(Stroke. 1995;26:1871-1876.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin II Contributes to Cerebral Vasodilatation During Hypoxia in the Rabbit
From the Department of Anesthesia, Neuroanesthesia Research Group, University of Iowa College of Medicine, Iowa City.
Correspondence to Mazen A. Maktabi, MD, Department of Anesthesia, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Background and Purpose Hypoxia increases cerebral blood flow (CBF). Hypoxia also exerts a major influence on the renin-angiotensin system. In addition to the circulating renin-angiotensin system, a local renin-angiotensin system appears to be present in the brain, and angiotensin II receptors have been identified in cerebral blood vessels. In this study we tested the hypothesis that endogenous angiotensin II attenuates dilatation of the cerebral vessels during hypoxia.
Methods Pentobarbital-anesthetized rabbits were prepared for measurement of blood flow (microspheres) and assigned to one of two groups: in group 1 (n=11), rabbits were subjected to 30 minutes of stable hypoxia (PaO2=34±1 mm Hg, mean±SD) followed by 15 minutes of reoxygenation (PaO2=177 to 200 mm Hg). Blood flow was measured four times: under control conditions, after 15 and 30 minutes of hypoxia, and after 15 minutes of reoxygenation. This was a control group to characterize changes in CBF during hypoxia. In group 2 (n=11), blood flow was measured as in the previous group except that an infusion of the angiotensin II receptor antagonist saralasin (1 µg · kg-1 · min -1 IV) was started with the onset of hypoxia and continued through reoxygenation to the end of the experiment. The goal of this group was to examine whether endogenous activation of receptors for angiotensin II influences increases in CBF during hypoxia. In a separate series of experiments we examined the influence of the angiotensin-converting enzyme (ACE) inhibitor captopril on the hypoxic response. Thus, in one group of rabbits we measured CBF in the same manner as in group 1 (n=13). In another group of rabbits we also measured blood flow as in group 1 except that rabbits received 10 mg/kg of the ACE inhibitor captopril before the control measurement (n=11). We tested for significant differences between groups using two-way ANOVA.
Results Under control conditions, CBF was similar in all groups and averaged 53±15 mL · min-1 · 100 g-1. During hypoxia, CBF increased to a greater extent in the absence versus the presence of saralasin (95±31 and 104±30 mL · min-1 · 100 g-1 versus 72±24 and 71±25 mL · min-1 · 100 g-1, respectively; P=.003). Increase in CBF during hypoxia was also significantly greater in the animals that did not receive captopril versus those that were treated with captopril (100±24 and 89±16 mL · min-1 · 100 g-1 versus 72±16 and 73±17 mL · min-1 · 100 g-1). To rule out the possibility that saralasin produced nonspecific attenuation of cerebral vasodilatation, we tested the influence of hypercapnia on CBF in the absence and presence of saralasin. During normocapnia, CBF values were not significantly different in the absence and presence of saralasin (57±17 and 64±6 mL · min-1 · 100 g-1, respectively; P>.05). Hypercapnia increased CBF similarly in the absence and presence of saralasin (81±22 and 91±19 mL · min-1 · 100 g-1; PaCO2=61±2 and 60±2 mm Hg, respectively; P>.05).
Conclusions Because the ACE inhibitor captopril and the angiotensin II receptor blocker saralasin attenuated increases in CBF during hypoxia, the findings suggest that endogenous release of angiotensin II contributes to the increase in CBF during hypoxia.
Key Words: angiotensins • cerebral blood flow • hypoxia • rabbits
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Introduction |
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Angiotensin II, a circulating hormone that exerts an important role in blood pressure regulation, is also a neurotransmitter. In the brain, all of the components of an independent RAS appear to be present.1 2 The brain RAS participates in regulation of blood pressure, sympathetic activity, vasopressin release, thirst, and sodium appetite.2 In the central nervous system, angiotensin II may act as a dilator of cerebral arterioles.3 Acute hypoxia reduces the activity of ACE4 5 and decreases plasma levels of angiotensin II.6 Thus, changes in endogenous levels of angiotensin II during hypoxia may have an important impact on changes in CBF.
