Journal of Cerebral Blood Flow and Metabolism
8:149-154 © 1988 Raven Press, Ltd., New York
Differences in Mortality Rate between Abrupt and
Progressive Carotid Ligation in the Gerbil: Role of
Endogenous Angiotensin II
Christine Kaliszewski, Leonardo A. Fernandez, and J. D. Wicke
Department of Surgery (Neurosurgery), Yale University School of Medicine, New Haven, and The Clinipad
Corporation Research Laboratories, Guilford, Connecticut, U.S.A.
Summary: Studies have shown that in comparison to
rapid occlusion of a vessel, gradual occlusion produces
less severe tissue ischemia due to a more effective devel­
opment of collateral circulation. As other studies have
shown that collateral circulation can be enhanced by
stimulation of the endogenous renin-angiotensin II
system, it was hypothesized that this system is involved
in the mechanism of protection against ischemia that ob­
tains during gradual vascular occlusion. To test this hy­
pothesis, mortality rates were evaluated in gerbils sub­
jected to gradual vascular occlusion by means of progres­
sive carotid ligation while simultaneously infused with
inhibitors of the renin-angiotensin II cascade-enala­
prilat or saralasin. Groups of animals with either abrupt
or progressive carotid ligation infused with saline served
as controls. Results showed that (1) in saline-infused an-
Gradual occlusion of a vessel results in a less de­
leterious effect on the tissue elements of the distal
territory in comparison to an abrupt occlusion. This
difference is due to the presence of adaptive mech­
anisms that require time to be engaged and cannot
be properly utilized when the occlusion is made
quickly. As a result of these adaptive mechanisms,
a more effective development of collateral circula­
tion occurs that reduces the severity of tissue isch­
emia. This effect can be seen not only in the arterial
side of circulation, such as cerebral or coronary ar­
teries (Svarzbein et aI. , 1974; Tomoike et aI., 1981;
Bache and Schwartz, 1983; Patterson et aI. , 1983),
but also in the venous side such as the portal vein
Received September 30, 1986; accepted October 21, 1987.
Address correspondence and reprint requests to Dr. Leonardo
A. Fernandez, at Section of Neurosurgery, Yale University
School of Medicine, 333 Cedar Street, New Haven, CT 06510,
U.S.A.
149
imals, there was a significant decrease in the mortality
rate of progressive-ligated animals when compared to
abrupt-ligated animals, and (2) administration of either
enalaprilat or saralasin to progressive-ligated animals re­
sulted in mortality rates that were indistinguishable from
those of saline-infused abrupt-ligated animals. These re­
sults suggest that the endogenous renin-angiotensin
system is indeed involved in an adaptive mechanism that
occurs during progressive ligation of the carotid artery,
and more specifically, that the relatively benign effect of
progressive carotid ligation may be due to the action of
angiotensin II to stimulate the development of collateral
circulation and reduce the severity of focal brain isch­
emia. Key Words: Angiotensin II-Blood pressure-Ce­
rebral ischemia-Collateral circulation-Enalaprilat­
Gerbillinae -Saralasin.
(Groszmann R, personal communication). Svarz­
bein et aI. (1974) reported that in the gerbil, there
was a substantial difference not only in the clinical
outcome, but also in the extent of change in brain
microcirculation that occurred between abrupt and
progressive ligation of the carotid artery. Progres­
sive carotid ligation would permit putative compen­
satory mechanisms to act more efficiently to main­
tain blood supply to the distal parts of the brain,
maintaining the viability of the sensitive cellular el­
ements and, therefore, lowering morbidity and
mortality. In the search for components of such a
compensatory mechanism, evidence suggests that
the renin-angiotensin system may play a signifi­
cant role (Fernandez et aI. , 1982).
When blood supply to the kidney is reduced after
a vascular obstruction, circulating levels of renin
and angiotensin II increase due to the stimulation of
renin release and the cascade to angiotensin II
(Peach, 1977). This increase in renin release acts,
150 C. KALISZEWSKI ET AL.
among other effects and independently of the levels
of blood pressure, to protect against ischemia of a
vascular territory by stimulating the development
of collateral circulation. Similar effects are seen
when the endogenous source of renin is removed
after the administration of exogenous angiotensin II
(Fernandez et aI., 1982). Recent data suggest that
infused angiotensin II serves a similar function in
protecting against brain ischemia. In gerbils with
focal cerebral ischemia due to an abrupt unilateral
carotid artery ligation, the administration of this
octapeptide produced a significant dose-dependent
decrease in mortality rate by restoring blood supply
to the ischemic part of the brain, which was not re­
lated to the pressor effect of this compound (Fer­
nandez et aI., 1986).
Compelling evidence indicates that endogenous
renin and a complete renin-angiotensin system
exist in a wide variety of locations, including the
brain (Deboben et aI., 1983; Ganong, 1984). The
brain renin-angiotensin system may have a func­
tion similar to that seen in the kidney, namely, pro­
tection against ischemia by facilitation of the devel­
