(Stroke. 2001;32:620.)
© 2001 American Heart Association, Inc.
Original Contribution |
Effects of Aging on Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits
From the Department of Neurological Surgery (M.N., I.D., K.T., T.O.), Department of Molecular Biology and Biochemistry (Y.N.), and Faculty of Health Sciences (S.A.), Okayama University Medical School, Okayama, Japan.
Correspondence to Isao Date, MD, Department of Neurological Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail idate333{at}med.okayama-u.ac.jp
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Abstract |
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Background and Purpose—The effects of aging on cerebral vasospasm after subarachnoid hemorrhage (SAH) remain to be elucidated. The aim of this study was to clarify age-related differences of vasospasm and of papaverine reactivity in the responses of basilar arteries after SAH in rabbits.
Methods—Rabbits receiving a single injection of arterial blood into the cisterna magna were divided into 3 groups: young (2 to 3 months old), adult (6 to 9 months old), and old (20 to 40 months old). Vertebrobasilar angiograms were obtained before SAH and 1, 2, 4, and 7 days after SAH. Papaverine was administrated selectively via the vertebral artery on day 2, and serial angiography was performed for up to 2 hours. Vessel structures were assessed with light microscopy on days 1, 2, 4, and 7 after SAH and at 10, 30, and 60 minutes after papaverine infusion.
Results—Mortality from
SAH in old rabbits was 40%, whereas that of young and adult rabbits
was 0%. Angiograms revealed that SAH induced maximal constriction of
the basilar arteries on day 2 in all age groups, and the constrictions
were significantly increased with age at all time points investigated.
The degree of dilatation of spastic basilar arteries after
intra-arterial papaverine administration significantly
decreased with age. Duration of the efficacy of papaverine became
significantly shorter with age. Vessel diameter returned to the
preinfusion value 
120, 60, and 30 minutes after infusion in young,
adult, and old rabbits, respectively. Light microscopy in old rabbits
showed luminal narrowing and corrugation of the internal elastic lamina
not only in the basilar arteries but also in small arteries and
intraparenchymal arterioles.
Conclusions—This study suggests that aging increases the degree of vasospasm in rabbits. The impaired reactivity to papaverine with aging might imply the early transition of the aged vessel to the papaverine-resistant chronic stage.
Key Words: aged • aging • angiography, digital subtraction • cerebral ischemia, transient • rabbits
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Aging is a major risk factor for poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH). Recent studies have shown that the incidence of SAH in the elderly, especially those older than 60 years of age, is increasing with the increased age of the general population1 2 3 and that earlier surgical intervention, including endovascular therapy, is indicated for those elderly patients with SAH.4 5
Cerebral vasospasm is the major cause of morbidity and mortality among patients operated on at early or delayed intervals after SAH.6 7 Lanzino et al,8 in a large study, reported that the incidence of symptomatic vasospasm increased with advancing age, although the incidence of asymptomatic vasospasm was lower in elderly than in younger patients. There is, however, controversy over the effects of aging on severity of vasospasm. Contractile responses of cerebral arteries to vasoconstricting agents have been shown to be potentiated with age,9 10 11 atherosclerosis,12 13 hypertension,14 and hypercholesterolemia.15 16 Thus, aging may affect the severity of vasospasm in which the pathogenesis is considered multifactorial. Therefore, it is crucial to know the effect of aging on cerebral vasospasm. However, there have been no experimental studies that have analyzed the relationship between age and vasospasm in vivo.
More recently, issues regarding intra-arterial infusion of papaverine for the treatment of vasospasm have been discussed, such as short duration of the effect,17 18 19 20 increasing intracranial pressure,21 transient neurological deficits,22 mydriasis,23 transient thrombocytopenia,24 and respiratory depression associated with vertebrobasilar infusion.25 Papaverine is a potent, non–endothelium-dependent vasodilator and a nonspecific inhibitor of phosphodiesterase in vascular smooth muscle. It has been reported that vasodilating responses induced by papaverine in intact vessels of the elderly are essentially unchanged.26 Several authors27 28 have reported that there are papaverine-sensitive and papaverine-resistant phases during the time course of vasospasm and that reversibility of vasospasm by papaverine depends on the period after SAH and on the severity of vasospasm.
Thus, the present study was designed to clarify age-related differences in vasospasm, as well as the efficacy of papaverine in relation to the responses of basilar arteries after SAH.