The goal of this study was to examine the influence of angiotensin II on CBF during hypoxia. Specifically, we tested the hypothesis that endogenous angiotensin II attenuates the normal increase in CBF during hypoxia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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General Preparation of Animals
The experimental protocol for this study was approved by the Animal Care and Use Committee of the University of Iowa. Fifty-four New Zealand White rabbits (weight, 2.0 to 3.4 kg) were used. The animals had free access to food and water until the time of surgical preparation. They were anesthetized with pentobarbital administered via an ear vein catheter at 30 to 50 mg · kg-1 IV followed by a continuous infusion (0.25 to 1.8 mg · kg-1 · min-1). After induction of anesthesia, the skin of the neck was infiltrated with bupivacaine (0.25%), a tracheotomy was performed, and the trachea was cannulated with an endotracheal tube. Gallamine triethiodide (5 mg · kg-1 IV) was administered after induction of anesthesia, followed by intermittent boluses of 1.5 mg · kg-1 to maintain muscle relaxation as needed. The animals' lungs were mechanically ventilated with air and supplemental oxygen and nitrogen (FIO2=0.5) to maintain a PaCO2 of approximately 35 to 45 mm Hg and PaO2 above 100 mm Hg (Small Animal Respirator, Harvard Apparatus Inc). Depth of anesthesia was assessed by noting the blood pressure change to periodic pressure on the tail. If a change in blood pressure occurred, additional pentobarbital (10 to 20 mg IV) was administered, and its rate of intravenous infusion was increased. A catheter was inserted into a femoral artery (after skin infiltration with bupivacaine) to monitor blood pressure and to sample arterial blood. A catheter was also inserted into a femoral vein for administration of fluids and drugs. Arterial blood gases were monitored two to three times during the surgical preparation and before each CBF measurement. Rectal temperature was monitored and maintained at 37°C to 38°C with a heating pad. Lactated Ringer's solution was infused at 7 to 10 mL · kg-1 · h-1 (Syringe Infusion Pump, Harvard Apparatus Inc) to maintain hydration.
Measurement of CBF
After the surgical preparation described above, a pigtail
polyethylene catheter was inserted into a femoral artery and advanced
via the aorta into the left ventricle for injection of
microspheres. Catheters were also inserted into both brachial
arteries to withdraw reference blood samples during injection of
microspheres. Blood flow was measured (see below for details)
with the use of, at random, 15-µm microspheres labeled with
46Sc, 95Nb, 153Gd,
85Sr, or 113Sn (New England Nuclear).
Microspheres (0.5 to 1.3x106) were injected
through the left ventricular catheter over 10 seconds.
Reference blood samples were withdrawn at a rate of 1
mL · min-1 from each brachial artery with the use of a
Harvard pump (Syringe Infusion Pump, Harvard Apparatus Inc)
started 15 seconds before injection of microspheres and
continuing for 1 minute after the injection.
At the end of each experiment, the anesthetized animal was killed with intravenous KCl. The brain was removed and fixed in formalin. The brain was later dissected into regional samples that consisted of the cerebral hemispheres, choroid plexus, caudate nucleus, thalamus, midbrain, pons, medulla, and cerebellum. Radioactivity of tissue samples and reference arterial blood samples was determined using a NaI well-type gamma counter (Packard Autogamma Counter, Packard Instruments). Isotope separation and blood flow calculation were performed with the use of standard techniques.7 8 CBF was calculated from the formula
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where QR is the reference blood sample withdrawal rate and CT and CR are counts in tissue and reference blood samples, respectively. The counts of the two reference blood samples were averaged. Values were used only when the counts in the reference blood samples did not differ by more than 10%.
Experimental Protocols
Experiment 1
Rabbits were prepared for measurement of CBF and assigned
randomly to one of two groups. In group 1 (n=11), hypoxia
(PaO2=34 to 35 mm Hg) was induced by
decreasing FIO2 (0.14 to 0.16) for 30
minutes. FIO2 was then increased to 0.5 for
15 minutes. Blood flow was measured four times: under control
conditions, after 15 and 30 minutes of stable hypoxia, and
after 15 minutes of reoxygenation. This group
served as a control to characterize changes in CBF during
hypoxia.
