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Bimodal treatment with nimodipine and low-molecular-weight dextran for focal cerebral ischemia in the rat.

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Bimodal Treatment with Nimodipine
and Low-Molecular-Weight Dextran for
Focal Cerebral Ischemia in the Rat
Antonio V. Salgado, MD," Stephen C. Jones, PhD,"t$ Anthony J. Furlan, MD," Ender Korfali, MD,"
Sam A. Marshall, BA,$ and John R. Little, MDS
We compared the effects of intravenous treatment with combined low-molecular-weight dextran and nimodipine (n =
9), or placebo (n = lo), on local cerebral blood flow after occlusion of the left middle cerebral and common carotid
artery in the rat: Treatment for a total of 4 hours with low-molecular-weight dextran ( 5 mg/kg/min) and nimodipine
(0.25 pglkglmin) produced a decrease in hematocrit from 46 -C 1 to 33 _t 1% at the end of the study and a statistically
significant increase in local cerebral blood flow, when compared to the control group, in 6 regions of interest: the
territories of the right middle ( p = 0.01), right anterior ( p = 0.007),and left anterior cerebral arteries ( p = 0.001); the
superior ( p = 0.03) and inferior border zone ( p = 0.003); and white matter in the right hemisphere ( p = 0.04).
The ischemic volume, defined as brain volume with a cerebral blood flow of less than the critical level of 25 d m i d 1 0 0
gm was determined as a percentage of total brain volume for the control and treatment groups. The group treated
with low-molecular-weight dextran and nimodipine showed a 31% decrease in ischemic volume ( p = 0.03). These
results indicate that a bimodal approach with low-molecular-weight dextran and nimodipine can be safely used in a
model of acute stroke and has a beneficial effect on local cerebral blood flow and ischemic volume when compared
with control subjects. After 4 hours, the potential exists that this treatment is therapeutic, assuming that the ischemic
volume progresses to infarction.
Salgado AV, Jones SC, Furlan AJ, Korfali E, Marshall SA, Little JR. Bimodal treatment with nimodipine
and low-molecular-weight dextran for focal cerebral ischemia in the rat. Ann Neurol 1989;26:621-627
Irreversible cerebral infarction is the final result of a
series of complex metabolic and hemodynamic events
111 that are dependent on decreased cerebral blood
flow (CBF) 127 and involve loss of calcium ion homeostasis 131. In ischemia, Ca2 extrusion deteriorates
when energy-dependent sequestering mechanisms are
no longer supported by CBF and when voltagesensitive and glutamate-activated Ca' channels open.
Most therapeutic interventions for acute focal cerebral ischemia have used single agents that act primarily
by increasing local CBF (1CBF) or by blocking the
metabolic processes involved in the ischemic cascade.
However, the lack of consistent beneficial effects in
anunal models and the f d u r e thus far to identify any
useful agent in controlled trials of human stroke suggest that the events leading to irreversible cerebral infarction are complex and may not lend themselves to
unimodal treatment strategies.
Prior studies have evaluated multimodal treatment
approaches in global 14-71 and multifocal [8} brain
From the "Departments of Neurology, +Brain and Vascular Research, and $Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH.
ischemia. In this study we tested the therapeutic effect
of isovolumic hemodilution with low-molecular-weight
dextran (LMWD) combined with nirnodipine in a rat
model of acute focal cerebral ischemia. The selection
of these agents was based on the hypothesis that
hemodilution with LMWD, which increases CBF in
normal cortex 191, not only would increase the blood
flow in the zone of marginal tissue viability that surrounds the core of ischemia but also would increase
the availability of nimodipine to the same area, allowing further vasodilator and protective metabolic effects, based on its properties as a Ca2+ channel blocker
{lo] and as a direct metabolic protector 1111.
Material and Methods
Animal Pveparution
A total of 19 animals (9 treated and 10 control)were studied.
