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Vascular Spasm in Cat Cerebral Cortex
Following Ischemia
MICHAEL N O E L HART, M.D.,
MARTIN D. SOKOLL, M.D.,
AND EDUARDO HENRIQUEZ,
LOYD R.
DAVIES,
M.D.
S U M M A R Y The reaction of brain parenchymal vessels in areas of
no-reflow following ischemia in cats was evaluated. A method was
devised by which brain biopsies following ischemia were quickly
frozen at — 170°C, sections were cut and stained and vessel internal
and external diameter measured. Vessels in the no-reflow areas had
smaller internal and external diameters and thicker walls when com-
pared to adjacent reflow areas as well as to normal control animals.
By utilizing a 2-way analysis of variance in which reflow versus noreflow vessel diameters were compared by region the differences were
found to be statistically significant (p < 0.05). The data raise the
possibility that there may exist normal regional differences in the size
of cerebral vessels.
FOLLOWING EXPERIMENTAL cerebral ischemia, the
failure to perfuse random areas of the brain after circulation has been re-established is a well-known phenomenon
variously referred to as no-flow or no-reflow state. 1 ' 2 The
cause of no-reflow is generally ascribed to blockage of
microcirculation, mainly because of ultra-structural studies
which have shown swelling of glial foot processes, endothelial swelling and increased numbers of intraluminal
flaps at the capillary level.3"5 Intraluminal clotting and
stagnation of hematopoietic elements have not been ruled
out as contributory causes, however.6'6
One of the major criticisms of the no-reflow observations
is that they do not coincide with patterns of ischemic brain
lesions in humans. However, we have observed perivascular
patterns of necrosis in human cerebral cortices following
ischemia combined with serum hyperosmolality.8 Upon reexamination of that material we concluded that the focal
ischemic areas were associated with penetrating vessels large
enough to contain significant amounts of smooth muscle in
their walls. This observation raised the question of whether
spasm of intraparenchymal cerebral vessels could occur and
if it could be contributory to post-ischemic no-reflow in the
From the Departments of Pathology and Anesthesiology, University of
Iowa College of Medicine, Iowa City, IA 52242.
VASCULAR SPASM IN CAT CORTEX AFTER ISCHEMIA///ar/ el al.
cerebral cortex. The present experiment is an attempt to
elucidate the role of intraparenchymal arterial spasm in the
experimentally ischemic cat brain.
Materials and Methods
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Eighteen 2-6 kg cats were studied. Each was anesthetized
with 30 mg/kg of intraperitoneal sodium pentobarbitol.
After anesthesia was established, the trachea was intubated
and the cat was ventilated to maintain a Paco 2 of 35 ± 4
torr with a Pao 2 of 80-100 torr and a pH of 7.25 -7.35. The
left femoral vein and artery were cannulated for drug injection and arterial pressure recording. The right femoral
artery was cannulated and a PE-50 catheter was inserted to
the area of the aortic-arch for dye injection. Arterial
pressure was continuously monitored with a Statham P23D6
transducer and recorded on a Beckman R-411 dynagraph.
After each animal was prepared and stabilized, the head was
placed in a stereotaxic head holder and a pneumatic tourniquet was placed securely around the neck and inflated to
1200 mm Hg for a period of 30 minutes. During the ischemic
period the skull was unroofed without damage to the dura or
superficial vessels. This was followed in order by 1-5
minutes of re-circulation, intra-aortic injection of 10%
fluorescein dye (0.25 mgm/K) and fifteen seconds of circulation to distribute the dye. Bilateral 1 X 1 X 0.4 cm biopsies were then taken either from the living animal or
immediately after the animal was killed by intravenous injection of a saturated solution of K G . The biopsies were
immediately (10-20 sec) frozen in isopentane cooled to
— 170°C in liquid nitrogen. Several 8/* thick sections at
about 100/* intervals were cut parallel to the surface from
each biopsy specimen. Sections were mounted on glass
slides, rapidly air dried and examined by fluorescent microscopy. Non-fluorescing (no-reflow) areas were circled and the
sections then stained with an ATPase9 method to outline the
vessels. Some additional sections were stained with H&E
and trichrome. The no-reflow areas as well as adjacent perfused areas were photographed and enlarged 250 or 400
times. Intraluminal and external diameters of arteries 70^
and larger (external diameter) were measured with a particle
size analyzer. Approximately 170 vessels were measured in
the no-reflow areas and 170 vessels from adjacent reflow
(fluorescein stained) areas utilized as controls were also
measured. Additional controls consisted of biopsies from 4
normal cats and from 4 cats which had been rendered hypoxic by ventilation with 95% nitrous oxide repetitively for 45
minutes total time. In both of these control groups the skull
was unroofed and fluorescein dye was injected as in the test
group. Approximately 120 vessels were measured from these
groups. Positive controls consisted of thin slices of brain
overlain with ergotamine and incubated for 1-2 hours at
37°C; mirror image slices of brain overlain with saline and
incubated at 37°C for 1-2 hours served as controls for the
ergotamine incubated sections. After incubation these sections were frozen at -170°C, sectioned, stained with
ATPase, photographed and measured as were the test biopsies.
