla oblongata.11 We recently reported that intracerebroventricular injection of a monoclonal antibody to Ang II or of an AT1-selective receptor antagonist (CV-11974) lowered the blood pressure and HR of Tg(+) rats, whereas it had a minimal effect on normotensive controls.13 These earlier studies led us to hypothesize that Ang II may act at central neural structures to promote the development of hypertension. Numerous studies have implicated the area postrema as a circumventricular organ at which Ang II can exert neurogenic actions. Furthermore, ablation of the area postrema has been effective in preventing the development of several forms of experimental hypertension.
The principal finding of this study is that the normal development of hypertension in mRen-2d Tg(+) rats was abated if area postrema tissue was removed before these animals entered the phase of rapidly developing hypertension. This observation bears a striking resemblance to the finding in SHRs, since in this strain the procedure was also effective in young rats.8 Although it should not be assumed that the similarity of the effects of area postrema lesions in Tg(+) and SHRs implies a commonality of dysfunctional brain mechanisms, there is evidence that central but not peripheral inhibition of the RAS can either lower blood pressure or prevent the development of hypertension in SHRs.26 27
Overactivity of the brain RAS and the sympathetic nervous system contributes to the pathogenesis of hypertension in both animals and humans. Since mRen-2d Tg(+) rats appear to have an overactive brain RAS, we assessed whether the contribution of the sympathetic nervous system to the prevailing level of blood pressure in the sham-lesioned and the area postrema–lesioned rats differed. Before ganglionic blockade, sham-lesioned rats had higher resting MAP than area postrema–lesioned rats. Ganglionic blockade with pentolinium produced a significantly larger reduction of blood pressure in the sham-lesioned rats than in the area postrema–lesioned group. Furthermore, we found that the blood pressure achieved by ganglionic blockade did not differ between sham-lesioned and area postrema–lesioned groups (97±7 and 85±2 mm Hg, respectively). This finding is consistent with the idea that the higher resting blood pressure of the sham-lesioned rats was associated with greater sympathetic outflow. One might suggest that the area postrema has similar influences on regulation of sympathetic outflow in DOCA-salt hypertensive rats7 and mRen-2d Tg(+) rats, since area postrema lesion in both models of hypertension reduced the contribution of the sympathetic nervous system to the prevailing level of blood pressure.
Although we favor the interpretation that area postrema lesion altered the contribution of the sympathetic nervous system to the prevailing level of blood pressure of mRen-2d Tg(+) rats, destruction of this circumventricular organ and subjacent tissue may cause a constellation of effects that disturb the homeostatic control of the cardiovascular system. These effects may include disturbances of the maintenance of body weight, as demonstrated in our studies, and alterations in food and water intake.28 29 30 31 Area postrema lesion of young mRen-2d Tg(+) rats was associated with a 2-week period when the rats did not gain body weight, whereas growth of sham-lesioned mRen-2d Tg(+) rats appeared normal. However, after this 2-week period, area postrema–lesioned animals exhibited a continuance of body weight gain such that the growth curve was reset. Although studies investigating the effect of area postrema on the development of hypertension have not reported a resetting of the growth curve,4 8 many studies concerned with the role of the area postrema in ingestive behavior have demonstrated resetting of the growth curve.28 29 30 31 32 Since it is well appreciated that correction of overweight is associated with lowering of blood pressure in hypertensive human subjects, can the attenuation of the hypertension produced by area postrema lesion in mRen-2 Tg(+) rats be attributed to a resetting of the growth curve? The results of the present experiments cannot critically negate this particular concern. However, we performed area postrema lesions in mature (13- to 15-week-old) SHRs with established hypertension and observed a 25% reduction in body weight of these animals but no diminution of the hypertension (K.M., C.F., D.B.A., 1995, unpublished observations). Clearly, future experiments should determine whether a reduction in body weight gain by itself might attenuate the development of hypertension of mRen-2d Tg(+) rats. The temporary reduction of body weight produced by area postrema lesion may be the result of polydipsia, polyuria, and changes in urinary sodium excretion and food preference, as reported by some investigators.28 29 30 The possible influence of these effects on the attenuated development of hypertension of area postrema–lesioned mRen-2d Tg(+) rats is unclear, since we did not monitor water and food intake or water and sodium excretion. In other studies concerned with the ability of area postrema lesion to prevent the development of hypertension, it did not appear that this effect of area postrema lesion could be attributed to changes in sodium or water balance.4 7
The area postrema is a unique circumventricular organ from several perspectives. Substantial evidence has demonstrated its importance in the neurogenic actions of circulating Ang II.1 2 33 34 35 36 37 The greater permeability of the area postrema vasculature to blood-borne substances may contribute to this effect. In addition, the area postrema has neural connections with many sites in the central nervous system involved with hydromineral balance, control of the autonomic nervous system, and central regulation of the cardiovascular system. These connections include projections to or from the NTS, the dorsal motor nucleus of the vagus, the nucleus ambiguus, the vasomotor neurons of the ventrolateral medulla, the lateral parabrachial nucleus, and the paraventricular nucleus of the hypothalamus. A characteristic feature of area postrema lesion in rats is a reduction in resting HR. Skoog and Mangiapane38 showed that the lower resting HR of area postrema–lesioned Sprague-Dawley rats may be attributed to an enhancement of cardiac vagal tone. Furthermore, Mangiapane et al8 showed that area postrema lesion in young SHRs was associated with a reduction in resting HR. More recently, we have observed that area postrema lesion of SHRs (13 to 15 weeks old) with established hypertension caused a significant reduction in resting HR (K.M., C.F., D.B.A., 1995, unpublished observations). We observed that resting HR was significantly lower in area postrema–lesioned mRen-2d Tg(+) rats 4 weeks after ablation of the area postrema. However, we did not determine the relative contributions of sympathetic and parasympathetic outflow to the resting HR of sham-lesioned or area postrema–lesioned rats.