In order to avoid possible anaphylactic reaction to LMWD,
12 gm
adult male Sprague Dawley rats weighing 307
(mean 5 SEM) were injected twice, 2 hours apart, with 1 ml
Address correspondence to Dr S. C. Jones, Department of Brain
and Vascular Research, FFZ-31, Research Institute, Cleveland Clinic
Foundation, 9500 Euclid Ave, Cleveland, OH 44 195-5070.
Received Jul 28, 1988, and in revised form Dec 16, 1988, and Mar
29, 1989. Accepted for publication Apr 1, 1989.
Copyright 0 1989 by the American Neurological Association 621
of LMWD intraperitoneally [ 12) the day before each experiment. The animals were fasted for 12 hours prior to surgery,
but had free access to water. O n the day of surgery, after
anesthesia was induced with 4% halothane, the animals were
mechanically ventilated with a mixture of 30% oxygen, 70%
nitrous oxide, and 0.5% halothane. Rectal temperature was
monitored and maintained at 37°C using a servocontrolled
heat lamp. The femoral vessels were cannulated to permit
constant determinations of mean arterial blood pressure
(MABP), blood sampling and exchange, and the administration of drugs and the radiopharmaceutical agent used to measure CBF.
Baseline total blood volume per body weight (TBV/BW)
was determined based on the dilution principle using Evans
blue 1131. Initial arterial oxygen tension (Paoz), arterial carbon dioxide tension ( P ~ c o ~pH,
) , arterial whole blood glucose concentration, and hematocrit were also obtained 30
minutes before occlusion.
After exposure of the calvarium, two electrocorticogram
screws were placed caudal to the bregma, and one in each
temporal region. The amplified bipolar electrocorticogram
signal was digitized for 30 seconds and analyzed using
Fourier transform frequency analysis with an electroencephalogram (EEG) analysis program (Rhythm by Stellate
Systems, Montreal, Canada). The total amplitude was o b
tained from 0.5 to 16 Hz.
The middle cerebral artery (MCA) was occluded from 2
mm proximal to the olfactory nerve to the inferior cerebral
vein according to a technique previously described 1141. In
addition, the ipsilateral common carotid artery was isolated,
coagulated, and transected. After surgery, halothane was decreased to 0.2% and the animal was paralyzed, with gallamine triethiodide (30 mglkg) supplemented as needed.
After MCA occlusion, Paoz, Pacoz, pH, arterial whole
blood glucose concentration, and hematocrit were obtained.
In an attempt to ensure uniformity of the ischemic insult, an
electrocorticogram was obtained for 30 seconds, 15 minutes
after occlusion of the MCA. Only anmals in which there was
at least a 50% reduction of the electrocorticogram amplitude
ipsilateral to the occlusion compared to the baseline electrocorticogram were selected for the study 1151.
33%. A group of 10 control animals received a 4-hour intraveous infusion of a mixture of nimodipine vehicle (0.0625
ml/kg/min) and saline solution (0.05 mYkg/min). Paoz,
Pac02, pH, arterial whole blood glucose concentration, and
hematocrit were measured every hour during the treatment
period. At the end of the infusion period a determination of
TBV/BW was repeated. Animals with MABP below 80 mm
Hg, or abnormal arterial blood gases or whole blood glucoses during the 4-hour treatment period were not included.
Measarement of Local Cerebral Blood Flow
and Ischemic Volume
After completion of the 4-hour infusion of drug, ICBF
was measured using the tissue equilibration technique [ 181.
During a 45-second period, 100 pCi/kg '*C-iodoantipyrine
mixed with 0.8 ml of saline solution was injected intravenously. Using 2 0 4 capillary pipettes, 10 to 15 timed arterial
blood samples were obtained during the 45-second time period. The animal was decapitated. The brain was carefully
removed and immediately frozen in chlorodifluoromethane
( - 44"C), and stored in a freezer at - 80°C. The brain was
subsequently sectioned at 20 pm in a cryostat ( - 12°C).
Every twentieth brain slice and 8 precalibrated methyl
methacrylate standards were exposed to x-ray film (Kodak
SB5) for 5 days. Blood samples were spotted on a filter
paper strip, numbered, and dried in preparation for liquid
scintillation counting.
