(Stroke. 2000;31:2478.)
© 2000 American Heart Association, Inc.
Original Contributions |
Angiotensin II AT1 Blockade Normalizes Cerebrovascular Autoregulation and Reduces Cerebral Ischemia in Spontaneously Hypertensive Rats
From the Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, Bethesda, Md.
Correspondence to Juan M. Saavedra, MD, Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, 10 Center Dr, Bldg 10, Room 2D-57, Bethesda, MD 20892. E-mail Saavedrj{at}irp.nimh.nih.gov
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Abstract |
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Background and Purpose—Angiotensin II, through stimulation of AT1 receptors, not only controls blood pressure but also modulates cerebrovascular flow. We sought to determine whether selective AT1 antagonists could be therapeutically advantageous in brain ischemia during chronic hypertension.
Methods—We pretreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls with the AT1 antagonist candesartan (CV-11974), 0.5 mg/kg per day, for 3 to 14 days, via subcutaneously implanted osmotic minipumps. We analyzed cerebral blood flow by laser-Doppler flowmetry, cerebral stroke in SHR after occlusion of the middle cerebral artery with reperfusion, and brain AT1 receptors by quantitative autoradiography.
Results—Candesartan treatment normalized blood pressure and the shift toward higher blood pressures at both the upper and lower limits of cerebrovascular autoregulation in SHR. Candesartan pretreatment of SHR for 14 days partially prevented the decrease in blood flow in the marginal zone of ischemia and significantly reduced the volume of total and cortical infarcts after either 1 or 2 hours of middle cerebral artery occlusion with reperfusion, relative to untreated SHR, respectively. This treatment also significantly reduced brain edema after 2 hours of middle cerebral artery occlusion with reperfusion. In SHR, candesartan markedly decreased AT1 binding in areas inside (nucleus of the solitary tract) and outside (area postrema) the blood-brain barrier and in the middle cerebral artery.
Conclusions—Pretreatment with an AT1 antagonist protected hypertensive rats from brain ischemia by normalizing the cerebral blood flow response, probably through AT1 receptor blockade in cerebral vessels and in brain areas controlling cerebrovascular flow during stroke.
Key Words: brain • hypertension • peptides • receptors • stroke
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Angiotensin II (Ang II) contributes to modulate blood pressure by stimulation of Ang II AT1 receptors in smooth muscle vascular cells, followed by vasoconstriction, and blockade of AT1 receptors with selective nonpeptide inhibitors is an effective treatment of hypertension in humans.1 Ang II receptors and angiotensin-converting enzyme (ACE) are present in cerebral microvessels and cerebral arteries,2 3 4 indicating that endogenous Ang II may modulate cerebrovascular flow. Blockade of Ang II formation by ACE inhibitors inhibits the vascular tone maintained by locally produced Ang II, resulting in vasodilatation of large cerebral arteries. The cerebral blood flow is theoretically maintained by compensatory vasoconstriction of smaller resistance arteries.5 Since these resistance arteries have a higher potential vasodilatory capacity during decreases in blood pressure and a lower vasoconstricting capacity during increases in blood pressure, the autoregulation is shifted toward lower pressures.6 7 Alterations in cerebrovascular autoregulation, with a shift toward higher blood pressures and a predisposition to ischemia and stroke, are present in genetic and experimental hypertension. Blockade of Ang II formation or bradykinin degradation with ACE inhibitors prevents and reverses these alterations, improves tolerance to hypotension,8 and protects against focal cerebral ischemia in spontaneously hypertensive rats (SHR).9 10 Acute administration of candesartan, a very potent AT1 receptor antagonist, to SHR shifts their cerebrovascular autoregulatory response to the left, in the direction of lower blood pressures, in a manner similar to that of ACE inhibitors.11 We sought to determine whether chronic administration of AT1 antagonists could protect hypertensive rats from the effects of cerebral ischemia and whether this effect was related to modulatory effects in cerebral blood flow and/or to blockade of central AT1 receptors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Animal Studies
Adult, 10-week-old male SHR (weight, 270 to 306 g) and age-matched male Wistar-Kyoto rats (WKY), (weight, 280 to 320 g) were purchased from Taconic Farms, Germantown, NY. The National Institute of Mental Health Animal Care and Use Committee approved all procedures.