opment of collateral circulation when blood flow
through a supply artery is impaired. If the renin­
angiotensin system plays a role in this compensa­
tory mechanism, then inhibition of this system
under conditions of progressive carotid occlusion
should minimize its beneficial effects and result in
more severe neurological deficits and an increased
mortality rate. To test this hypothesis, abrupt or
progressive unilateral carotid ligations were per­
formed in gerbils, and either an angiotensin-con­
verting enzyme inhibitor or an angiotensin II
blocker was infused during the period of gradual
occlusion. The results of these experiments show
that (1) progressive carotid ligation produced a sig­
nificantly lower mortality rate than abrupt ligation,
and (2) the mortality rate of progressively ligated
animals when the renin-angiotensin system was in­
hibited was raised to that of abruptly ligated an­
imals.
MATERIALS AND METHODS
Adult male gerbils (Meriones unguiculatus; Tumble­
brook Farm, Inc., West Brookfield, MA, U.S.A.),
weighing between 68 and 94 g, were used. They were
kept in controlled-temperature rooms at 24°C, with pe­
riods of light and darkness of 12 h each. The animals
were fed rat chow (Ralston Purina, St. Louis, MO,
U.S.A.) and tap water ad libitum. Surgical procedures
were performed under sodium pentobarbital anesthesia
(60 mg/kg of body weight, i.p.) using clean, but not
sterile, technique. Animals were placed in the supine po­
sition, the neck region was cleaned with ethanol 95%,
and a midline incision was made exposing the superficial
J Cereb Blood Flow Metab, Vol. 8, No.2, 1988
left jugular vein and right carotid artery. A polyethylene
cannula, primed with the solution to be systemically in­
fused, was placed in the jugular vein.
Unilateral carotid ligations were performed using two
different methods: abrupt and progressive. For abrupt li­
gations, the right carotid artery was tied with a 4-0 silk
thread after a 0.2-ml bolus of saline solution was adminis­
tered i.v., and infusion of saline solution was started im­
mediately thereafter by means of syringe driven by an
infusion pump (Harvard Apparatus, Millis, MA, U.S.A.).
For progressive ligations, the right carotid artery was se­
quentially constricted at 2-h intervals to 0.23, 0.13, and
0.0 mm. This was done by applying aneurysm clips main­
tained at the desired opening by interposing a wire of the
proper diameter between the jaws of the clip. Immedi­
ately before a clip with the opening of 0.23 mm was ap­
plied to the right carotid artery, a bolus injection of the
drug to be infused was given i.v. in a volume of 0.2 ml.
The infusion was started immediatly thereafter by con­
necting the jugular vein cannula to the infusion device.
Two hours later, the clip was changed for one with an
opening of 0.13 mm for an additional 2 h, at ""hich time, a
complete carotid ligation was performed with a 4-0 silk
thread. Care was taken to not to release the carotid ste­
nosis already obtained during the change of clips.
The degree of progressive vessel ligation obtained
under each condition was determined as follows: First, a
dissecting microscope and measuring reticle was used to
determine in vivo the resting-state external diameter of
the right carotid artery in nine animals (mean ± SEM,
0.55 ± 0.01 mm), the thickness of the freshly-cut vessel
wall (0.05 ± 0.003 mm), and by calculation, the lumen
area of the resting-state vessel (0.16 mm2). Next, by trig­
onometry, the lumen area under progressive ligation was
calculated, assuming that the thickness of the vessel re­
mained constant. For the 0.23-mm clip, lumen area was
0.077 mm2; for the 0.13 mm clip, the lumen area was
0.025 mm2; and for total ligation, the lumen area was 0.00
mm2• These yield lumen areas of 48%, 16%, and 0%, re­
spectively, of the resting-state vessel.
Sham carotid ligations were also performed to deter­
mine if the drugs alone had any effect on survival. These
ligations were performed by gently manipulating the right
carotid artery immediately before, 2 h into, and at the end
of the 4-h infusion period.
All infusions were maintained for 4 h at a rate of 0.135
mllh, during which time the wound was covered with
gauze moistened with saline. A mandatory single supple­
mentary dose of anesthesia (15 mg/kg, i.p.) was given to
each animal at 3 h after the beginning of the infusion pe­
riod or, if required, before this time. As the same regimen
of anesthesia was given to all animals, any protective ef­
fects possibly attributable to barbiturates would be iden­
tical in each group (Corkill et aI., 1978; Lawner et aI.,
1979). At the end of the 4-h infusion period, the venous
cannula was removed, the jugular vein was tied, the skin
was closed, and the animals were returned to their cages
to recuperate from the anesthesia. Mortality was evalu­
ated at 24 and 48 h after carotid ligation. Differences in
mortality rates between groups were analyzed using the
log-rank test (Peto et aI., 1977).
Six groups of animals were studied: (1) Abrupt-saline:
25 animals with abrupt carotid ligation infused with sa­
line. (2) Progressive-saline: 50 animals with progressive
carotid ligation infused with saline. (3) Progressive-enala­
prilat: 25 animals with progressive carotid ligation in-
 ANGIOTENSIN II IN BRAIN ISCHEMIA 15 1