Three autoradiographic sections from each animal were
selected for CBF analysis as shown in Figure 1: (1) a frontal
section caudal to the olfactory lobes, at the rostral pole of the
caudate-putamen, and rostral to the genu of the corpus callosum (bregma + 2.2 rnm); (2) a middle section at the rostral
end of the third ventricle, at the level of the anterior commissure, and rostral to appearance of the hippocampus
Left I Right
Drug Administration
Twenty minutes after occlusion of the MCA, 9 animals received a $-hour continuous intravenous infusion of LMWD
(10% Dextran 40, 5 mg/kg/min) in saline solution and
nimodipine (0.25 pglkglmin, 0.2 mg/ml) predissolved in a
mixture of 50% polyethylene glycol 400 and 50% ethanol
(Miles Laboratories, West Haven, CT), using Harvard model
901 (Harvard Apparatus, South Natick, MA) and Sage
model 355 (Sage Instruments, Cambridge, MA) infusion
pumps. Due to the known photosensitivity of nimodipine,
the infusion system was protected from light. In addition,
3 mVkg of whole blood was removed every hour and centrifuged. The plasma fraction was then reinjected intravenously. The dose of nimodipine was selected based on prior
reports showing a twofold increase in lCBF with a dose of
0.1 pg/kg/min 116}, while 1.0 pgkg/min produced a reduction in MABP 116, 171, possibly negating the beneficial effects of nimodipine. The dose of LMWD used in this study
was found to reduce the hematocrit to between 30% and
Pig I . Autoradiographicsections. Lorai cerebral bloodjow was
measured in 7 regions of interest selected fmm each of the three
sections (frontal, m i d i e , and posterior). NC = normal cortex,
ACA = idt and right anterior cerebral artery, BZS = border
zone superior, IC = ischemic cortex, BZI = border zone inferior, W M = white matter.
622 Annals of Neurology Vol 26 N o 5 November 1989
(bregma -0.3 mm); and (3) a posterior section where the
hippocampus first appears in the lateral position (bregma
-4.3 mm). These particular sections were selected to ensure
that the entire territory of the MCA would be included in
the ICBF analysis and to control for variation in section
For each of the three sections, ICBF was determined using
a quantitative image analysis system (191 in 7 regions of
interest (ROI), defined on anatomical and lCBF criteria: ( 1 )
the ischemic cortex with ICBF below 25 mVmid100 gm
1201;(2)the superior border zone, the cortical area anatomically located between the core of ischemia and the left anterior cerebral artery territory, with decreased ICBF when
compared to the contralateral cortex; (3) the inferior border
zone, the cortical area adjacent and inferior to the core of
ischemia, with decreased ICBF when compared to the contralateral cortex; (4)the cortex of the ipsilateral anterior cerebral artery territory; ( 5 ) the cortex of the contralateral anterior cerebral artery; (6)the normal cortex of the contralateral
MCA territory; and (7) the contralateral white matter. Border zone areas were chosen because the metabolic derangement caused by focal cerebral ischemia occurs nonuniformly
in the zone of ischemia, which has been divided into 3 distinct areas {21): a central zone that progresses to infarction, a
border zone or zone of ischemic penumbra with postulated
marginal tissue viability, and a collateral zone. The ICBF
values were averaged by ROI.
Ischemic volume was calculated using at least 8 equally
spaced autoradiograms 1221, from the most frontal section to
the level of the inferior colliculi. In each autoradiographic
section, both the total brain area and the ischemic area were
determined. The ischemic area was defined as the area with a
CBF under 25 mYmid100 gm, chosen to represent the criti-
cal level of ischemia under which brain tissue progresses to
infarction 120). The percentage of the total brain area with a
CBF under this critical level was calculated using the algorithm for the volume of a frustum of a cone. The presumption, based on the work of Tyson and colleagues [20),is that
this ischemic volume at 4 hours progresses to infarction and
is therefore representative of the neuropathological determined infarct volume 122).