TABLE 1
x Values of Measurements
Intraluminal D
Ext D
Wall
thickness
51.4M
96.3M
184.4/x
209.4M
66.5M
56.6 M
74.4M
148.9M
37.3M
No-reflow areas
Adjacent reflow areas
Normal and hypoxia
control cats
were usually 0.5 - 1.5 mm in diameter and more often involved the superficial cortex although they were also present
in the deeper cortex and even in the white matter. None of
the 8 control animals displayed significant no-reflow areas as
evidenced by even distribution of dye throughout the cortex
and white matter with the exception of one anoxic cat which
showed two small cortical areas devoid of dye. No intraluminal clots were seen in any of the vessels. The normal and
hypoxic cats were grouped together because measurements
were similar in each.
Smaller vessel lumens and thicker walls from the noreflow areas in contrast to adjacent reflow areas and nonischemic control cats indicate that the no-reflow vessels are
in a state of contraction (spasm) (table 1). The ergotamine
incubated brain slices indicate both the fact that intraparenchymal vessels can undergo spasm (table 2) and that
they can be frozen, sectioned, dried, stained and measured in
that state of spasm.
The data were also approached by a 2-way analysis of
variance using control versus no-reflow as well as regional
differences (table 3). The regional values represent vessel
measurements in one no-reflow area with adjacent control
reflow areas as a set. Utilizing this method, there is a significant (p < 0.05) difference between the internal diameters of
control versus no-reflow areas (fig. 1). Although for external
diameter and wall thickness the comparisons of no-reflow
and control values showed a significant difference, the
regional differences were also significant.
Discussion
Focal perfusion deficit following experimental brain
ischemia has been demonstrated in several animal
models.1-2 Ultrastructural changes in the areas of no-reflow
in some of these models have shown fairly consistent swelling of the glial foot processes on the capillary basement
membrane, often combined with endothelial swelling and increased numbers of intraluminal flaps with resultant narrowing of the capillary lumens.3- * These findings have led investigators to believe that the cause of no-reflow lies at the
level of the microcirculation. The possibilities of intraluminal clotting or increased platelet adhesiveness have had
their advocates6-7 although other investigators have shown
little or no beneficial effect of heparin use with ischemia.10- "
The possibility that focal no-reflow results from occlusion
of larger vessels is suggested by re-appraisal of some earlier
experiments. First, Ginsberg and Myers2 have shown large
TABLE 2
Ergotamine Controls
~~~
Intraluminal D Ext D
Results
Biopsies of all 18 ischemic cats contained areas devoid of
fluorescein dye indicating absence of blood flow. These areas
53
Ergotamine incubated brain
Ergotamine control
21.8M
47.8M
135.4M
144.3M
Wall
thickness
56.8M
48.3M
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TABLE 3 Two-way Analysis of Variance (Control versus NoReflow and Region)
Region
A.
X
No reflow'
s.d.
Internal Diameter
2.06
A-1
1.52
1.15
A-2
0.51
A-3
1.71
0.92
1.82
B-l
0.84
1.24
B-2
0.82
1.69
B-3
0.35
1.56
Total
0.90
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Control vs. No-Reflow
Region
Interaction
i
2.11
B.
x
B.d.