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Materials and Methods |
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Animal Preparation
All procedures were approved by the Animal Care and Use Committee of Okayama University and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
One hundred twenty-seven male New Zealand White (NZW) rabbits weighing 1.7 to 4.5 kg each were used for this study; 45 were classified as young (2 to 3 months), 30 were adult (6 to 9 months), and 52 were old (20 to 40 months). All animals were housed singly at our institution with free access to food and water. Animals were anesthetized with ketamine hydrochloride (40 mg/kg IM) and pentobarbital sodium (20 mg/kg IV) supplemented at 5 to 10 mg · kg-1 · h-1 via ear vein. Spontaneous respiration was permitted throughout the experiment. The femoral artery was exposed by sterile technique, and a catheter was placed to measure systemic blood pressure and heart rate and to obtain arterial blood. Arterial blood gases were monitored and maintained within normal levels throughout the experiment. The PaCO2 was adjusted to be maintained at 35 to 40 mm Hg by supplemental anesthetic. Body temperature was maintained between 37°C and 38°C with a heating pad.
Experimental Design
All animals underwent baseline cerebral angiography 3
to 6 days before induction of SAH. Three rabbits in each group served
as controls. The rabbits subjected to SAH were randomly assigned to 4
groups of different days after SAH: day 1 (10 young, 4 adult, and 10
old), day 2 (18 young, 9 adult, and 20 old), day 4 (10 young, 10 adult,
and 10 old), and day 7 (4 young, 4 adult, and 9 old). Angiography was
repeated on days 1, 2, 4, and 7. Serial angiograms before SAH and on
days 1, 2, 4, and 7 were also obtained in the same rabbits (3 young and
3 old). After completion of angiography, animals were killed at each
time point after SAH, except for 33 surviving day 2 rabbits, which were
used for papaverine infusion. Perfusion fixation was performed in each
SAH animal and in control animals for histological
analysis.
Papaverine (5 mg/kg; 15 young, 6 adult, and 12 old rabbits) diluted to 3 mL of normal saline was manually infused over 5 minutes via the left vertebral artery on day 2. Serial angiography was repeated over the subsequent 2 hours to monitor the arterial caliber. The concentrations of papaverine used in the present study ranged from 0.28% to 0.66%, which was within recommended concentrations without toxicity to the arterial wall.29 In all, 9 young and 6 old rabbits were killed at 10, 30, and 180 minutes and at 10 and 30 minutes after infusion, respectively, when the basilar artery diameter returned to preinfusion value. Perfusion fixation was performed at each time point.
Angiography and Induction of SAH
The anesthetized rabbits were placed in a
supine position, and a 4F angiocatheter was introduced through the
exposed femoral artery. Then the catheter was advanced into the left
vertebral artery, and vertebrobasilar angiograms were obtained by
manual injection of 0.2 to 0.4 mL of nonionic contrast medium. A
magnification standard of 1-mm width of the lead string was included in
each angiogram.
The anesthetized rabbits were placed in a prone
position with the nose 30° below horizontal. With the use of
aseptic techniques, a midline nuchal incision was made, and muscles
were cleared to expose the atlanto-occipital membrane. The cisterna
magna was punctured by a 24-gauge butterfly needle. One to 1.5 mL of
cerebrospinal fluid was withdrawn, and 1 mL/kg fresh nonheparinized
autologous arterial blood that had been taken from the
central ear artery was injected over 5 minutes. The needle was
withdrawn, and nuchal muscles and skin were closed with sutures. The
animals were then placed in a head-down position for 20 minutes to
facilitate blood settling around the basilar
artery.
Analysis of Angiograms
The basilar artery diameter was measured at 3 points:
1 mm proximal to the basilar bifurcation, the midportion of the
basilar artery, and 1 mm distal to the vertebrobasilar
junction.27 All angiograms
were corrected for variations using the magnification standard in each
radiograph. Each artery diameter at the 3 points was averaged for the
final value. The basilar artery diameter was expressed as a percentage
of the pre-SAH diameter.
Histological Study
After the rabbits were anesthetized and
killed, perfusion fixation was performed transcardially with 200 mL of
physiological phosphate buffer solution at 37°C,
followed by 500 mL of a solution of 4%
paraformaldehyde and 0.1%
glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.4)
at a perfusion pressure of 1500 mm H2O.
The brain was removed, immersed in fixative, and stored at 4°C for a
minimum of 1 week. Sections of 4.5-µm thickness were cut on an
ultramicrotome, mounted on glass slides, and stained with elastica van
Gieson for light microscopy.