Statistical Analysis
Repeated measures analysis of variance was performed to
assess the importance of differences due to treaunent, time
(or area), and treatment by time interactions. Both univariate
and multivariate models were used. When a significant interaction of treatment and time was found, specific linear
comparisons were made at each time point to determine
treatment differences. Statistical software was used to generate descriptive statistics (mean and SEM) and to perform all
statistical tests [23). A p value less than 0.05 was considered
significant and a value greater than 0.1, not significant (NS).
General Finding
There were no significant differences in Pao,, P a m z ,
pH, MABP, or arterial whole blood glucose concentration (Table 1) between groups throughout the 4hour study period. At the beginning of the study TBV/
BW was 9.01 L 0.16 mVlOO gm and 9.31 ? 0.20 mV
100 gm (NS) in the treatment and control groups,
respectively, and at 4 hours, 8.83 +- 0.26 d 1 0 0 gm
versus 8.88 2 0.14 mVlOO gm (NS). When compared
Table 1. Physiological Data"
1 hour
2 hours
3 hours
Treaunen t
4 hours
151 2 8
146 ? 6
7.50 2 0.02
7.48 ? 0.01
46 f 1
44 f 1
9.01 f 0.16
9.31 -t 0.20
7.44 ? 0.03
7.44 ? 0.01
44 f 1
44 ? 1
109 ? 6
112 f 3
91 f 8
85 t 5
139 f 5
131 k 6
123 f 9
113 f 4
37 f 1
45 t 1
97 f 11
83 2 9
7.45 & 0.01
7.44 f 0.02
114 f 7
109 2 3
33 f 1
44 f 1
117 c 12
82 ? 8
35.3 f 0.6
35.5 e 0.6
7.43 f 0.01
7.40 f 0.01
113 +- 7
106 2 3
31 f 1
43 f 1
8.83 f 0.26
8.88 2 0.14
128 f 19
81 f 8
34.2 f 1.0
35.1 t 0.6
* 0.01
'Values are mean 2 SEM.
PaCo, = arterial carbon dioxide tension, Pao, = arterial oxygen tension, MABP = mean arterial blood pressure, Hct
= total blood volume per body weight, glucose = arterial whole blood glucose concentration.
hematocrit, TBV/BW
Salgado et al: Bimodal Stroke Treatment
A 1
~ ~ 0 3 0 D1- 0 0 0 1
TIME (hrs)
Fig 2. Hematocrit values in the treatment and control groups,
during the 4-hour study period. The treatment group showed a
statistically signifcant reduction ofthe hemtocrit at 1 hour (p
= 0.002)which persisted until the end of the study period. NS
= not significant.
to the control group, the treatment group showed an
increase in whole blood glucose concentration. However, this difference was not statistically significant at
any time during the study period. The final whole
blood glucose concentration was 117 ? 12 mg/dl in
the treatment and 82 f 8 mgldl in the control group
(NS). The effect of treatment on the hematocrit is
shown in Figure 2. The reduction in hematocrit became statistically significant at 1 hour ( p = 0.002) and
remained so until the end of the study. The final hemoglobin value for the treatment group was 12.4 ?
0.4 g d d l , which was above the lower limit of normal
for rats (12.0 &dl) [24]. Electrocorticogram amplitude reduction on the left after occlusion of the MCA
was 62 f 2% and 64 -+ 2% in the treatment and
control groups, respectively.