fused with the angiotensin-converting enzyme inhibitor of 6% and 20%, whereas abrupt unilateral carotid
enalaprilat {N-[(S)-I-carboxy-3-phenylpropyll-L-Ala-L­ ligation produced mortality rates of 28% and 48% at
Pro; Merck Institute for T herapeutic Reasearch, West
24 and 48 h, respectively, when animals were in­
Point, PA, U.S.A.} After a bolus injection of 22 J.1g/kg, an
infusion dose of 1 J.1g/kg/min was given, as calculated fused with saline (the log-rank test yielded X2 =

from the work of Gross et al. (1981). (4) Progressive-sara­ 6. 15, df= 1, P < 0. 025). When animals were in­
lasin: 25 animals with progressive carotid ligation infused fused with inhibitors of the renin-angiotensin
with the angiotensin II blocker saralasin (SarI, Alas, an­ system, the angiotensin-converting enzyme inhib­
giotensin II; Norwich-Eaton Pharmaceuticals, Norwich,
itor enalaprilat, or the angiotensin II blocker sara­
NY, U.S.A.). After a bolus injection of 180 J.1g/kg, an in­
fusion dose of 10 J.1g/kg/min was given after the work of lasin, progressive carotid ligation resulted in cumu­
Pals et al. (1971) and Riegger et al. (1977). (5) Ten gerbils lative mortality rates that were markedly increased
with sham-operated carotid artery ligation given a bolus to levels indistinguishable from those of the abrupt­
injection and infused with enalaprilat, in a manner iden­ saline groups. The log-rank test indicated a signifi­
tical to group 3. (6) Ten animals with sham-operated ca­
cant difference in survival across all four groups
rotid artery ligation given a bolus injection and infused
with saralasin, in a manner identical to group 4. (X2 = 11. 0, df= 3, P < 0. 025).
All the drugs were dissolved in NaCl solution (0.9% It was initially hypothesized that infusion of ena­
wt/vol). T he number of animals in the progressive-saline laprilat or saralasin would counteract the more be­
group was increased over the numbers of animals in the nign effect of progressive ligation and cause the
other non-sham groups because the mortality rate in this
mortality rates for these two groups to approach
group was expected to be relatively low (Svarzbein et aI.,
1974). that of the abrupt-saline group. To test this hy­
In a separate series of experiments, the effect of the pothesis, the results of these three groups were sep­
infused substances on blood pressure was measured in arately compared. The log-rank test indicated no
gerbils subjected to abrupt carotid ligation. An additional detectable difference in mortality rates among
femoral catheter allowed measurement of mean blood
abrupt-saline, progressive-enalaprilat, and progres­
pressure via an external transducer (Statham 23dc;
Statham Gould, Hato Rey, Puerto Rico, U.S.A.) and sive-saralasin groups (X2 0. 55, df
= 2, P > 0. 1),
=

