Experimental Study on the Genesis of
Cerebral Vasospasm
BY RICHARD P. WHITE, PH.D., A. AINSWORTH HAGEN, PH.D., HOWARD MORGAN, M.D.,
WILLIAM N. DAWSON, M.D., AND JAMES T. ROBERTSON, M.D.
Abstract:
Experimental
Study on
the Genesis of
Cerebral
Vasospasm
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• The cerebral vasospasm produced by blood, fractions of blood, and blood-borne agents administered intracisternally was studied arteriographically to attain a better understanding of the
genesis of vasospasm. The results indicate this phenomenon is multifarious in origin, involving a
number of spasmogens. Whole blood, platelets, platelet extracts, some isolated components of
platelets, plasma, thrombin, histamine, serotonin and prostaglandins Fi o , E2 and F 2a produced a
significant incidence and duration of spasm. Norepinephrine and prostaglandin Ei were inactive. Spasm produced by arachidonic acid and red blood cells was of questionable significance.
Compared to whole blood, thrombin usually produced spasm which was more delayed in
onset while most other active substances produced a shorter-lived spasm. However, among the
pure substances tested, serotonin, prostaglandin E2 and prostaglandin F2o induced spasm in
small doses which most nearly resembled that observed with whole blood.
The hypothesis that the course of spasm depends upon synthesis of spasmogens by brain
and blood is advanced. Prostaglandin synthesis plays a major role in this concept.
Additional Key Words
Introduction
• In attempts to study experimentally mechanisms
involved in the cerebral vasospasm which follows intracranial bleeding in humans, many investigators
have given blood intracisternally to animals and noted
the presence of vasospasm by arteriography. Others
have applied blood topically to exposed cerebral
vessels and recorded vascular changes photographically. Reports agree that blood can produce
cerebral vasospasm in a wide variety of species.
However, there is diverse opinion as to what specific
factor(s) in blood might be primarily responsible for
the spasmogenic phenomenon. In most studies the
range of substances examined were so select that the
inferences drawn have excluded large numbers of
possible agents and mechanisms which may be involved in vasospasm. An exception to this has been the
report of Kapp et al.1 (1968) who tested experimentally a wide variety of blood components and bloodborne agents suspected of causing vasospasm. Their
results clearly showed that a number of factors in
blood, especially platelets, are spasmogenic when
washed topically onto an exposed basilar artery in
cats.
The present study was performed to ascertain
whether substances found to be spasmogenic by Kapp
From the Departments of Neurosurgery and Pharmacology,
University of Tennessee Medical Units, 800 Madison Avenue,
Memphis, Tennessee 38163.
This study was supported in part by grant USPHS GR
NS06826.
52
platelets
prostaglandins
spasmogens
et al.1 in cats might apply to another species when introduced into the cisterna magna, where the milieu
more nearly resembles the clinical setting. Moreover,
additional substances were tested for spasmogenicity.
Methods
Mongrel dogs of both sexes, weighing from 14 to 29 kg, were
anesthetized with pentobarbital sodium (30 mg per
kilogram) given intravenously and maintained with
supplemental amounts. Tracheostomy was routine. The
right vertebral artery was cannulated at the base of the neck
in order to obtain arteriograms of the basilar artery by injecting rapidly 5 ml of Hypaque 60% (meglumine
diatrizoate). The experimental substances were administered
into the cisterna magna as follows. With the animal on its
side the cisterna magna was tapped with an 18-gauge spinal
needle atraumatically (confirmed by cell count of the
cerebrospinal fluid and at autopsy). In experiments in which
plasma or blood was given, 2 ml of cerebrospinal fluid was
collected and discarded prior to injection. In others, the substance tested was mixed in the cerebrospinal fluid (CSF) and
the mixture injected into the cisterna magna. Harvested
platelets, however, were given in 0.9% saline (volume 2 ml)
to avoid aggregation by calcium in CSF. The animal was
then placed on its back for the remainder of the experiment
in all cases except those given blood. The latter were placed
on their ventral surface with the head tilted 15° lower for ten
minutes to enhance contact of blood around the basilar
artery as suggested by other investigators. 2 ' 3
Arteriograms were obtained with the x-ray unit at a
fixed distance from the head, prior to and usually at 5, 15, 30
and 60 minutes after the injection of the experimental substance and hourly thereafter for at least three hours. Control
procedures consisted of the collection and injection of CSF
alone, the injection of CSF containing substances such as
Stroke, Vol. 6, January-February 1975
EXPERIMENTAL STUDY O N THE GENESIS OF CEREBRAL VASOSPASM
Pike, Upjohn Pharmaceutical Co.). All doses were computed as the active base. The tromethamine salt of F 2a is
water soluble; the remaining prostaglandins were dissolved
in 95% ethanol (5,000 Mg per milliliter) with the maximum
volume added to 2 ml of CSF being 0.05 ml. This vehicle of
ethanol was inactive. A 20 mg per kilogram dose of indomethacin was dissolved in 10 ml of 0.1 M phosphate
buffer (pH 8.0) and infused intravenously at a rate of 1 ml
per minute. This dose should be more than sufficient to inhibit significantly the synthesis of prostaglandins by platelets
and other peripheral tissue.5 It did not change respiratory
rate, ECG, or blood pressure at any time during or after the
infusion. Similarly, blood gases, pH and platelet count taken
at 20 and 40 minutes from the start of the infusion were not
altered. One hour after indomethacin, 4 ml of blood from
one femoral artery was removed and injected into the cisterna magna.