Fig 3. Local cerebral bloodfEow (CBF) values for the 7 regions of
interest in the control and treatment groups. Local CBF was
significantly increased in all regions of interest surrounding the
core of ischemia. NC = right n o m l cortex, RACA = right
anterior cerebral artery, LACA = kji anterior cerebral artery,
BZS = lefi border zone superior, IC = lefi ischemic cortex, BZI
= lejit border zone inferior, W M = white matter, NS = not
Local Cerebral Blood Flow and Ischemic Voltlme
lCBF values in both groups are shown in Table 2. The
combined intravenous infusion of nimodipine and
LMWD produced a significant increase in lCBF in all
ROIs surrounding the core of ischemia, as well as in
the contralateral white matter, when compared to the
same areas in the control group (Fig 3). Among all the
regions studied, ICBF in the territory of the left anterior cerebral artery showed two distinct patterns in
both the control and the treatment group. In the control group 6 animals had lCBF below 180 ml/min/100
gm and a mean of 105 5 10 ml/min/100 gm, and 4
had ICBF above this value and a mean of 220 f 12 mY
mid100 gm ( p = 0.0001). Similarly, in the treatment
group 4 animals had ICBF below 346 mVmid100 gm
and a mean value of 223 k 38 ml/min/100 gm, and 6
animals had ICBF above this value and a mean value of
619 t 59 ml/rnin/lOOgm ( p = 0.001).
Ischemic volume was 6.90 t 0.65% in the control
group and 31% lower, 4.71
0.63%, in the treatment group ( p = 0.03) (Fig 4).
Table 2. Local Cerebral Blood Flow“
Region of Interest
461 ? 64
234 +: 40
443 ? 78
151 r 20
k SEM.
NC = normal cortex; RACA and LACA = nght and left anterior cerebral artery, respectively; BZS
cortex; BZI = border zone inferior; WM = white matter.
70 r 14
40 & 4
“mVmin/100 gm; mean
624 Annals of Neurology Vol 26 No 5 November 1989
border zone superior; IC = ischemic
8 -
7 6 5 4 -
3 2 1 0
Fig 4. Percentage of ischemic volume (* SEMI in the control
and tveatment groups. Ischemic volume was calcdated as the percentage of total brain volume with a cerebral bloodflow of less
than 25 mllminl100 gm, chosen as the critical level of ischemia
under wbicb brain tissue progresses to infarction 1201.. The
treatment group showed a statistically significant reduction in
ischemic volume (p = 0.03).
The present report shows that bimodal therapy with
LMWD and nimodipine can be safely used in a model
of focal cerebral ischemia, and that this combination
has a beneficial effect on ICBF and ischemic volume
when compared with a control group.
Although the mechanism by which ICBF is increased with low hematocrit remains controversial 125,
261, hernodilution produced by LMWD [9, 27,281 or
by other methods [29, 301 has been shown to increase
ICBF in most studies. Conversely, fibrinogen concentration and hematocrit, the primary determinant of viscosity, have been shown to correlate inversely with
lCBF in stroke patients 131). Hemodilution to a
hematocrit of approximately 35 using LMWD also has
the advantage of inhibiting erythrocyte aggregation
1321 and decreasing platelet adhesiveness 1331 without
changing oxygen delivery, as derived theoretically by
Hint [34]. Hemodilution with LMWD has been
shown to increase ICBF from 19% to 40% in the
cortical area surrounding focal ischemia in different
species, when compared to control values [27,28, 351.
Nimodipine is a calcium-entry bloclung agent with
preferential vasodilator action on cerebral vessels {lo].
In addition, since calcium influx plays a major role in
the ischemic cascade, it has been postulated that calcium antagonists might be useful in blocking the sequence of events that ultimately lead to cell death 1361.
In normal brain preparations, nimodipine has been
shown to increase ICBF 1171. In models of focal isch-
emia, nimodipine given 30 minutes before ischemia
attenuated the reduction in ICBF after occlusion of the
MCA in untreated control subjects 1371, but in our
laboratory no effect was found when the drug was
started 15 minutes before occlusion of the MCA 1381.
When given after ischemia, nimodipine failed to modify ICBF distribution in one study {39], but produced
an 80% increase in lCBF in another 140).