polygraph (Grass Instruments, Quincy, MA, U.S.A.), as suggesting that the action of these drugs was as ex­
previously described (Fernandez et aI., 1986). At the end pected. Even though the mechanism of action of
of the recording period, these animals were killed. the drug and ligation procedure in each experi­
mental condition was different, each shared the
RESULTS
common purpose of minimizing the effectiveness of
Neither neurological deficits nor deaths were ob­ the renin-angiotensin system, either by not al­
served in the sham-operated carotid ligated groups lowing sufficient time for the system to play a role
treated with enalaprilat or saralasin. Mortality rates (abrupt-saline group) or by actively blocking the
for the other groups are summarized in Fig. 1. As system (progressive-enalaprilat and progressive­
previously reported (Kahn, 1972; Berry et ai., saralasin groups). Therefore, for the final analysis,
1975), death was always preceded by behaviorally­ mortality rates in these three groups were com­
manifested neurological deficits of varying de­ bined into a single large group with n 75 and
=

grees. Progressive unilateral carotid ligation over a were compared to that of the progressive-saline
period of 4 h produced cumulative mortality rates group. The log-rank test indicated that the differ-

60

•/INFUSION /. PROGRESSIVE + ENALAPRILAT (N=251

= / " PROGRESSIVE+SARALASIN (N=25)

50 / ABRUPT+SALINE (N=2S1
//'/
/.,
40
// FIG. 1. Cumulative mortality rates in groups of
� v/ gerbils with abrupt or progressive carotid liga­
OJ /./
!;t 30 ,'/ tion after a 4-h infusion of saline, enalaprilat, or
n::
/,;; saralasin. The log-rank test indicated a signifi­
>- �
�
·i + cant difference across all four groups (X2
20 ... PROGRESSIVE SALINE (N = 50)
-' /'
<t /' 11.0, df = 3, P < 0.025).
....
n:: .4- ,/'
0 10 ;l ,/'
"
�
�
�
��

02 4 24 48

TIM E IN HOURS

J Cereb Blood Flow Metab, Vol. 8, No.2, 1988

152 C. KALISZEWSKI ET AL.

ences between these two groups was significant (X2
= 10. 69, df 1, p < 0. 005).
= to a particular anatomical configuration of the vas­
Blood pressure results are summarized in Fig. 2.
A bolus injection of enalaprilat produced no
change, but with time, continuous infusion resulted
in a slight decrease in mean arterial pressure. In
contrast, a bolus injection of saralasin produced a
sharp rise in mean blood pressure due to the partial
agonistic effect of the compound (Pals et al. , 1971;
Riegger et aI. , 1977), which rapidly declined and
stabilized during infusion to a level slightly higher
than the preinjection level. Although the changes in
blood pressure during infusion were in opposite di­
rections for enalaprilat and saralasin, mortality
rates for ligated animals given the two drugs were
not different, giving support to an earlier suggestion
that mortality rates do not seem to be related to
blood pressure levels (Fernandez et al., 1986).
DISCUSSION
The gerbil has been proven to be a useful experi­
mental animal for studies of cerebral ischemia
Kahn, 1972; Berry et al. , 1975; Ohno et aI. , 1984;
for a long list of references, see Robinson, 1985). It
has been established that a high percentage of
gerbils develop focal brain ischemia leading to
stroke and eventual death following a simple abrupt
unilateral carotid ligation (Kahn, 1972). This is due
cular supply to the brain (Kahn, 1972; Berry et al. ,
1975). In susceptible animals, immediately after
abrupt unilateral carotid ligation, there is a signifi­
cant and persistent reduction of flow in the ipsilat­
eral hemisphere that leads, after a certain period of
time, to enzymatic, chemical, and morphological
changes as a result of tissue ischemia (Berry et al. ,
1975; Ito et aI. , 1975; Mrsulja et al. , 1979, Crockard
et aI. , 1980). These changes correlated with the ap­
pearance of behavioral manifestations of progres­
sive neurological deficits of varying degrees,
ranging from head cocking to coma, and eventually
leading to death (Berry et aI. , 1975; Ohno et aI. ,
1984).
The results of the present experiments confirm
the previous findings of Svarzbein et al. (1974) that
survival was markedly enhanced in the gerbil if uni­
lateral carotid occlusion took place gradually over a
period of 4 h, rather than being abruptly performed.
These congruent observations imply the presence
of adaptive mechanisms that are engaged only grad­
ually and that act more efficiently when blood flow
through the carotid artery is progressively rather
than abruptly brought to a halt. Using direct micro­
scopic observation, Svarzbein et al. (1974) noted
that abrupt unilateral carotid ligation produced a

140

130

� 120
e
e

ILl no
§
� FIG. 2. Effect of saline, enalaprilat, or
IE 100 saralasin on mean blood pressure before,

�
during, and after infusion in groups of
gerbils with abrupt unilateral carotid liga­
90 tion. Data shown are means ± SEM.

�
2
Z 80 II
I
I
70

"
60 ENALAPRILAT IN ••)
��I �__�____�I ____�__��__-L__�I
____ ____

PRE- 0 10 20 30 !50 60 70 POST-

INFUSION INFUSION
TIME (minutll'