In group 2 (n=11), blood flow was measured as in the previous group except that an infusion of the angiotensin II receptor antagonist saralasin (1 µg · kg-1 · min-1 IV) was started after the control measurement and continued to the end of the experiment. The goal of this group was to examine whether endogenous activation of receptors for angiotensin II influences increases in CBF during hypoxia. We used this dose of saralasin because it completely blocks the hypertensive response to 100 ng · kg-1 · min-1 IV of angiotensin II.9
Experiment 2
The results of experiment 1 indicated that saralasin attenuated
increases in CBF during hypoxia (see "Results"). To rule
out the possibility that saralasin produced a nonspecific inhibition of
cerebral vasodilatation during hypoxia, we tested whether it
would also attenuate increases in CBF during hypercapnia. Thus, rabbits
were prepared for measurement of CBF and assigned randomly to one of
two groups. In group 3 (n=4), blood flow to the brain was measured
three times: under control conditions, at the end of a 5-minute period
of hypercapnia (PaCO2=55 to 65 mm Hg), and 5
minutes after normocapnia was resumed. We produced hypercapnia by
adding carbon dioxide to the inspired gases. In group 4 (n=4), blood
flow to the brain was measured as in group 3, except that an infusion
of the angiotensin II receptor antagonist
saralasin (1 µg · kg-1 · min-1) was
started before the control measurement and continued to the end of the
experiment.
Experiment 3
In experiment 1, blocking the effect of endogenous
angiotensin II by antagonizing angiotensin II
receptors with saralasin attenuated increases in CBF during
hypoxia (see "Results"). To confirm this new finding, we
tested whether blocking the influence of endogenous
angiotensin II by inhibiting its production (rather
than blocking its receptors) with an ACE inhibitor would
also attenuate increases in CBF during hypoxia. Rabbits were
prepared for measurement of blood flow and assigned to one of two
groups. In group 5 (n=13), hypoxia
(PaO2=34 to 35 mm Hg) was induced by
decreasing FIO2 (0.14 to 0.16) for 30
minutes. After hypoxia, FIO2 was
increased to 0.5 for 15 minutes. Blood flow was measured four times:
under control conditions, after 15 and 30 minutes of stable
hypoxia, and after 15 minutes of
reoxygenation. This was a second control group to
again characterize changes in CBF during hypoxia.
In group 6 (n=11), blood flow was measured as in the previous group except that the ACE inhibitor captopril, 10 mg/kg IV, was administered 15 minutes before the control blood flow measurement. In pilot studies this dose of captopril completely blocked the hypertensive response to angiotensin I (1 µg/kg IV) when tested before the first and after the last blood flow measurement. This dose of captopril blocks 75% of ACE activity in cerebral cortex.10 The goal of this group was to test whether production of angiotensin II mediates increases in CBF during hypoxia.
Statistical Analysis
Statistical analysis of blood flow was performed with
the use of two-way ANOVA to compare the changes in blood flow
between groups. The different groups were treated as a
"between-group" factor (factor A) and measurement interval
treated as a "within-group" factor (factor B). The difference
between groups was considered significant for AxB at
P<.05.
Within each group, repeated-measures ANOVA followed, when indicated, by Dunnett's t test was performed to compare values during hypoxia and reoxygenation with the control observation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of Hypoxia
In group 1, hypoxia produced a marked increase in total blood flow to the brain (P<.05, Fig 1
).
During hypoxia, arterial pressure did not change
significantly. However, it decreased slightly 15 minutes after
reoxygenation (P<.05, Table 1). Arterial PCO2
and pH did not change significantly during hypoxia or after
hypoxic reoxygenation (Table 1).
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, n=11) and presence (
, n=11) of the
angiotensin II receptor antagonist saralasin.
Saralasin infusion (1
mg · kg-1 · min-1) was started after
control measurement and continued to the end of the experiment.
*Significantly different from own control at P<.05;
$significantly different from corresponding observation in
the other group.
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Influence of Blocking Angiotensin II
Receptors
In the presence of saralasin (group 2), blood flow to the brain
increased significantly during hypoxia (P<.05, Fig 1
). However, brain blood flows were significantly less than during
hypoxia alone (P=.003). This finding suggests that
the angiotensin II receptor antagonist
(saralasin) attenuated the increase in total CBF during
hypoxia. Saralasin by itself did not influence total blood flow
to the brain under control normoxic conditions (group 4, Table 2).
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Influence of Hypercapnia
In groups 3 and 4, blood flow to the brain significantly increased
during hypercapnia (Table 2, P<.05). Increase in blood flow
to the brain was not altered by saralasin (P>.05). This
suggests that saralasin attenuates the dilator response of blood
vessels of the brain to hypoxia without producing nonspecific
inhibition of dilator responses to hypercapnia.
Effect of Captopril
In the presence of captopril (group 6), blood flow to the brain
increased significantly during hypoxia (P<.05, Fig 2). However, this increase was significantly less than
the value obtained during hypoxia alone (P=.02).