Osmotic minipumps were implanted subcutaneously the day after arrival at the National Institute of Mental Health to deliver drugs at a constant infusion rate12 : candesartan (0.5 mg/kg per day for 3, 7, or 14 days), propranolol (0.5 mg/kg per day for 14 days), or vehicle (0.1N Na2CO3). The experiments were blinded to knowledge and therapy assignments. Arterial pressures in conscious rats were measured 1 day before treatment and the last day of treatment by the tail-cuff method.12 At 10 weeks of age, the arterial blood pressure in SHR was clearly high and had reached steady values.
Quantitative Autoradiography
Quantitative autoradiography of Ang II
AT1 and AT2 receptors in
brain sections was performed by incubation with
0.5x10-9 mol/L
[125I]Sar1-Ang II (2200
Ci/mmol, iodinated at New England Nuclear) (total binding),
in the presence of selective AT1
(10-6 mol/L
losartan, Dupont Merck) or AT2
(10-7 mol/L CGP 42112,
Neosystems, or 10-6 mol/L
PD 123319, Parke Davis) ligands, respectively, to determine the amount
of AT1 and AT2
receptors.13 14 Sections were further stained with
hematoxylin-eosin for histological analysis,
and structures were identified according to Paxinos and
Watson.15
Cerebral Blood Flow Autoregulation
We studied the upper and lower parts of the cerebral blood flow
autoregulation curve in SHR and WKY anesthetized with
ketamine (100 mg/kg IP) and xylazine (10 mg/kg IP) and
ventilated with intratracheal intubation with 0.35% halothane in 70%
nitrous oxide and 30% oxygen. Systemic blood pressures were increased
with a phenylephrine infusion or decreased by
hemorrhage.12 16 Cerebral blood flow was
determined with a laser-Doppler flowmetry probe (BPM2,
Vasamedics, Inc).12
Reversible Middle Cerebral Artery Occlusion
We performed reversible middle cerebral artery occlusions in SHR
with reperfusion after 1 or 2 hours, with an intraluminal thread
technique.17 Rats were anesthetized with 3.0%
halothane and maintained with 1.0% halothane in 70% nitrous oxide and
30% oxygen under a ventilator with intratracheal intubation. We
monitored cerebral blood flow by laser-Doppler flowmetry at
3 points on the surface in the affected hemisphere: point A, 1 mm
from the midline and outside of the site of ischemia; point B,
3 mm from the midline and closer to the site of ischemia;
and point C, 5 mm from the midline and at the periphery of the
zone of ischemia (Figure 4
). Ventilation was
adjusted to keep blood pH between 7.35 and 7.45,
PaCO2 between 32 and 40 mm Hg,
and PaO2 between 130 and 180
mm Hg. Rectal temperature was maintained between 36.5°C and 37.5°C
with a heating pad.
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, control SHR; •, SHR treated with CV-110974).
*P<0.05, **P<0.01, treated vs control,
for groups of 6 animals.
Measurement of Volume of Injury
We determined the infarct volume after 24 hours of
ischemia with the
2,3,5-triphenyltetrazolium chloride (TTC)
method18 with image scanning and computerized
microdensitometry after correction for brain swelling.19
Cerebral edema was measured by subtracting the volume of the
nonaffected hemisphere from the volume of the affected hemisphere
divided by the volume of the nonaffected hemisphere.
Statistical Analysis
We assessed changes in Ang II receptor binding in treated and
untreated rats using Student’s t test (Figures 1 and 2). We used 2-way ANOVA to calculate the effect of duration of
treatment on autoregulation curves (Figure 3A) and cerebral
blood flow changes during occlusion and reperfusion (Figure 4
).
We used a 1-way repeated-measures ANOVA to compare cerebral blood flow
within a group and to determine the upper and lower limits of
cerebrovascular autoregulation curves (Figures 3B and 3C). We
used 1-way ANOVA to assess the effects of candesartan and
propranolol on blood pressure (see Results) and changes in
infarction volume and edema after occlusion and reperfusion (Figure 5). We performed post hoc analysis for
significance with Tukey’s multiple comparison test.