J Cereb Blood Flow Metab. Vol. 8, No.2. 1988

 ANGIOTENSIN II IN BRAIN ISCHEMIA
narrowing of the caliber of pial vessels and a
slowing and eventual cessation of blood flow,
which resulted in cortical pallor. In contrast, no
changes were observed in pial vessels during and
after a 4-h period of progressive ligation. It appears
that gradual ligation of the carotid artery over a pe­
riod of time as short as 4 h is of sufficient duration
to produce sustained activation of mechanisms that
protect against brain ischemia. The observations of
Svarzbein et ai. (1974) indicate that this protection
is achieved by maintaining blood flow into territory
normally irrigated by the vessel, even after com­
plete ligation.
The present data also point to the involvement of
the renin-angiotensin system in the adaptive mech­
anism for maintaining blood flow to ischemic brain
areas. Blocking the renin-angiotensin system
during progressive carotid ligation appears to in­
hibit this adaptive mechanism, as evidenced by an
increase in mortality rate to levels not different
from those seen after abrupt carotid ligation. The
exact mechanism of involvement of the renin-an­
giotensin cascade, however, is not yet known. Nei­
ther renin nor angiotensin I alone appears to be the
active agent. The results obtained with enalaprilat,
which inhibits the angiotensin-converting enzyme,
thus preventing the transformation of angiotensin I
to angiotensin II (Peach, 1977), and with the angio­
tensin II blocker saralasin, point to angiotensin II
as being the compound critical in the adaptive pro­
cess during progressive carotid ligation.
The means by which angiotensin II accomplishes
this protective effect remains to be determined. It
has been reported that angiotensin II stimulates the
formation of new vessels both in vivo and in vitro
(Fernandez et aI., 1985; King et aI., 1986). How­
ever, the duration of infusion and the time of evalu­
ation in the present experiments (4 h and up to 2
days, respectively) is rather short for neovascular­
ization. As it was previously discussed, it seems
more likely that the protection is the result of a spe­
cific action of angiotensin II to rapidly activate
preexisting, hitherto "in reserve" collateral
pathways (Fernandez et aI., 1982, 1986).
Extrarenal renin, or isorenin, is an ubiquitous
substance that has been found in many organs (De­
boben et aI., 1983). Intrinsic renin in the brain was
identified almost simultaneously by Fisher-Ferraro
et ai. (1971) and by Ganten et ai. (1971), and a com­
plete renin-angiotensin system, including the pres­
ence of renin substrate, angiotensin I, angiotensin­
converting enzyme, and angiotensin II, has been
demonstrated in this organ (Printz and Gregory,
1981; Ganong, 1984). Different actions have been
attributed to the presence of angiotensin II in the
153
brain, including neurotransmission, increase in per­
meability, blood flow regulation, modulation of
blood pressure, dipsogenesis, secretion of antidi­
uretic hormone, and catecholamine release
(Ganong, 1984; Phillips, 1987). Taking into consid­
eration results from preceding and present experi­
ments, it may well be that the brain angiotensin II is
also involved in maintaining an acceptable provi­
sion of blood in the central nervous system to pre­
vent the development of ischemia. It is possible
that in clinical situations, such as chronic cerebral
ischemia due to progressive stenosis of the internal
carotid arteries or the circle of Willis (Moyamoya
disease), the endogenous brain angiogenic factor
recently postulated by Matsushima and Inaba
(1986) may actually be angiotensin II.
Although the hypothesis that the brain renin-an­
giotensin system is involved in protection against
ischemia is appealing, it is not known for certain
whether brain or blood-borne angiotensin II is re­
sponsible for this effect. In the present experi­
mental conditions, inhibitors of the renin-angio­
tensin system were administered systemically, and
the presence of the blood-brain barrier may limit
the movements of these compounds into the brain.
However, this barrier is known to be disrupted
under conditions of ischemia (Ito et aI., 1976; Ra­
poport, 1976; Chui et aI., 1981), and thus, the
overall permeability could be increased not only to
circulating angiotensin II, but also to the infused
compounds (Robertson and Khairallah, 1972).
Even if the barrier is not disrupted, these com­
pounds could be acting on brain structures located
outside the blood-brain barrier (Ganong, 1984) or,
most likely, the vessels themselves. In this regard,
it is of importance that angiotensin II receptors
have been identified in the cerebral microvessels
(Speth and Harik, 1985), but the exact anatomical
location of these receptors is not yet known. As
Speth and Harik pointed out, it will be interesting
to know whether these receptors are located to­
ward the lumen or toward the antiluminal aspect of
the brain microvessels. The physical location could
indicate whether blood-borne angiotensin II or the
intrinsic-to-the-brain angiotensin II is involved in
the present proposed mechanism.
The evidence presented here suggests that the
protective mechanism that improved survival
during progressive artery ligation is related to the
endogenous renin-angiotensin sy stem. This
system, through the formation and action of angio­
tensin II, acting most likely on cerebral micro­
vessels, maintains blood supply within levels nec­
essary to preserve metabolism, structure, and func­
tion of the cellular elements of the brain. This effect
J Cereb Blood Flow Metab, Vol. 8, No.2, 1988
154 C. KALISZEWSKI ET AL.
appears to be due to an efficient development of
collateral circulation to the region of the brain nor­
mally serviced by the gradually occluded vessel.
Acknowledgment: This work was supported by the
Gilchrist Foundation. The authors gratefully acknowl­
edge Dr. Kurt Stenn, Shirley Tirrell, and Dr. Kenneth
Taylor for their encouragement and assistance. The au­
thors also thank Dr. Charles S. Sweet from Merck Insti­
tute for Therapeutic Research and Dr. Frank F. Ebetino
from Norwich-Eaton Pharmaceuticals for their generous
gifts of enalaprilat and saralasin.
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