This finding suggests that inhibition of conversion of
angiotensin I to angiotensin II also attenuated
increases in CBF during hypoxia. Intra-arterial
pressure tended to be lower in the animals that received captopril.
However, this did not achieve statistical significance versus the
animals that did not receive captopril (Table 3).
Arterial blood gas values were also similar in both groups
(P>.05).
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, n+11) of the ACE
inhibitor captopril. Captopril (10 mg/kg IV) was given
before control measurement. *Significantly different from own control
at P<.05; $significantly different from
corresponding observation in the other group.
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Influence of Hypoxia on Regional Blood Flow (Data Not
Shown)
Blood flow to the choroid plexus did not change significantly
during hypoxia versus control conditions (P>.05).
In contrast, blood flow to the caudate, thalamus, midbrain, pons,
medulla, and cerebellum increased significantly during hypoxia
(P<.05). Saralasin and captopril attenuated increases in
blood flow to the midbrain, pons, medulla, and cerebellum in a fashion
similar to that of total CBF (P<.05). However, saralasin
and captopril did not decrease blood flow response to hypoxia
in the caudate nucleus and thalamus (P>.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are two major findings in this study. First, the angiotensin II antagonist saralasin attenuates increases in blood flow to the brain during hypoxia without altering increases in CBF that are produced by hypercapnia. Second, inhibition of ACE also attenuates increases in CBF during hypoxia. These two findings suggest that endogenous release of angiotensin II with activation of angiotensin II receptors contributes to increases in CBF during hypoxia. Since we11 and others6 have previously reported that plasma angiotensin II concentrations do not increase during acute hypoxia, those findings imply that increases in CBF during hypoxia occur partially in response to angiotensin II produced locally in the brain and are not dependent on an increase in plasma concentrations of angiotensin II.
Systemic and Cerebral RAS
The circulating RAS, with its effector peptide
angiotensin II, exerts a major influence on
cardiovascular function and body fluid and sodium
homeostasis.12 13 14 The juxtaglomerular
apparatus is one of the sites producing renin that cleaves
angiotensinogen to the decapeptide angiotensin
I.15 Angiotensin I is converted to the
octapeptide angiotensin II by ACE, which is present in
the endothelium and other cells.15 16 17
In addition to the circulating RAS, an independent RAS is present in the brain. This brain RAS participates in regulation of blood pressure, sympathetic activity, vasopressin release, thirst, and sodium appetite.1 2 Electrophysiological studies have shown that angiotensin II is a neurotransmitter.1 2 It is found in synaptic terminals and excites neurons at very low doses (10 to 12 mol/L) with high specificity.2 It has also been suggested that angiotensin II may play a role in the control of cerebral autoregulation.18 19 Although angiotensin II is a potent vasoconstrictor in the systemic circulation, it exerts both dilator and constrictor influences on the cerebral circulation. For example, angiotensin II contracts canine20 21 and monkey21 cerebral vessels in vitro, and when applied topically, it constricts cerebral vessels in cats22 23 and hamsters.24 Studies by us and others, however, have shown that angiotensin II may have little effect,25 26 cause small increases,9 or produce significant increases in CBF27 28 when given intravascularly. Further, angiotensin II induces endothelium-dependent pial artery dilatation in rabbit and rat cerebral arteries,3 29 and large concentrations of angiotensin II via the carotid artery increase blood flow to the brain in the rabbit.30 A recent report suggested that both angiotensin receptor subtypes (AT1 and AT2) mediate vasodilatation in brain arterioles, in vivo, under physiological conditions.31
ACE was originally identified in plasma, but it is also present on endothelial cells throughout the circulation.16 17 ACE is present in large concentrations in the brain.18 32 33 Cerebral microvessels also contain ACE, which suggests that angiotensin II may be synthesized in the vessel wall.34 35 36 37 38
Blood vessels of the choroid plexus are devoid of blood-brain barrier, and circulating vasoactive substances are able to cross the endothelium, reach vascular smooth muscles, and exert important hemodynamic influences on blood flow.9 27 28 For example, we previously reported that circulating angiotensin II decreases blood flow to the choroid plexus.9 27 In this study blood flow to the choroid plexus did not decrease during hypoxia. This suggests that plasma concentrations of angiotensin II did not increase during hypoxia and confirms our recent report11 and that of other investigators6 that plasma concentrations of angiotensin II do not increase during acute hypoxia. These findings suggest that the source of angiotensin II that contributed to the increase in CBF during hypoxia in this study is not the systemic circulation.