Besides the differences in species, several factors
have been postulated to explain these markedly different results on the effect of LMWD and nimodipine on
lCBF in focal cerebral ischemia, including the time the
infusion was started in relation to the induction of ischemia 139, 411, the duration of the infusion 1391, the
association of impaired autoregulation in the ischemic
models [42] combined with the lower MABP induced
by nimodipine 1171, the low level of local blood flow
with slow delivery of the agent to the area of ischemia
1391, the elevated plasma concentration of glucose
produced by nimodipine 1171, and a reduction of the
vasodilator response seen after occlusion of the MCA
This study showed that the combined use of nimodipine and LMWD produced a statistically significant increase in ICBF in all regions studied surrounding the
core of ischemia. The fact that two distinct groups of
lCBF were found in the territory of the left anterior
cerebral artery (i.e., outside the occlusive field of the
MCA) suggests that the area of hyperemia surrounding the area of ischemia can extend into other vascular
territories, and may be enhanced by this particular
The effectiveness of LMWD and nimodipine in reducing infarct size has not been established unequivocally. In one prior report, the severity of neurological
deficit and the size of hemispheric infarction in dogs
treated with LMWD prior to occlusion of the MCA
were reduced 1441. In another study, although hemispheric infarction tended to be larger among untreated
animals than among dogs receiving LMWD after occlusion of the MCA, the difference did not attain statistical significance [271. Finally, in a recent report, isovolumic hemodilution with LMWD in a reperfusion
stroke model in dogs was associated with a statistically
significant reduction in infarct size 1281. The effect of
nimodipine on infarct volume has been tested in both
preocclusion and postocclusion models. Pretreatment
with nimodipine reduced the volume and extent of
cellular damage in the periphery but not in the core of
the lesion [373. Two subsequent studies using postocclusion treatment showed different results. In one report, nimodipine did not produce any signhcant difference in the extent of ischemic damage or in overall
infarct volume among treated animals, when compared
with control animals 1391, while in another study, nimodipine decreased infarct size and produced smaller
Salgado et al: Bimodal Stroke Treatment
infarcts with earlier treatment [41).In a clinical trial of
nimodipine, in which LMWD was also administered to
both the treatment and the control group, an improvement in neurological status was noted 145).
The results of this study showed a significant reduction in ischemic volume, determined as percent of total
brain volume, of 31%, due to treatment with combined LMWD and nimodipine. If we make the presumption, based on the correlation of the critical level
of lCBF and neuropathologically defined infarction
documented by Tyson and colleagues 1201, that any
brain tissue with a ICBF less than 25 d m i d 1 0 0 gm
will eventually progress to infarction, this ischemic volume at 4 hours is predictive of infarct volume. With
the same reasoning, a therapeutic effect of bimodal
LMWD and nimodipine on infarct size could be supported.
The use of combined treatment with nimodipine
and LMWD in our study at the selected doses did not
produce any significant changes in MABP, as previously reported with nimodipine alone 116, 41). Nimodipine has been reported to produce hyperglycemia
1171. In our study the animals receiving LMWD and
nimodipine tended to have increased blood glucose
concentrations when compared with the control group,
although this difference did not attain statistical significance. The effect of hyperglycemia on outcome in focal cerebral ischemia is unclear and could possibly augment or reduce damage, depending on the level of
collateral circulation 1461. However, these effects occur at blood glucose concentrations greater than those
observed in our animals, so would not affect the results
of this study, or counteract the beneficial effect of nimodipine [17).
The effect of Ca2+ channel blockers on the series of
metabolic events that ultimately lead to irreversible
cell death is controversial. In one report, nimodipine
given after occlusion of the MCA in the baboon enhanced the entry of calcium into the brain cell when
compared to control animals 147). Evidence for a direct protective metabolic effect of Ca2+ channel blockers was suggested in subsequent reports I l l , 48). It
is possible that the simultaneous administration of
LMWD increases the brain availability of nimodipine,
allowing for an increased protective effect on the ischemic cascade. However, additional studies are required
to document this mechanism.
This investigation was supported in part by US Public Health Service grant NS 24343 and American Heart Association grant
The authors wish to express their thanks to Mary Shea, Datong Wei,
and Alejandro Perez-Trepichio for their technical expertise, to Kirk
Easley for his statistical assistance, and to Dr A. Scriabine for providing premixed nimodipine and vehicle solutions.
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treatment, molecular, ischemia, nimodipine, low, focal, weight, rat, bimodal, dextran, cerebral
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