Statistical Analysis
All values are expressed as mean±SEM. Student’s
t tests were used to compare
physiological variables. To compare the degree
of vasospasm within groups over time and between groups at each time,
ANOVA was performed, followed by Scheffé’s F test for multiple
comparisons. For comparisons between groups after papaverine infusion,
a 2-way ANOVA was performed, with age and time as the 2 factors of
analysis. Different age groups were then compared at each time,
with probability value adjusted by Fisher’s protected least
significant difference method. A value of
P<0.05 was considered
significant.
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Results |
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Among animals subjected to SAH, none of the young or adult rabbits died before the post-SAH angiography and papaverine infusion study. In contrast, 21 of the 52 old rabbits died before the experiments, due not to procedure-related complications but to the insult caused by SAH. Eighteen (86%) of 21 rabbits died within 24 hours and 3 (14%) died within 48 hours. Mortality of the old rabbits from SAH was 40%. SAH produced focal neurological signs only in 2 (6%) of the surviving 31 old rabbits. One had hemiparesis and the other showed transient apathy and involuntary movements. Both rabbits were older than 3 years of age at the time of experiment.
Physiological
Variables
Physiological variables for
intact rabbits are shown in the
Table
.
Body weight was significantly higher in adult and old rabbits than in
young rabbits (P<0.01). Mean
arterial pressure was significantly higher in adult rabbits
than in young or old rabbits
(P<0.05). Pulse pressure was
significantly higher in old rabbits than in young and adult rabbits
(P<0.05). Heart rate and
arterial
PCO2
were not significantly different among the groups. Angiographic pre-SAH
lumen diameter of the basilar artery was significantly larger in adult
and old rabbits than in young rabbits
(P<0.05).
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Regarding papaverine infusion, other than mean arterial pressure, there were no significant differences in variables among groups (data not shown). Mean arterial pressure was significantly lower after papaverine infusion than before papaverine infusion only in adult rabbits.
Angiographic Vasospasm
Time Course After SAH
The magnitude of vasospasm showed maximal constriction
of the basilar artery on day 2 in all groups (61± 2%, 52±2%, and
44±2% in young, adult, and old rabbits, respectively;
Figure 1). In young rabbits, arterial caliber
returned almost to the pre-SAH baseline value on day 7 (93±4%),
whereas in adult and old rabbits, it showed no significant difference
between day 2 and day 7 (61±2% and 48±6% in adult and old rabbits,
respectively).
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P<0.01 vs adult; 
P<0.05 vs adult.
The magnitude of vasospasm showed increasing severity with
advancing age at all time points investigated. A significant difference
was observed between young and old rabbits at day 1
(P<0.01), among all groups at
day 2 and day 4 (P<0.05), and
between young and adult rabbits
(P<0.01) and young and old
rabbits (P<0.01) at day 7.
Representative serial angiograms before SAH and on days
1, 2, 4, and 7 in a single rabbit from the young group and a single
rabbit from the old group are shown in
Figure 2.
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Papaverine Infusion
During intra-arterial infusion of
papaverine, transient respiratory depression, including respiratory
arrest, was frequently observed. The magnitude of vasospasm showed
significant relaxation induced by papaverine in all groups
(P<0.001), but the degree of
relaxation decreased with advancing age
(Figure 5). Duration of the efficacy of papaverine was
transient in all groups and decreased with advancing age. Vessel
diameter returned to the preinfusion value in 120, 60, and 30
minutes after infusion in young, adult, and old rabbits, respectively.
Representative serial angiograms after papaverine
infusion in the same young rabbit and the same old rabbit are shown in
Figure 6.
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Histopathological Findings
Changes After SAH
In young rabbits, corrugation of the internal elastic
lamina (IEL) was observed on day 2 and day 4 and resolved on day 7
(Figure 3). Meanwhile, in old rabbits, corrugation of the IEL
was observed on days 1, 2, 4, and 7. The corrugation of IEL appeared
earlier and persisted longer in old than in young rabbits. The degree
of corrugation became more severe with advancing age. Thickening of the
media and adventitia was greater in old than in young rabbits at all
time points investigated. Adult rabbits showed a similar trend to that
of old rabbits (data not shown). Corrugation of IEL and thickening of
the media and adventitia were observed in small arteries and
intraparenchymal arterioles in old rabbits but not in young rabbits
(Figure 4).