External Diameter
5.16
A-1
1.24
A-2
3.55
0.91
3.94
A-3
1.35
B-l
4.44
1.32
4.92
B-2
0.99
4.78
B-3
0.30
4.37
Total
1.21
Control vs. No] Reflow
Region
Interaction
Region
X
No reflow
s.d.
C. Vessel Wall Thickness
A-1
1.55
0.22
A-2
1.20
0.22
A-3
1.11
0.27
B-l
1.31
0.26
B-2
1.84
0.14
B-3
1.54
0.04
Total
1.41
0.34
Control vs,• No Reflow
Region
Interactioi i
Difference
0.05
0.82
2.43
1.28
1.49
3.87
2.16
0.83
2.12
0.30
1.39
3.02
1.78
1.62
2.43
0.74
1.01
2.59
1.03
1.37
F
22.005
1.747
2.431
No reflow
Region
Control
a.d.
X
p-value
0.0001
0.130
0.0397
Control
s.d.
4.80
Difference
-0.36
1.25
4.77
1.22
1.29
6.37
2.43
1.13
-0.66
3.78
2.12
0.87
5.79
1.79
6.07
1.29
1.24
0.66
5.03
1.74
p-value
0.0047
0.0055
0.0106
F
8.4702
3.5723
3.1846
X
Control
s.d.
Difference
-0.20
1.35
0.24
-0.01
1.19
0.19
0.14
1.25
0.36
-0.48
0.83
0.39
-0.46
1.38
0.20
0.28
1.82
0.29
-0.18
1.23
0.39
F
6.1527
16.6475
6.0471
p-value
0.0142
0.0001
0.0002
VOL 9, No
1, JANUARY-FEBRUARY
1978
cortical areas of impaired reperfusion following total circulatory arrest in monkeys. By utilizing the technique of injecting a carbon black suspension just prior to termination
of the experiment they show coronal brain sections having
large cortical areas devoid of carbon black. Other investigators have reported similar findings.1' " These observations appear more consistent with occlusion of larger,
penetrating cortical vessels than with capillary occlusion,
otherwise there has to be an explanation for simultaneous
occlusion of many capillaries in one area with sparing of the
capillaries in adjacent areas. Second, the perivascular
lesions seen in humans following circulatory arrest combined with hyperosmolality are predominantly situated
around penetrating cortical vessels and not associated with
capillaries.8 The further possibility that larger vessel occlusion might be caused by spasm is suggested by Wade and
associates13 who have demonstrated increased concentrations of potassium in rat brain interstitial fluid following
ischemia and have postulated that the no-reflow state which
they observed might possibly be due to vascular contraction
since it is known that high potassium concentrations can
cause contractions of vascular smooth muscle.14 Zervas et
a/.15 also imply that vascular contraction might play a role in
cerebral ischemia following their observation that dopamine
was decreased in the brains of ischemic gerbils. In the present study, contraction (spasm) of the penetrating cortical
vessels is indicated by smaller lumens and thicker walls in
the no-reflow areas following ischemia. Proof that spasm
can occur in these intraparenchymal vessels is supplied by
the demonstration of spasm in the brain slices incubated
with ergotamine, a drug chosen because of its known pharmacological effect of directly inducing smooth muscle contraction. 16 This positive control experiment using
ergotamine also shows that vessels can be "frozen" in their
physiologic state and examined morphologically, a compromised analysis of form and function which cannot be
achieved with any other conventional fixative to the best of
our knowledge.
The rapid freezing technique results in excellent preservation of morphology of both meningeal and cortical vessels
(fig. 2). Vessels in the areas of no-reflow which are presumed
to be in spasm have thick, heavily stained walls (fig. 3) which
rules against the possibility of edema causing the increased
mural thickness.
It has been suggested that ergotamine has a greater direct
contractile effect on venous than arterial smooth muscle."
In the present model we cannot rule out the possibility that
some of our measured vessels were veins. Although we excluded from measurement all vessels with thin walls, there
remains the possibility that some veins could go into spasm,
acquiring thicker walls and then appearing as arteries or
arterioles on section. However, we do not feel that venous
spasm occurred frequently because numerous veins in the
non-reflow areas remained thin walled with large lumens.