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, SHR controls;
, SHR treated with candesartan). *P<0.01, treated
animals vs controls. Right, Autoradiograms of
125I-Sar1-Ang II binding. A and C, Control SHR.
A, AT1 binding, incubated in the presence of
10-7 mol/L CGP 42112. C, AT2
binding, incubated in the presence of 10-6
mol/L losartan. B and D, SHR treated with candesartan. B,
AT1 binding, incubated in the presence of
10-7 mol/L CGP 42112. D, AT2
binding, incubated in the presence of 10-6
mol/L losartan. NTS indicates nucleus of the solitary tract;
AP, area postrema; and IO, inferior olive. Bar=1
mm.
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,
treated with propranolol). *P<0.05,
**P<0.01 for groups of 6 to 8 animals. |
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Effects of Candesartan on Ang II AT1 and AT2 Receptor Expression in Brain Areas and Middle Cerebral Artery
Treatment with candesartan, 0.5 mg/kg per day for 14 days, decreased AT1 binding in both the nucleus of the solitary tract and area postrema of treated SHR compared with control SHR. No difference was noted in AT2 binding in the inferior olive of SHR after candesartan treatment (Figure 1
). The middle cerebral artery of
SHR predominantly expressed binding to AT1
receptors (Figure 2), and binding to
AT2 receptors was only approximately 10% of the
total binding (results not shown). In this artery, candesartan
treatment, 0.5 mg/kg per day for 14 days, decreased
AT1 binding by 80% (Figure 2).
Effects of Drug Treatments on Blood Pressure
Systolic blood pressures were measured in 6 rats of each
group by the tail-cuff method. Blood pressures were significantly
higher in untreated SHR compared with untreated WKY. In both WKY and
SHR, systolic blood pressures were progressively decreased by
treatment with candesartan 0.5 mg/kg per day. A similar decrease
occurred after treatment with propranolol. After 14 days of
treatment, the blood pressure in SHR was not significantly different
from that of untreated WKY. Blood pressures were as follows: WKY,
124±5 and 75±5 mm Hg for control and candesartan-treated,
respectively (P<0.05); SHR, 166±3, 112±3, and
116±4.5 mm Hg for control, candesartan-treated, and
propranolol-treated rats, respectively (P<0.05,
candesartan versus control and propranolol versus control).
There was no significant difference in blood pressure between
candesartan- and propranolol-treated rats.
When determined under anesthesia and basal conditions, there was a significant difference of baseline mean arterial blood pressures between untreated WKY and untreated SHR. In both WKY and SHR, treatment with 0.5 mg/kg per day candesartan significantly reduced baseline mean arterial blood pressure as early as after 3 days of treatment, and the reduction in baseline mean arterial blood pressure was more pronounced in SHR after 14 days of treatment (results not shown).
Effects of Candesartan on Cerebrovascular Autoregulation
Control SHR showed a significant shift to the right, toward higher
blood pressures, compared with WKY at both the upper and the lower
parts of the autoregulation curve (Figure 3B and 3C).
Treatment with candesartan significantly shifted the upper and lower
limits of autoregulation in both WKY and SHR, toward the left, in the
direction of lower blood pressures. The change occurred as early as
after 3 days of treatment, progressed gradually with the duration of
treatment, and was greater after 14 days of treatment (Figure 3A). When SHR were treated with candesartan for 14 days, there
was a significant difference in both the upper and lower limits of
autoregulation compared with untreated SHR controls. In SHR treated for
14 days, the lower limit of autoregulation was no longer significantly
different from that of untreated WKY (Figure 3C).