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heparin used in the fraction of blood, and CSF containing
the vehicle for some of the drugs administered (details of
which will be given in Results). Systemic blood pressure
(femoral), heart rate, ECG, and respiratory rate were
monitored routinely; blood gases, platelet count, and pH
values were obtained in some animals (presented in Results).
The degree of spasm of the basilar artery in a given experiment was independently assessed by at least two of the
authors, quantified by using a standard comparator (Edmund Scientific Co., Barrington, New Jersey) and with a
surgical microscope.
Platelets were obtained from heparinized blood (5 units
per milliliter of blood) or blood treated with K2
ethylenediaminetetraacetic acid (EDTA): final concentration 1% in blood. This blood was centrifuged for 15 minutes
at 600 RPM after which the plasma containing most of the
platelets was removed. The plasma was then centrifuged at
3,000 RPM for 15 minutes to collect the platelets, the
plasma supernatant being removed. This supernatant was
used in some experiments. The platelets were suspended in 2
ml of saline for injection or after boiling used to make
aqueous extracts as described by Kapp et al.4 Further isolation of spasmogenic substance from platelets was accomplished on Sephadex G-10 and G-25 columns. The substance was proved to be free of serotonin, using
serotonin 4- u C as an indicator of retention time on the
column. In seven experiments, 2 ml of red blood cells were
obtained by centrifugation and suspended in isotonic saline
prior to injection into the cisterna magna.
The commercial chemicals tested for spasmogenicity
were arachidonic acid, norepinephrine bitartrate, histamine
dihydrochloride, serotonin creatinine sulfate (Nutritional
Biochemicals Corporation), thrombin (Upjohn and ParkeDavis Companies: 1,000 NIH units/vial) and prostaglandins
Ei, E2, F l a , F 2a , and F 2a tromethamine (courtesy Dr. John
Results
Table 1 compares results obtained with blood and
various fractions of blood. As shown, all of the major
components of blood tested produced spasm in some
animals. However, the incidence and duration of
spasm obtained with red blood cells were extremely
low, suggesting that a contaminant from the extraction procedure might be responsible. Compared to
whole blood, platelets and platelet extracts produced
an early short-lived (less than 60 minutes) spasm,
whereas thrombin induced spasm that usually
appeared later but persisted throughout the observation period. It is also obvious that (1) none of the
agents studied, including blood, always produced
spasm and (2) in some animals recovery occurred
TABLE 1
Incidence of Cerebral Vasospasm Induced by Blood and Blood Components Injected into the Cisterna Magna in Dogs
Agent
Plateletsf
Platelets!
Platelets!
+ plasma§
Plasma§
Platelet extractf
Platelet extract!
Platelet Sephadex
RBC**
Thrombin
1,000 u
100 u
Blood, 4 ml
Blood, 2 ml
Incidence of spasm by serial arterlogrami (nninutes)
Spasm
perN
s
.15
30
60
120
5/6
4/4
5/7
3
4
3
4
2
3
2
2
3
0
0
5
0
0
1
0
0
1
5/6
3/4
5/6
3/3
3/7
1
3
5
0
1
1
3
1
0
2
3
3
0
2
1
2
2
0
3
0
2
1
0
1
0
1
0
0
0
0
9/10
1
2
2
4
11
6
4
6
13
6
8
6
8
6
9
1
6
4
7
1
6
4
6/6
13/16
7/7
180
240
300
111
711
111
311
(3)11
(4)11
(3)11
Degree of
maximuim
spasm'*
Mild
Severe
2
1
2
3
3
3
4
2
2
2
1
1
3
3
1
1
2
4
1
8
4
9
6
*Mild (10% to 30% reduction), severe (>30% reduction).
fObtained from 10 ml blood (EDTA).