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Changes After Papaverine Infusion
In young rabbits, corrugation of the IEL decreased
within 10 minutes after infusion and disappeared within 30 minutes
(Figure 7). Thinning of the media was observed within 10
minutes and was maintained at 30 minutes. At 180 minutes, thickening of
the media and corrugation of the IEL recurred, and this finding was
consistent with that of angiography. Meanwhile, in old rabbits,
corrugation of the IEL and thickening of the media were already
observed at 10 and 30 minutes after
infusion.
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Discussion |
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This is the first study to examine the in vivo effects of aging on cerebral vasospasm and on cerebral vascular responses to intra-arterial infusion of papaverine after SAH. There are 4 major new findings in this study. First, a high mortality rate due to initial hemorrhage was noted in older rabbits. Second, the degree of vasospasm was augmented and the resolution of vasospasm after maximal constriction was impaired more strongly with advancing age. Third, small arteries were more susceptible to vasospasm in old rabbits than in young and adult animals. Fourth, vasodilator responses to intra-arterial infusion of papaverine were impaired with aging.
Hemodynamic
Parameter
Several studies have shown that animals become
hypertensive with
age.30 31 NZW
rabbits used in this study had a tendency for mean arterial
pressure to rise in adult animals, but this subsided in older animals.
A similar trend has been reported with aging in
rabbits,32 33
rats,34 and
humans.35 Pulse pressure was
significantly increased in old rabbits, as described
previously.33 Therefore,
increased pulse pressure in old rabbits may influence vascular
structure and reactivity after SAH.
Vasospasm and Aging
Previous clinical studies have suggested that the
severity of angiographic vasospasm is not affected by
age36 37 38
or that it is less severe in elderly
patients39 40 41 42
and that the incidence of symptomatic vasospasm is
lower,43
similar,40 or
higher8 42 44 45
with advancing age. In the present study, constricting responses of
the basilar arteries exposed to SAH increased with aging at all time
points investigated. In addition, the resolution of vasospasm after
maximal constriction on day 2 was impaired with aging. In particular,
old rabbits showed severe and continuous vasospasm with nearly maximal
constriction even on day 7, although a rabbit model of SAH with single
injection of arterial blood into the cisterna magna usually
represents a mild to moderate vasospasm of the basilar artery,
the diameter of which returns to the pre-SAH level within a week, as
previously demonstrated in a similar fashion in a
canine46 and a
rabbit47 single-SAH model.
This pattern in old rabbits is similar to that observed in a canine
double-SAH model, which is considered an established SAH model with
severe vasospasm that lasts for 14
days,46 suggesting that the
rabbit basilar arteries exposed to SAH are vulnerable to vasospasm with
aging.
In contrast to vasospasm in large arteries with impaired endothelium-dependent relaxations,48 49 it has been suggested that small arteries and intraparenchymal arterioles are resistant to vasospasm after SAH because of the preserved endothelium-dependent relaxations50 51 and a pial barrier that prevents erythrocytes in the subarachnoid spaces from entering into the perivascular spaces surrounding the penetrating arterioles.52 These findings are in agreement with the clinical findings of SAH in humans. Symptomatic vasospasm closely correlates with the narrowing of the major cerebral arteries and is usually reversible with timely transluminal balloon angioplasty. However, recent studies using the microvascular corrosion cast technique suggested that constrictions of small arteries and intraparenchymal arterioles in rats53 and dogs54 55 occurred after SAH. In addition, morphological changes of intraparenchymal arterioles, such as tapered narrowing with external folding, decreased internal diameter of arterioles, and increased wall thickness, were reported.54 55 Also, human pial arteries ranging from 300 to 900 µm ID showed hyperresponsiveness to contractile agents and spontaneous contractile activity within 48 hours of SAH.56 In the present study, we have histologically confirmed the vasospasm of brain stem small arteries and intraparenchymal arterioles in old rabbits with symptomatic vasospasm. This finding is supported by previous reports that diffuse severe and peripheral vasospasm had serious effects on the clinical state and outcome of elderly patients,43 57 that severe cerebral infarction due to diffuse vasospasm was found more commonly in aged patients,43 57 58 and that severe generalized angiographic vasospasm was seen without an increase of mean flow velocities by transcranial Doppler ultrasound.59 Thus, augmented constricting responses of large as well as small arteries and of intraparenchymal arterioles may predispose the aged to delayed cerebral ischemia.