Effects of Temporary Occlusion and Reperfusion of the Middle
Cerebral Artery
In preliminary experiments, we determined that untreated SHR were
far more sensitive to ischemia after middle cerebral artery
occlusion than WKY. Because of this and the higher incidence of stroke
in hypertension, we confined our studies to SHR. In a preliminary
experiment in untreated SHR, we determined the course of the
ischemia/reperfusion and the response of the cerebral
circulation. When middle cerebral artery was occluded successfully,
cerebral blood flow values did not significantly change when measured
1 mm from the midline, outside of the site of ischemia
(point A on Figure 4). However, cerebral
blood flow values decreased to <30% of baseline values when measured
closer to the site of the ischemia, at point B, 3 mm from
the midline, and at point C, 5 mm from the midline (Figure 4B1, 4B2, and 4C1). Both points B and C are considered to be
located at the periphery of the zone of ischemia. Some animals
developed subarachnoid hemorrhage or subdural hematoma,
as determined by a decrease in cerebral blood flow values to <30% of
baseline at point A or by a sudden cerebral blood flow reduction to
<30% of baseline values at point A and absence of cerebral blood flow
restoration at points B or C during reperfusion. Other animals did not
develop cerebral infarction during the procedure, as determined by the
restoration in cerebral blood flow to >50% of baseline values at
point C, corresponding to the site of the ischemia, within 30
minutes after the occlusion. In these animals with early restoration of
cerebral blood flow, cerebral infarction never occurred, as
demonstrated by histological staining with TTC 24 hours
after reperfusion. Rats with incomplete ischemia or
subarachnoid hemorrhage (2 vehicle controls and 1
treated with candesartan) were not included in the study.
In the rats submitted to successful occlusions, there were no
significant differences in baseline cerebral blood flow between control
and candesartan-pretreated rats before ischemia. Blood pH and
concentrations of blood gases remained within normal limits and were
similar among all groups (Table).
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Cerebral blood flow decreased after successful middle cerebral artery
occlusion. Abrupt reductions in cerebral blood flow were approximately
20% of baseline values at point A, 80% to 88% at point B, and 76%
to 90% at point C. After reperfusion following either 1 or 2 hours of
ischemia, cerebral blood flow at points A or B (Figure 4) was restored to values not significantly different from those
before the occlusion.
We did not find significant differences in cerebral blood flow
restoration after AT1 blockade at point A
(results not shown). In our experiments, point B corresponds to the
more peripheral, marginal zone of ischemia (Figure 4). At point B, pretreatment with the AT1
antagonist did not alter the initial abrupt decrease in
blood flow (Figure 4B1 and 4B2). However, when animals were
pretreated with candesartan, the decrease in blood flow at point B was
significantly reduced 30 to 90 minutes after middle cerebral artery
occlusion (Figure 4B1 and 4B2). This effect was significant when
the middle cerebral artery was occluded for either 1 or 2 hours (Figure 4B1 and 4B2). Point C is an area still marginal but closer to
the central core of ischemia. At point C, when submitted to
ischemia for only 1 hour, there was no difference in the
decrease in blood flow during ischemia between
candesartan-pretreated and vehicle-treated rats (Figure 4C1).
After reperfusion, candesartan-pretreated rats restored their cerebral
blood flow to 112% of baseline values. In vehicle-treated rats, the
blood flow at point C remained decreased to 64% of baseline values
(Figure 4C1). Thus, when the middle cerebral artery was occluded
for 1 hour, the cerebral blood flow was, at point C, completely
restored only in candesartan-pretreated rats. Pretreatment with
candesartan followed by 2 hours of ischemia and reperfusion
resulted in only a partial restoration of blood flow at point C
(results not shown), indicating that the effect of candesartan
pretreatment was dependent on the duration of the ischemia.
Ischemia resulting from middle cerebral artery occlusion
resulted in brain injury of the ipsilateral hemisphere, including
cortical and subcortical (striatum-pallidum) areas, and significant
ipsilateral brain edema. In the candesartan-pretreated rats submitted
to 1 hour of ischemia, total (cortical plus subcortical) and
cortical volumes of injury corrected for edema volume were
significantly decreased by 58% and 64% relative to those in control
vehicle-treated rats (Figures 5A and 5B
and 6). A similar decrease in the volume
of ischemia after candesartan treatment occurred when the
period of ischemia was increased to 2 hours (Figure 5A and 5B). In subcortical areas, the volume of injury was not affected
either by the duration of the ischemia or by pretreatment with
candesartan (Figure 5C).