Connections between the area postrema and cardiovascular regulatory sites of the medulla oblongata probably account for the ability of circulating Ang II to reduce baroreflex sensitivity.39 40 41 One concern in our study was whether aspiration of area postrema tissue also caused damage to the subjacent NTS. Although examination of histological sections obtained from the brains of rats subjected to area postrema lesion indicated only minor damage to the NTS immediately adjacent to the area postrema, similar values of baroreflex sensitivity for reflexly evoked tachycardia in sham-lesioned and area postrema–lesioned rats suggested that area postrema lesion did not extensively damage baroreceptor endings in the NTS and interneuronal pathways of the baroreceptor reflex. However, some studies have reported that area postrema lesion increases baroreflex sensitivity in Wistar-Kyoto8 and Sprague-Dawley rats,38 42 whereas other reports have shown that area postrema lesion of SHRs8 or Sprague-Dawley rats43 was not associated with improvement of the baroreflex.
In the present study, left ventricular weight was determined in sham-lesioned and area postrema–lesioned mRen-2d Tg(+) rats. The left ventricular weight in area postrema–lesioned rats was significantly lower than that in sham-lesioned rats. To the best of our knowledge, this is the first report that attenuated development of hypertension produced by area postrema lesion prevents left ventricular hypertrophy. The ratios of left ventricular weight to body weight in the sham-lesioned rats (3.22±0.08 mg/g) and area postrema–lesioned rats (2.72±0.08 mg/g) compared favorably with ratios of left ventricular to body weight that we determined in renovascular hypertensive Sprague-Dawley rats (3.70±0.10 mg/g) and normotensive controls (2.57±0.06 mg/g),44 respectively. Since left ventricular hypertrophy represents remodeling of the myocardium caused by hypertension, it is likely that prevention of left ventricular hypertrophy in area postrema–lesioned rats was caused by a reduced pressure overload on the heart, less sympathetic drive to the heart, or both.
Studies investigating the role of the area postrema in hypertension have yielded an interesting finding. The development of hypertension can be prevented if area postrema tissue is removed before presentation of hypertensinogenic stimuli to the animal.4 7 In addition, it now appears that ablation of the area postrema in either young (ie, prehypertensive) SHRs8 or mRen-2d Tg(+) rats prevents the full expression of hypertension in these two animal models typified by a genetic predisposition for the development of hypertension. The relation between an initiating stimulus in these various models of hypertension and the area postrema is further emphasized by our finding that removal of the area postrema in SHRs with established hypertension did not diminish the level of hypertension (K.M., C.F., D.B.A., 1995, unpublished observations). Although we cannot define the mechanisms that account for the inability of area postrema lesion in adult SHRs to reverse the hypertension, we do not think that this lack of effect can necessarily be attributed to an irreversible effect of vascular hypertrophy, since AT1 receptor antagonists are known to be a very effective antihypertensive agent in SHRs. Instead, we favor the notion that the area postrema plays a key role in determining the degree of sympathetic outflow during the developing stage of hypertension. An important facet of future research investigating the relation between the area postrema and hypertension (especially in genetic models of hypertension) will be identification of the initiating stimulus and the mechanisms resident in the area postrema at which the initiating stimulus acts to promote enhanced sympathetic drive as a causative factor in the development of hypertension.
In conclusion, ablation of the area postrema markedly attenuated the development of hypertension in mRen-2d Tg(+) rats. The attenuation in the development of hypertension might be attributed to the decrease in sympathetic outflow. This finding suggests that the area postrema participates in the generation of the increased sympathetic drive to arterial pressure that characterizes this model of hypertension. The underlying mechanisms responsible for this action of the area postrema have yet to be determined.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants NIH HL-51952 and NIH HL-50066. The authors are grateful to Takeda Chemical Industries, Ltd, for their generous donation of CV-11974.
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Footnotes |
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Reprint requests to David B. Averill, PhD, Hypertension Center, Division of Surgical Sciences, The Bowman Gray School of Medicine of Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1032.
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