Regarding in vivo studies of cerebral vasospasm among various animals such as rats, rabbits, cats, pigs, dogs, and primates, the canine "2-hemorrhage" model is most frequently used, but the best model of vasospasm that accurately reflects human SAH seems to be the primate model.60 In an aging study, however, large animals such as primates and dogs are not suitable because of the limited number available, their high cost, and the difficulty in knowing the accurate age of the animals. As previously shown in a rabbit model, SAH with a single injection of arterial blood into the cisterna magna produced a maximal (30% to 40%) reduction in basilar artery diameter at 2 to 3 days after SAH,61 62 mimicking the situation observed in monkeys63 and humans.64 65 Thus, we consider rabbits to be the most suitable and largest in vivo aging model of SAH that closely reflects human SAH.
A limitation of the present in vivo study is that old rabbits used were 20 to 40 months of age without atheromatous changes, which represents 50 to 60 years of age in humans. In view of the definition of aged or senescence as the age at which mortality approximates 50%, we confirmed the caged-rabbit mortality rate as being >50% within 3 years of age in our institution. Thus, the old rabbits used in the present study are consistent with the term "the old." It is likely that differences in responses between groups are related to differences in age, but we cannot exclude the possibility that other factors may also contribute.
Efficacy of Papaverine and Aging
It has been reported that the ability of papaverine to
reverse vasospasm depends on the amount of time since SAH and on the
severity of
vasospasm.19 27 28
The present study demonstrated angiographically the reduced in vivo
maximal vasodilating responses of the basilar arteries on day 2 to
intra-arterial infusion of papaverine during aging and the
decreased duration of the effect of papaverine with aging. These may be
attributable to the increased severity of vasospasm with
aging.
The magnitude of relaxation in young rabbit basilar arteries to papaverine was 100% of pre-SAH levels. This perfect resolution of vasospasm in the young rabbit by papaverine is consistent with a previous report using a rabbit model of SAH with gradual injection of an extremely large volume (6 mL in total) of arterial blood.27 That report indicated that there are 2 phases to arterial narrowing based on the in vivo relaxation responses to papaverine (an early, pharmacologically reversible phase and a later, irreversible phase) and that a papaverine-resistant phase emerges at day 3. In this sense, the adult and old rabbits in the present study demonstrated reduced maximal vasodilatation by papaverine on day 2, suggesting that they had already become resistant to papaverine on day 2 and that aging may accelerate the earlier transition of the vessel after SAH to the papaverine-resistant chronic stage.
Speculations on the Mechanisms Involved and
Implications
On the basis of previous studies and our own findings,
several explanations can be suggested. With respect to the increased
severity of vasospasm at the earlier stage after SAH during aging, one
hypothesis could be an augmented contraction to vasocontractile agents.
Previous studies have shown that vasoactive agents such as
serotonin,9 10 11
endothelin-1,33
thromboxane,12 13 14 66
histamine,9 66 and
prostaglandin
E2,12 all of which have been
considered as possible spasmogens, increase the direct contractile
effect with aging. In addition to the direct contracting effect,
threshold concentrations of endothelin-1 potentiate contractions
induced by low concentrations of norepinephrine and
serotonin in human
arteries.67 The potentiating
effects of the peptides increase with
age.68 This may contribute
to the increased severity of vasospasm with age not only in the basilar
artery but also in small arteries and intraparenchymal
arterioles.
Another possible explanation is the impairment of endothelium-dependent relaxation. It has been well established that endothelium-dependent relaxations are less effective in cerebral vessels of old animals than in those of younger ones. In the present study, pulse pressure was significantly higher with age, suggesting that endothelium-dependent relaxations were impaired during aging, as previously shown in rabbits.69 In addition, it is well known that endothelium-dependent relaxations are also impaired in large arteries after SAH.48 49 These facts in combination may predispose the vessels to the impaired balance between endothelium-dependent contraction and relaxation, leading to the increased and continuous vasospasm of the basilar arteries with age.
In summary, this study demonstrates that aging renders the brain vulnerable to SAH, leading to augmented constricting responses of large conducting arteries, small arteries, and intraparenchymal arterioles with aging. Impaired reactivity to papaverine with aging may be a consequence of the early transition of the vessel to the papaverine-resistant chronic stage, in which functional and morphological changes take place. Even though further studies are necessary to elucidate how the mechanism of vasospasm is altered with age, our study suggests that future therapy should be focused on clinical vasospasm in the elderly not only in large arteries but especially in the microcirculation.
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Acknowledgments |
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This study was supported in part by a Grant-in-Aid for Scientific Research (B) 08457367 and a Grant-in-Aid for Exploratory Research 08877189 from the Ministry of Education, Science, Sports and Culture, Japan.
Received August 9, 2000; revision received December 12, 2000; accepted December 14, 2000.
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