The no-reflow areas decreased slightly in size as deeper
sections were examined. Also, these areas did not neatly surround one penetrating vessel as was seen in human cases8 but
usually encompassed two or more arterioles or arteries.
Both of these observations raise the possibility of spasm in
VASCULAR SPASM IN CAT CORTEX AFTER ISCHEMIA/tfarr et al.
55
4iO,
3 5 .
2.5 .
FIGURE 1. Graph of vessel internal
diameters in control freflow) versus nore flow areas for six separate cortical
regions.
UJ
<
a
1.5 .
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1.0 .
0 5
CONTROL
the pia-arachnoid vessels prior to parenchymal penetration,
a possibility which cannot be ruled in or out on the basis of
this study because the pia-arachnoid vessels were sectioned
at many different angles rendering them difficult to measure
and because there is no proof that pia-arachnoid vessels
observed overlying a no-reflow area actually penetrate into
that same area rather than entering the brain at another site.
These brain biopsies were sectioned at intervals and consequently the same vessels were sometimes measured at 2 or
even 3 locations. This was done because the no-reflow areas
might likely be down-stream from the region of vessel spasm
NO
REFLOVV
and because of the possibility that vessels might be in spasm
segmentally as observed in rabbit basilar artery experimentally stretched.18 Segmental spasm in our experiment was
suggested by the observation that some vessels became
smaller and thicker in some sections only to be seen with
larger lumens and thinner walls in subsequent deeper sections.
The measurements of the non-ischemic control vessels
falling between no-reflow and reflow values might be explained by individual animal variation although the
possibility exists that the ischemic cat brains displayed an
FIGURE 2. Frozen section of control
cerebral cortex showing excellent preservation of meninges, parenchyma and vessels.
Arteries {A) have thick, darkly staining
walls while veins (V) are thin-walled, less
dense and uneven. ATP'ase. Original
magnification X 40
56
STROKE
VOL 9, No
1, JANUARY-FEBRUARY
1978
FIGURE 3. Artery in an area of spasm
showing a very small lumen and thick,
densely staining walls. A TP'ase. Original
magnification X 400
I
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overall vascular dilatation with superimposed focal spasm.
However, if that were true the hypoxic vessels might have
displayed vessel calibers more similar to the ischemic vessel
reflow areas than to the normal controls since it is known
that systemic hypoxemia and systemic hypercapnea produce
increased cerebral blood flow19'20 presumably due to
vascular dilatation, at least of the pial vessels. This underscores the lack of understanding of the relationships
between pial and parenchymal vessels. Harper 21 has
postulated that there is a reciprocal relationship between
pial and parenchymal vessels; when the pial vessels dilate,
the parenchymal vessels might constrict under certain circumstances and vice versa. It does not appear that overall
vasodilatation and focal vascular spasm in the same vessels
are mutually exclusive events either; focal spasm could conceivably be superimposed upon generalized cerebral and
meningeal vasodilatation. Although our 4 hypoxic control
cats showed no evidence of cerebral vasodilatation, they
were inadequate for that type of study. After repeated
hypoxia in the 4 control cats it became difficult to maintain
adequate cardiac output. This produced a mild hypotensive
ischemia superimposed upon the hypoxia, which probably
accounts for the 2 small no-reflow areas seen in 1 of those
brains.
The procedure of unroofing the skull might be expected
to cause spasm of meningeal vessels accounting for focal
no-reflow areas in the cortex; this did not likely occur in the
present experiment however, because we did not observe noreflow areas in the 8 control cats, (with one exception mentioned previously) all of which underwent the skull unroofing procedure exactly as the test animals.
Our data which show differences in regional measurements suggest that there may be normal regional variations
in vessel concentration, size and reactivity. By further defining size of reactive versus non-reactive vessels as well as
vessel concentration in future studies we might possibly be
able to predict those areas which would be prone to vascular
spasm. Preliminary counts have shown comparable numbers
of 70-300 fi diameter vessels per unit area in both the noreflow as well as the adjacent reflow areas. This finding
suggests that vessel spasm is random in regard to vessel density. The spasm could be caused by hypoxia in combination
with local accumulation of vasoactive metabolites, direct
stimulation of vascular smooth muscle by intraluminal
hematopoietic elements during stasis or by neurogenic
stimulus perhaps mediated by venous engorgement. Emerson and Parker22 have shown that increased cerebral venous
pressure in the dog results in a corresponding drop in
cerebral blood flow, presumably due to active vasoconstriction of precapillary vessels. Thus, it is not inconceivable that spasm might be initiated at the venous
level. These possibilities also need further study.