^Obtained from 20 ml blood (EDTA).
§Two milliliters of heparinized platelet-poor plasma.
llTimes at which arteriograms were occasionally taken; numbers in parentheses represent selected additional determinations.
**Two milliliters of red blood cells, heparinized6 or EDTA.1
Stroke, Vol. 6, January-February 1975
53
WHITE, HAGEN, MORGAN, DAWSON, ROBERTSON
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regardless of the agent used to induce spasm.
Moreover, doubling the amount of blood present did
not increase the incidence or duration of the spasm
generated. These findings clearly indicate that blood
contains a number of spasmogenic agents, that some
(thrombin) may act largely indirectly, and that the
duration of the spasm depends upon the maintenance
of a critical level of the spasmogen around the
vasculature.
Table 2 summarizes a dose-response study with
substances known to be present in blood or CSF and
which might play a role in the genesis of vasospasm.
Of the prostaglandins tested, PGE, was inactive
whereas PGE? and PGF2a were active over a wide
range of doses. They also produce only a monophasic
response (contraction).
Serotonin was active in lower doses (about 0.2 fig
per kilogram), but in higher doses (10 ng per kilogram
or more) it failed to produce constriction, and often
dilated (5 of 16 animals). This dilation is not likely due
to a biphasic effect of serotonin because it occurred
early and was transient. It may be due to inhibition of
enzymes or receptors by the salt moiety; it is not due
to a change in CSF pH. The higher doses were given
because of reports that serotonin will enhance
prostaglandin release from the brain6 and because 10
mg of this salt were used to produce cerebral
vasospasm in monkeys.7 Arachidonic acid was given
because it is a precursor for PGE2 and F2o synthesized
by platelets8 and it might be likewise in the brain,
thereby increasing to CSF levels of prostaglandins.
The short-lived spasm caused by arachidonic acid
suggests that this assumption may be correct and that
infusions of this substance into the CSF could cause a
more sustained constriction. The fact that histamine
caused spasm, though transient, was surprising despite
previous reports that it constricts basilar arteries when
applied topically.1'9 In this regard, norepinephrine
dihydrochloride will cause constriction when applied
topically1'9 but proved ineffective when given intracisternally (table 3) and even produced a transient
dilation in some animals.
Table 3 compares the course of the spasm
produced by equimolar (1 X 10- 6 M) doses of
histamine, serotonin and prostaglandin F2a. That is,
the same number of molecules were added to 2 ml of
CSF and given intracisternally. The results show that
histamine produced the briefest and PFG2a the longest
response, suggesting that the latter has the greatest
affinity for the vessel, is metabolized the slowest, or
produces a long-lasting secondary action. However,
histamine or serotonin might be longer-acting entrapped in blood where the normal flow of CSF would
be interrupted. The fact that the spasm caused by any
of these agents spontaneously lysed suggests, again,
that critical levels in CSF are necessary to maintain
spasm.
Indomethacin pretreatment (20 mg per kilogram
i.v.) failed to prevent 4 ml of autogenous blood from
generating spasm in four of six animals. The incidence
of spasm was only slightly less than in the control
group (13 of 16, table 1) and the percent with spasm at
120 minutes was comparable in both groups (33% and
46%, respectively). Moreover, whatever amount of indomethacin was present from the intracisternal blood
had no effect on spasm produced by a subsequent injection of PGF2a into the cisterna magna.
Other observations were as follows. Nine dogs
given CSF alone failed to manifest spasm. Four of
these were observed for three hours and the remaining
for two hours. The spasm seen may be segmental and
usually, but not always, involves branches of the
basilar and the anterior spinal artery. In retrospect,
such variation may be due, in part, to the beveling of
TABLE 2
Dose-Response Study of Spasmogenicity Caused by Naturally Occurring
cisternally in Dogs
Dose (pa/kg)
Incidence of spasm/total number
Agent
Prostaglandins
Ej
F,.