Brain edema was dependent on the duration of the ischemia and
was significantly higher after 2 hours of ischemia compared
with 1 hour of ischemia (Figure 5D). Pretreatment with
candesartan decreased brain edema after 1 or 2 hours of
ischemia, but the change was significant only after 2 hours of
ischemia (Figure 5D).
Conversely, pretreatment with propranolol, administered at
a dose that decreased blood pressure to a degree similar to that of
candesartan, did not modify either the volume of ischemia or
the brain edema resulting from the middle cerebral artery occlusion
with reperfusion, as determined after 2 hours of ischemia
(Figure 5A through 5D).
In conclusion, candesartan pretreatment reduced ischemic injury in the cortex of SHR submitted to 1 or 2 hours of ischemia and reduced brain edema in SHR submitted to 2 hours of ischemia.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Our results demonstrate that selective antagonism of Ang II AT1 receptors by chronic peripheral administration of the AT1 antagonist candesartan normalizes cerebrovascular autoregulation and protects against brain ischemia in genetically hypertensive rats.
There is a relationship between alterations in cerebral blood flow and vulnerability to ischemia in hypertensive subjects. In genetic and experimental hypertension, cerebral arteries are less compliant because of increased thickness with smooth muscle proliferation.9 20 This results in a shift of the cerebrovascular autoregulatory curve to the right, in the direction of higher blood pressures, with a decreased capacity for vasodilatation in the face of reduced perfusion pressures.11 Hypertensive subjects are predisposed to brain ischemia and stroke in part because of their decreased capacity for cerebrovascular adaptation to the reduction in blood flow during stroke.10
After the initial discovery of the presence of Ang II receptors in brain arteries,2 4 we studied the effects of the AT1 antagonist candesartan in cerebral blood flow autoregulation. In normotensive rats, candesartan treatment shifted the autoregulatory curve to the left.12 This suggested that stimulation of AT1 receptors by Ang II results in a normal vasoconstrictor tone in cerebral arteries. Under resting conditions, cerebral blood flow does not change after AT1 receptor blockade, probably because of a compensatory vasoconstriction of small cerebral resistance arteries.21 Studies on SHR revealed that acute11 and chronic12 administration of candesartan results in a normalization of the upper part of the cerebrovascular autoregulatory curve. The normalization of cerebrovascular autoregulation in SHR by chronic candesartan treatment extends to both the upper and the lower parts of the autoregulatory curve (Reference 12 and present results) and is progressive over time, as demonstrated here. The increased capacity to vasodilate resulting from AT1 blockade may be due to a decrease in the medial thickness of cerebral arteries and inhibition of the injury-related proliferation of smooth muscle, in a manner similar to that of ACE inhibitors.5 9 20 Thus, the normalization of cerebrovascular autoregulation by candesartan in SHR may be the result of antagonism of enhanced Ang II constrictive and growth-promoting effects in the cerebral circulation.22 23 This results in improvement of brain artery compliance with increased capacity for vasodilatation of cerebral arteries.
To establish whether the normalization of cerebrovascular flow by
chronic pretreatment with candesartan was related to its protective
effect against brain ischemia, we studied cerebral blood flow
after stroke. During stroke, if cerebrovascular responses were
normalized by AT1 blockade, the capacity for
vasodilatation in areas receiving collateral circulation could be
improved and restored, and blood flow could be more easily maintained
or recovered than in control untreated subjects. After chronic
candesartan treatment, we found this to be precisely the case.