Role of Angiotensin II Receptors
Previous studies have demonstrated that angiotensin II
receptors are present in several brain regions,1 39
and angiotensin II binding sites have been identified on
cerebral blood vessels.19 40 41 In this study saralasin
attenuated a hypoxia-mediated increase in CBF, suggesting
that activation of angiotensin II receptors was in part
responsible for the increase in CBF. In contrast, neither saralasin nor
captopril attenuated increases in blood flow to the caudate nucleus and
the thalamus during hypoxia. Previous 125I binding
studies have reported that the caudate nucleus is nearly without
angiotensin II binding sites, and except for the
subthalamic nucleus, the thalamus showed only moderate labeling of
angiotensin II binding sites.1 Thus, the lower
density of angiotensin II receptors in these areas may
account for the lack of influence by the angiotensin II
receptor antagonist saralasin and the ACE
inhibitor captopril during hypoxia.
The specificity and selectivity of saralasin has been previously
demonstrated in several vascular beds.9 42 43 Saralasin
inhibited the vasoconstrictor effect of angiotensin II in
the choroid plexus without affecting vasoconstriction in response to
vasopressin.9 Saralasin also blocks both vasoconstrictor
and vasodilator influences of angiotensin II in cerebral
arteries without affecting vasodilator and vasoconstrictor effects of
solutions with high and low concentrations of K+,
respectively.42 43 We previously reported that saralasin
has no effect on CBF under control conditions.9 In this
study saralasin also had no significant influence on blood flow to the
brain under control conditions (Table 2). Selectivity of effects of
saralasin in attenuating the cerebral vasodilator effects of
hypoxia is supported by the finding that saralasin did not
alter increases in CBF produced by hypercapnia (Table 2).
Peptide hormones in general and angiotensin II do not penetrate the blood-brain barrier.44 Saralasin is a peptide derivative of angiotensin II that is not likely to cross the blood-brain barrier. We can only speculate on the mechanism by which intravascularly administered saralasin attenuated hypoxia-induced increases in CBF. Toda and Miyazaki42 suggested that angiotensin II dilates cerebral vessels through angiotensin II receptors since angiotensin II antagonists saralasin and [Sar1, Ile8]angiotensin II blocked the dilatory effects of angiotensin II. Another possibility is that saralasin blocked an increase in cerebral metabolism partially produced by endogenous brain angiotensin II during hypoxia. CMRO2 might have been changed by saralasin through blocking angiotensin II receptors in the neuronal cells of the circumventricular organs (area postrema, subfornical body, or supraoptic crest). These areas lack the blood-brain barrier and display chemosensitivity to angiotensin II.45 However, CMRO2 is not altered by angiotensin II.30 Therefore, it seems unlikely that attenuation of CBF increase during hypoxia by saralasin is due to an attenuation of CMRO2.
It is clear from our findings that saralasin and captopril did not completely abolish increases in CBF during hypoxia. Other mechanisms also contribute to dilatation of cerebral vessels under these conditions. These mechanisms may be related to release of adenosine46 or to stimulation of ATP-sensitive potassium channels.47 The relative contribution and the specific conditions under which each mechanism is triggered are not clear. Since in this study we only investigated the role of angiotensin II at moderate levels of hypoxia, we speculate that these alternative mechanisms may be active concomitantly with angiotensin II at the same level of hypoxia, may provide backup roles, or may be triggered at milder or more severe levels of hypoxia.
In summary, inhibition of production of angiotensin II by an ACE inhibitor and blocking angiotensin II receptors with a receptor antagonist attenuate cerebral vasodilatation during hypoxia. Thus, endogenous activation of angiotensin II receptors in the brain appears to play an important role in regulation of CBF changes during hypoxia in the rabbit.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was funded by the 1993 B.B. Sanky Anesthesia Advancement Award from the International Anesthesia Research Society (Dr Maktabi) and by the Department of Anesthesia at the University of Iowa. The authors thank Drs Bradley Hindman, Frank Faraci, and Johnny Brian for their critical review of this manuscript and Dr John H. Tinker, Head of the Department of Anesthesia at the University of Iowa, for his continuous support.
Received April 12, 1995; revision received June 19, 1995; accepted July 20, 1995.
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