E2°
Arachidonic acid
Norepinephrine
Serotonin
Compounds Injected Intra-
50
0/3
—
—
—
500
20
0/8
8/10
16/16
11/13
5
0/3
0/5
4/5
4/5
1
—
—
5/5
5/5
0.1
—
—
4/5
5/5
0.01
—
—
0/5
0/5
Spaim
(0.42-0.38)*
—
—
7/7
No
Yes
Yes
Yes
100
2/3t
2/5f
100
0/1
500
0/5
20
0/8
100
0/4
Yes
20
0/5
10
0/2
Histamine
(1.5-0.02)*
0/8
(0.24-0.14)*
7/8
(1.5-0.01)*
8/9
No
Yes
Yes
•Originally administered as micromolar solutions (1 X lO^M or less).
fConstriction of basilar artery transient and mild.
54
Stroke, Vol. 6, January-February 7975
EXPERIMENTAL STUDY O N THE GENESIS OF CEREBRAL VASOSPASM
TABLE 3
Incidence and Duration of Spasm Caused by Equimolar Doses of Histamine, Serotonin and Prostaglandin
Agent
Histamine
Serotonin
PGF2O
Incidence of spoiim/ieriaf arteriogrcim (minutes)
Spasm
per N
6/6
6/7
7/7
5
4
6
7
13
4
6
7
30
60
130
180
5
5
7
4
5
7
1
1
6
0
1
5
140
(Dt
(3)t
Degree of
maximum
spasmt
Mild
Severe
3
1
1
3
5
6
•Sufficient drug mixed with 2 ml of CSF to make 1 X 10~6M solution prior to injection into the cisterna magna.
fMild (10% to 30% reduction), severe (>30% reduction).
^Numbers in parentheses represent selected additional determinations.
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the needle which would direct the flow of the liquid injected. Constriction was not related to changes in
blood gas levels, blood pressure, or other vital activity,
as previously reported by others.2-10 Three peaks were
eluted from the Sephadex G-10 or G-25 columns and
were identified by observing optical densities at
wavelengths of 254 and 278. Only the intermediate
peak had spasmogenic activity (table 1). Additional
studies are needed to determine if this is a polypeptide
as suggested by Kapp et al.,4 but it is apparently of low
molecular weight. Plasma and saline solutions containing EDTA (1%) caused vasodilatation of the
basilar, hyperpnea, and tetany. Heparin was inactive
in this regard. Autopsy revealed that blood produced a
coagulum which extended at least the length of the
-basilar artery; other solutions, including thrombin, did
not produce a coagulum.
Discussion
The results clearly indicate that the origin of
experimental vasospasm is multifarious and support
the findings of Kapp et al.1 (1968) in another species
using different procedures. The fact that some agents
injected into the cisterna magna only produced a
short-lived spasm does not eliminate them as important factors in the genesis of spasm. Under proper
conditions, they may be synthesized by elements in
blood and by brain tissue in sufficient amounts to induce spasm. Concerning the latter, norepinephrine,
histamine, prostaglandins and serotonin are among
substances known to be synthesized in the brain, some
of which may account for the recent finding11 that extracts of hypothalamic tissue produce spasm when
given intracisternally to dogs. Vasopressin and oxytocin were not responsible for this spasm.11 The present study also would rule out norepinephrine,
prostaglandin E1( red blood cells, and certain components of platelets as likely spasmogens.
By any standard of comparison, prostaglandins
Ej and F2Q must be considered as spasmogens involved
in the genesis of cerebral vasospasm. In minute
amounts they generated spasm of long duration. Both
are known to be synthesized by platelets; thrombin
stimulates this synthesis.8 Both are known to be synStroke, Vol. 6, January-February 1975
thesized by brain.6 The concept that the brain may be
a source for spasmogens was first clearly stated by
Schmidt 12 and more recently used to explain
vasospasm seen clinically13 and produced experimentally.14' 15 Moreover, prostaglandin Ej is associated
with and causes inflammation8: it may be responsible
for the report2 that the severest vasospasm produced
by intracisternal blood was in one dog with meningitis.