Candesartan pretreatment significantly decreased the volume of
ischemic injury in the cortex area in rats occluded for 1 or 2
hours. A beneficial effect of candesartan pretreatment was also
demonstrated in rats submitted to 2 hours of ischemia, as
evidenced by a significant decrease in cerebral edema. These effects
are probably a result of higher perfusion than that of control
untreated rats at the periphery of the ischemic brain lesion
(points B and C, Figure 4), areas probably receiving collateral
circulation from unoccluded brain arteries. During ischemia, in
the periphery of the ischemia zone, blood flow is reduced to
approximately 15% to 20% of preischemia values (Reference
24 and present results). AT1
blockade significantly reduced the decrease in cerebral blood flow 30
to 90 minutes after middle cerebral artery occlusion and improved the
recovery of blood flow that occurs during reperfusion in the area of
penumbra, at the periphery of the ischemic
lesion.24 This can be explained by improved capacity for
vasodilatation resulting in increased collateral flow to the marginal
area of ischemia. In addition, blockade of
AT1 receptors could also decrease the stimulation
of superoxide and peroxynitrite production by Ang II in blood
vessels.25 26 Superoxide ion formation by Ang II could
produce cytotoxic effects, including increases in blood-brain barrier
permeability,27 and this may explain the decrease in
cerebral edema after candesartan pretreatment.
In addition, peripheral administration of candesartan inhibits AT1 receptor binding in brain areas such as the nucleus of the solitary tract, contributing to regulate cerebrovascular flow through modulation of central sympathetic activity and in turn modulation of the brain Ang II system12 28 and in the middle cerebral artery. Chronic peripheral administration of candesartan inhibits binding to AT1 receptors to the same extent in brain areas outside and inside the blood-brain barrier, indicating that under the conditions of our experiments, candesartan readily penetrates the blood-brain barrier (Reference 2929 and present experiments).
In SHR, both the central sympathetic activity and the central Ang II system are activated.28 Activation of the central Ang II system in SHR has been demonstrated by increased Ang II formation in the brain, increased Ang II AT1 receptor expression, and normalization of blood pressure by central administration of AT1 receptor antagonists.28 Central inhibition of AT1 receptors in areas regulating the sympathetic system could contribute to normalize cerebral blood flow and result in additional beneficial effects.
Candesartan binds in an insurmountable fashion30 and was probably not washed off completely during our incubation procedures. For this reason we cannot determine whether decrease in receptor binding is due to receptor occupancy or downregulation.
Because candesartan pretreatment improves the restoration of blood flow after ischemia, we propose that normalization of cerebrovascular autoregulation by AT1 blockade is an important mechanism underlying the protective effects of candesartan.
An important question is whether the protective effects of inhibition of the Ang II system could be simply the result of the reduction in blood pressure. There is evidence that this may not necessarily be the case. The effects of AT1 blockade on cerebrovascular autoregulation are important for the improvement and restoration of blood flow during and after stroke, as reported here and as has been demonstrated not only in hypertensive but also in normotensive rats.12 Treatment of normotensive rats with ACE inhibitors or by brain AT1 blockade with centrally administered irbesartan improves neurological outcome after stroke,31 32 and ACE inhibitors at doses lower than those required to normalize blood pressure reduce cerebral edema in stroke-prone rats.33 In addition, as demonstrated here, normalization of blood pressure in SHR after treatment with propranolol does not protect from the results of ischemia. For these reasons we hypothesize that the protective effects of candesartan are not necessarily dependent on its effects on blood pressure.
The possible role of the relationship of AT1 and AT2 receptors in cerebral arteries is of interest. In vivo administration of Ang II can dilate34 or constrict21 brain arteries. It is possible that the effects of Ang II depend on a balance of stimulation of cerebrovascular AT1 and AT2 receptors. In young rats, large cerebral arteries predominantly express AT2 receptors, as determined by autoradiography.4 However, the number of AT2 receptors in cerebral arteries decreases with age,4 and in adult rats, brain vessels such as the middle cerebral artery predominantly express AT1 receptors. In adult rats the functional Ang II receptors in cerebral arteries are of the AT1 subtype, and their stimulation produces vasoconstriction, as determined in vitro.22 It is possible that under conditions of AT1 blockade in cerebral arteries, the cerebrovascular tone is shifted to vasodilatation, resulting in a decreased reduction of blood flow under conditions of ischemia. The possible role of brain and/or cerebrovascular AT2 receptors during brain ischemia remains an open question.
Continuous pretreatment with an AT1 antagonist such as candesartan normalized cerebral blood flow autoregulation in genetically hypertensive rats, raised the resistance against cerebral hypotension, and effectively restricted the volume of ischemic injury, resulting in the prevention of brain injury after temporary ischemia. Treatment with candesartan has been reported to decrease end-organ damage after ischemia.35 Our demonstration of effective and selective AT1 blockade after chronic peripheral administration of candesartan indicates that this compound may be effective as a preventive treatment of neuronal injury in clinical conditions.