We used the 30 minute neck choke technique in these
animals because it produces definable no-reflow areas. An
additional group of 9 cats was kept alive for 2 days to 2
weeks following 30 minutes of neck choke without skull unroofing. The brains of these cats were interesting in that they
showed neuronal necrosis of hippocampal neurons and
Purkinje cells, both of which are presumed to be selectively
vulnerable to hypoxia. The cerebral cortices of these animals
showed random ischemic damage, in some areas the necrosis
appeared "pseudolaminar" while in other areas the necrosis
was in patches which encompassed several small arteries.
Many of the vessels in these patches of necrosis as well as the
vessels in the "pseudolaminar" areas of necrosis showed
reactive changes of endothelial proliferation. These observations support the conclusion that ischemic brain damage
entails very complicated mechanics and several mechanisms
might be operative. The technique of freezing and measuring
vessels should be applied to brains rendered ischemic by
means other than the choke method.
Acknowledgment
The authors wish to thank Mr. James C. Torner for statistical analysis.
VASCULAR SPASM IN CAT CORTEX AFTER ISCHEMIA/tfa/7 et al.
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Xenon Inhalation Method: Significance of
Indicator Maldistribution for Distinguishing
Brain Areas with Impaired Perfusion
An Index for Total Flow
URS W. BLAUENSTEIN, M.D.,
JAMES H. HALSEY, JR.,
M.D.,
EDWIN M. WILSON, D . S C , AND EDWARD L. WILLS, P H . D .
S U M M A R Y This paper introduces a new index for the assessment
of regional cerebral blood flow. The index is proportional to total
flow, and is obtained from the ratio of regional count rate to arterial
indicator input to a region. This index is a more sensitive indicator of
impaired perfusion than the traditional flow rate indices which ex-
press flow per unit mass of tissue per minute. It accounts for brain
tissue partly or totally deprived of its blood supply. Examples of
clinical application are reported.
A good correlation with the findings of computer-assisted
tomography has been found.
THE CLINICAL APPLICATION of the 133Xe inhalation
method for the assessment of regional cerebral blood flow
(rCBF) in cerebrovascular disease is still limited by
methodological difficulties.
In addressing the problem of indicator maldistribution in
ischemic brain regions1"6 — commonly referred to as "look
through" phenomenon or artifact3"6 — 86Kr has been cited as
a better alternative to 133Xe if the surface of the brain is
directly accessible. 4 ' 5 However, for non-invasive measurements of rCBF the converse appears to be true. The primary
characteristic emission of 85Kr is predominantly fi particle
(99.6% (3; 0.4% 7). Thus, measurements with 85Kr are either
limited to a depth of 2.5mm below the brain surface in the
open skull,6'7"9 or, when detecting the 7 emission through
the intact skull, require doses several times greater than with
133
Xe. For whichever 7 is detected, indicator maldistribution is equally possible whether using the inhalation
or the injection method.
The localization and quantitation of impaired indicator
delivery to brain regions partly or totally deprived of their
blood supply would clearly be of clinical diagnostic value.
They may be achieved by appropriate analysis of the indicator clearance curves which seem to contain the necessary
information about indicator maldistribution. A parameter
for total flow may offer a solution for this methodological
problem. Our preliminary experience with such a parameter
is reported here.
From the Stroke Research Center and Department of Neurology, University of Alabama Medical Center, Birmingham, AL 35294.
Supported in part by NINCDS Grants NS 08802 and NS 11109.
Dr. Blauenstein was supported in part by the Swiss Biologico-Medical
Scholarship Foundation.
Vascular spasm in cat cerebral cortex following ischemia.
M N Hart, M D Sokoll, L R Davies and E Henriquez
Stroke. 1978;9:52-57
doi: 10.1161/01.STR.9.1.52
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