Since prostaglandin synthesis by brain normally varies
some fivefold,6 this concept may be linked to
prostaglandin synthesis to explain why not all patients
incur cerebral vasospasm after hemorrhage, why
spasm is often delayed in onset, why head trauma may
generate spasm13 and why indomethacin failed to prevent vasospasm in the present study, assuming adequate dosage. This drug enters the brain poorly and
does not inhibit brain prostaglandin synthetase activity.16 Also, the thrombin is an antagonist of indomethacin8 which in CSF may readily negate the
latter's effect. Moreover, preliminary experiments indicate that thrombin alone given intracisternally
dramatically increases prostaglandin levels in the
CSF 17 and can stimulate platelet synthesis of
prostaglandins in CSF. 17 This agent, therefore, may
play a dual role in the genesis of vasospasm. Lastly,
CSF obtained from lumbar puncture in patients with
cerebral vasospasm have abnormal quantities of
prostaglandin F2n18 which the present study indicates
is only one of several which could be responsible for
this condition.
The spasm caused by thrombin is of special interest because it has not been heretofore hypothesized
in the genesis of vasospasm. The use of this agent in
neurosurgery may be ill-advised, especially at closure
because the spasm generated was usually delayed in
onset (table 1). The results with histamine and
prostaglandin E2 were also interesting because both
substances given intravenously are depressor agents in
dogs but were constrictor when present in the CSF.
Histamine dihydrochloride has been shown by others
to cause constriction when applied topically to the
basilar artery in cats and dogs, exposed1 or isolated.9
Norepinephrine creatinine sulfate also constricts
basilar arteries when applied topically1-9 but was inac55
WHITE, HAGEN, MORGAN, DAWSON, ROBERTSON
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tive in the present study. Perhaps norepinephrine
failed because it is normally rapidly taken up by sympathetic nerve endings in the area19 as well as being
washed away by the normal flow of CSF. Indeed, the
latter may be responsible for the spontaneous reversal
of the spasm produced by the various substances
tested. In this regard, Echlin20 has shown in monkeys
that a saline wash will reverse spasm produced by subarachnoid blood.
The present study and others clearly indicate that
the genesis of cerebral vasospasm is complex, as it
appears to be clinically. Blood does not always
generate spasm14 and the spasm generated may spontaneously lyse and reappear.2'21 Pure compounds
given intracisternally may induce a spasm which is
mainly segmental22 or may affect some arteries more
than others. The presence of blood for 24 or more
hours in the cisterna magna, when spasm is absent,
will increase the sensitivity of the basilar artery to
PGF 2 Q . 2 3 Among the many spasmogens studied, it is
likely that some act synergistically, an unexplored
possibility. Experimentally the anesthetic employed
might also alter the vascular responses produced by a
given spasmogen, though in our experience (unpublished data) penthrane does not prevent or relieve
spasm induced by blood or prostaglandin F2a. Also,
some of the pure compounds studied (histamine,
serotonin, and prostaglandin F2a) are spasmogenic
when applied to the isolated basilar artery of dogs
where, presumably, the pentobarbital used initially
would not be active.9 The vascular spasmogen
serotonin will also increase the release of prostaglandins from brain.6 Reserpine pretreatment might
prevent vasospasm3 by reducing levels of serotonin,
histamine, and norepinephrine;3 by inhibiting
prostaglandin release from tissue;24 by inhibiting
platelet function;25 and by inhibiting phosphodiesterase activity.26 The latter effect apparently interferes with the contraction process (which all
spasmogens cause) and promises to be of value in the
reversal of spasm.27 Indeed, the variety of substances
reported to be effective in reversing spasm suggests
that in suitable dosage they have a common mode of
action, e.g., nitroglycerin,28 phenoxybenzamine,22
phentolamine,29 theophylline,27 and choline.30
Nevertheless, the fact that spasm can be reversed by
saline wash20 indicates that spasmogens are responsible for this contraction. The present study and
others14'15> "•18 indicate that prostaglandins could be
of paramount importance in the genesis of cerebral
vasospasm and that a suitable inhibitor of prostaglandin activity or synthetase could significantly alter
its course.
Acknowledgments
The authors wish to acknowledge the technical assistance of Mrs.
Marion Johnson and Miss M. Rachel Fraser.
56
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Stroke, Vol. 6, January-February 1975
57
Experimental Study on the Genesis of Cerebral Vasospasm
RICHARD P. WHITE, A. AINSWORTH HAGEN, HOWARD MORGAN, WILLIAM N.
DAWSON and JAMES T. ROBERTSON
Stroke. 1975;6:52-57
doi: 10.1161/01.STR.6.1.52
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