It appears that the protective effects of AT1 receptor antagonism with candesartan pretreatment are likely to be related to the normalization of cerebrovascular autoregulation in the marginal ischemia zone, resulting in decreased neuronal injury. In addition, possible therapeutically beneficial effects include a normalization of blood-brain barrier permeability, which is increased during ischemia, resulting in decreased cerebral edema, and the specific inhibition of brain AT1 receptors, resulting in normalization of brain sympathetic activity, which is increased during hypertension.
The present data demonstrate an important role for Ang II in cerebrovascular control and indicate that therapeutic inhibition of the central Ang II system, and in particular pretreatment with selective AT1 receptor antagonists such as candesartan, could reduce neuronal injury resulting from cerebral ischemia.
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Acknowledgments |
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This study was supported by ASTRA GmbH Germany. We thank Dr Bernd Friedrich, ASTRA GmbH Germany, for a general supply of candesartan and Dr Ines Armando for help with the statistical analysis.
Received March 3, 2000; revision received June 12, 2000; accepted July 11, 2000.
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Editorial Comment
Center for Hypertension and Renal Disease Georgetown University Washington, DC
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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The brain can tolerate high degrees of variability in its levels of blood flow. However, sudden and massive reduction of blood flow that occurs during brain ischemia results in neuronal death at the core of the infarct. Because certain levels of cerebral blood flow are necessary to maintain neural function and cellular integrity, at the periphery of the lesion the degree of blood flow reduction can determine the development of processes leading to either survival or delayed neuronal death. Vasodilatation of collateral circulation during ischemia can reduce the loss of blood flow and allow neuronal survival, protecting brain function.
In hypertensive patients the absolute level of cerebral blood flow is similar to that in normotensive subjects. In hypertension, however, the cerebrovascular autoregulation (that is, the capacity of cerebral blood vessels to constrict or dilate in response to alterations in pressure to maintain a constant level of blood flow) is shifted toward higher pressures. This shift, the result of higher vascular tone and smooth muscle hypertrophy leading to stiffness of cerebral vessels, is a consequence of chronic systemic hypertension. A shift toward higher pressures in the autoregulatory curve impairs the tolerance to lower perfusion rates during brain ischemia and can make ischemic episodes in hypertension more frequent and more severe.R1
Many factors regulate cerebral blood flow. Evidence continues to accumulate indicating the involvement of angiotensin II in the regulation of the processes occurring in cerebral ischemia. Chronic inhibition of angiotensin-converting enzyme normalizes cerebrovascular autoregulation, which shifts the autoregulation curve to the left, signaling an improved capacity to vasodilate.R2 This led to the speculation that the normalization of blood flow that followed blockade of angiotensin II production played a central role in the reduction of the occurrence of stroke and circulatory alterations during ischemia in stroke-prone spontaneously hypertensive rats.R3
The preceding study provides evidence that pretreatment with candesartan, administered peripherally, reduced the volume of cortical infarcts and the brain edema after middle cerebral artery occlusion in genetically hypertensive rats. Candesartan is a potent, insurmountable angiotensin II AT1 receptor antagonist that gains access to the brain after peripheral administration and inhibits brain and cerebrovascular, in addition to peripheral, AT1 receptors.R4
Several aspects of the present study are noteworthy. Cerebral blood vessels of adult genetically hypertensive rats predominantly express the physiologically active AT1 receptors, and candesartan blocks these receptors. The AT1 antagonist is able to reverse the alterations in cerebrovascular autoregulation that are characteristic in genetic hypertension, shifting the autoregulatory curve toward the left, in the direction of improved vasodilation. Pretreatment with candesartan partially prevents the decrease in blood flow in the marginal zone of ischemia that is characteristic in stroke. These findings indicate that peripheral administration of candesartan results in a decrease in cerebrovascular vasoconstrictor tone and in a higher capacity of the collateral circulation to vasodilate during stroke. This is probably due to a reversal of the structural abnormalities that develop in cerebral blood vessels during chronic hypertension and to the blockade of cerebrovascular AT1 receptors. Additional beneficial effects may be, as demonstrated here, the result of AT1 receptor blockade in brain areas such as the nucleus of the solitary tract that contribute to regulate cerebral blood flow. Maintenance of a certain level of blood flow, crucial for neuronal survival, can explain the protective effect of candesartan during stroke. The effects of AT1 blockade are not necessarily related to the decrease in blood pressure, because not all antihypertensive compounds offer a similar protective effect.
The present study may offer an explanation of the possible mechanism for the improved neurological outcome and reduced cFos and c-Jun expression after stroke when another AT1 antagonist, irbesartan, is administered into the brain,R5 and it emphasizes the possible important role of the brain and cerebrovascular angiotensin II system in the regulation of cerebral blood flow. It appears from the present results that the effects in cerebrovascular flow are important for the protective effect of AT1 antagonism in brain ischemia.R6 It is also possible that blockade of AT1 receptors in selective brain areas by candesartan, as demonstrated here, could contribute to the enhanced capacity to vasodilate, through a reduction in central sympathetic tone. AT1 receptor blockade could also enable cerebrovascular AT2 receptors to become functionally predominant, contributing to improved capacity to vasodilate, which is an interesting and testable hypothesis that the researchers can examine.
Chronic blockade of brain and cerebrovascular AT1 receptors partially prevents the reduction in blood flow during brain ischemia. This, in turn, could significantly decrease the cascade of receptor activation, loss of energy stores, release of excitotoxic amino acids, disintegration of membranes, activation of proteolytic enzymes, formation of free radicals, and fragmentation of DNA that lead to neuronal death and permanent loss of function.
The question remains of the possible clinical implications of the recent findings. Oral administration of AT1 antagonists is a common antihypertensive therapy in humans. Studies are under way to determine whether long-term treatment with AT1 antagonists such as candesartan, which gain access to the brain, can reduce the incidence and severity of stroke in hypertensive patients and whether antihypertensive medication improves cognition in the elderly.R7 If improvement of cerebral blood flow plays a role in preventing cognitive deterioration in chronic hypertension, blockade of cerebrovascular and brain AT1 receptors in addition to peripheral antihypertensive effects could be therapeutically advantageous.
Received March 3, 2000; revision received June 12, 2000; accepted July 11, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1. Strandgaard S, Paulson OB. Regulation of cerebral blood flow in health and disease. J Cardiovasc Pharmacol. 1992;19(suppl 6):S89–S93.
2. Muller F, Lartaud I, Bray L, Atkinson J, Janian P, Burlet C, Capdeville C. Chronic treatment with the angiotensin I converting enzyme inhibitor, perindopril, restores the lower limit of autoregulation of cerebral blood flow in the awake renovascular hypertensive rat. J Hypertens. 1990;8:1037–1042.[Medline] [Order article via Infotrieve]
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5. Dai W-J, Funk A, Herdegen T, Unger T, Culman J. Blockade of central angiotensin AT1 receptors improves neurological outcome and reduces expression of AP-1 transcription factors after focal brain ischemia in rats. Stroke. 1999;30:2391–2399.
6. Inada Y, Wada T, Ojima M, Sanada T, Shibouta Y, Kanagawa R, Ishimura Y, Fujisawa Y, Nishikawa K. Protective effects of candesartan cilexetil (TCV=116) against stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens. 1997;19:1079–1099.
7. Hansson L, Lithell H, Skoog I, Baro F, Banki CM, Breteler M, Castaigne A, Correia M, Degaute JP, Elmfeldt D, Engedal K, Farsang C, Ferro J, Hachinski V, Hofman A, James OF, Krisin E, Leeman M, de Leeuw PW, Leys D, Lobo A, Nordby G, Olofsson B, Opolski G, Prince M, Reischies FM. Study on Cognition, and Prognosis in the Elderly (SCOPE): baseline characteristics. Blood Press. 2000;9:146–151.[Medline] [Order article via Infotrieve]
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