(Stroke. 2001;32:1665.)
© 2001 American Heart Association, Inc.
Original Contributions |
Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage
Vasospasm Caused by Cisternal Injection of Recombinant Platelet-Derived Growth Factor–BB
From the Laboratory for Cerebrovascular Disorders, Research Institute of National Cardiovascular Center (Z.Z., J-H.X., H.Y.), Department of Neurosurgery (I.N., N.S., H.S., H.Y.), and National Cardiovascular Center (H.K.), Osaka, Japan.
Correspondence to Hiroji Yanamoto, MD, DMSci, Laboratory for Cerebrovascular Disorders, Research Institute of National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail hyanamot{at}res.ncvc.go.jp
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Background and Purpose—Plasma serine protease cascade, including the complement system and thrombin, is activated in the subarachnoid space during the acute phase after subarachnoid hemorrhage (SAH). To examine the effect of protease cascade–based inflammation and subsequent vascular repair in the development of cerebral vasospasm, we examined the effect of 2 synthetic serine protease inhibitors—FUT-175, an inhibitor of thrombin and the complement system, and argatroban, a selective inhibitor of thrombin—on the development of cerebral vasospasm in a rabbit SAH model.
Methods—One hundred Japanese White male rabbits were used in the study. The SAH was simulated by a single injection of autologous arterial blood into the cisterna magna. To evaluate the development of cerebral vasospasm, the caliber of the basilar artery was measured on x-ray film before and at 2 days after SAH. Nine groups of rabbits (n=6 each) were treated with continuous intravenous injection of FUT-175 (2.5, 5, 10, or 20 mg/d), argatroban (1.25, 2.5, or 5 mg/d), or the same amount of saline (vehicle) for 48 hours, starting 40 minutes after SAH. Two days after SAH, the expression of homodimer of platelet-derived growth factor–BB (PDGF-BB) in the basilar artery was examined with immunohistochemical techniques. In 20 normal rabbits, 5 µg of recombinant PDGF-BB or vehicle was injected into the cisterna magna, and the basilar arteries were examined on angiograms for 48 hours.
Results—Significant differences were observed in the caliber of the basilar arteries between the vehicle group and the groups with the 3 larger doses of FUT-175 (vehicle, 52±5.0%; 5 mg, 79±5.7%; 10 mg, 80±2.5%; 20 mg, 80±3.7%) and between the vehicle group and the groups with the 2 larger doses of argatroban (vehicle, 52±6.4%; 2.5 mg, 81±9.0%; 5 mg, 85±4.1%) (P<0.05). In the histological examination, administration of effective doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the endothelial and medial smooth muscle cell layers. Exogenous PDGF-BB caused delayed and prolonged vasoconstriction on normal basilar arteries.
Conclusions—Activation of the serine protease cascade and/or thrombin after SAH was demonstrated to play an essential role in the development of cerebral vasospasm. The expression of PDGF-BB–like protein in the arterial walls correlated with the development of cerebral vasospasm. Elevated PDGF-BB level in the subarachnoid space was found to induce delayed and chronic vasoconstriction.
Key Words: cerebral vasospasm • growth factors • subarachnoid hemorrhage
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Introduction |
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Cerebral vasospasm after subarachnoid hemorrhage (SAH) remains an unresolved process that causes delayed cerebral ischemia with morbidity or mortality in addition to primary brain damage due to SAH.1 Numerous studies have hypothesized that delayed induction of vasoconstrictive substances, supposedly spasmogen(s) released in the subarachnoid space, affects cerebral arteries surrounded by thick blood clot and causes sustained vasoconstriction.2 3 In clinical treatment, a calcium antagonist was shown to improve overall outcome within 3 months of aneurysmal SAH; however, the intermediate factors by which the calcium antagonist exerts its beneficial effect for vasospasm remain unclear.4 Thus, despite the recent substantial progress in our understanding of cerebral vasospasm, including the alterations of gene expressions, production or depletion of chemical mediators, and structural abnormalities in cerebral arteries after SAH, development of a clinically effective inhibitor targeting a key etiology of cerebral vasospasm remains a challenge for basic researchers.3 5
The intracellular analysis of prolonged narrowing of cerebral vessels has demonstrated that such narrowing accompanies components of vasculopathy, which differs from the physiological vasoconstriction that occurs under normal conditions.6 7 In the pathological characteristics of cerebral arteries, attacks of inflammatory responses on the cerebral arteries after SAH have been implicated in the pathogenesis of cerebral vasospasm.8 9 Plasma protease cascades precede initial noncellular inflammatory responses comprising the coagulation, fibrinolytic, and complement systems in the acute phase in the subarachnoid space after SAH.10 11 12 13 14 These responses are considered to initiate a process intended to repair injured cerebral arteries after SAH. In a rabbit SAH model, we used a specific broad-spectrum, nonselective serine protease inhibitor, FUT-175 (nafamostat mesylate), to study the role of the activated protease cascade in the development of cerebral vasospasm, and we used argatroban, a selective serine protease inhibitor for thrombin, to study the role of thrombin, a component of the protease cascade. In addition, expression of platelet-derived growth factor–BB (PDGF-BB), a growth factor possibly induced by thrombin activation, was studied on the arterial wall after SAH.15 16
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Materials and Methods |
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One hundred male Japanese White rabbits weighing 3.0 to 3.5 kg (Shimizu Experimental Animal, Kyoto, Japan) were used. The experimental protocols were approved by the Animal Research Committee at the Research Institute of the National Cardiovascular Center. All efforts were made to minimize suffering and the number of animals used.
Subarachnoid Hemorrhage
Rabbits were anesthetized with an
intramuscular injection of 150 mg (3 mL) of ketamine
(Ketalal, Sankyo Co) and 20 mg (1 mL) of
xylazine (Seractal, Bayer Co). SAH was simulated
by transcutaneous single injection of autologous nonheparinized
arterial blood. One milliliter of fresh
arterial blood, aspirated via a catheter inserted in the
right femoral artery, was injected into the cisterna magna with the
animal in a tilted, head-down, prone position. Before the injection,
1.0 mL of cerebrospinal fluid (CSF) was removed. After the injection,
the animal was maintained in the same position for 40 minutes to allow
the injected blood, following a mixture with CSF, to completely
coagulate around the targeted basilar artery.
Angiographic Examination
Rabbits were anesthetized with intramuscular
anesthetic (as described above) with additional local subcutaneous
anesthesia (0.5% lidocaine) at the right femoral region.
An angiographic 4F catheter (designed by H.Y.; Medikit Co) was inserted
from the right femoral artery into the left vertebral artery under
fluoroscopy. Iopamidol (0.5 mL; 300 mg of iodine per 1.0 mL) was
injected manually to take a frontoposterior vertebrobasilar angiogram
at a constant exposure (50 kV, 8 mA) and at a constant magnification
with medical x-ray film (Konica NIF, new A, No.
20289).8 17
Angiography was performed before SAH (day 0) to determine the baseline
caliber of the basilar artery and then repeated 48 hours after SAH (day
2). The caliber of the basilar artery was measured at 3 corresponding
cross sections (the midpoint of the basilar artery and 0.5 cm above and
below) in a blind manner with the use of a computer-assisted image
analysis system (SD-510C, WACOM). The mean value of the 3
measurements was expressed on days 0 (before SAH) and
2.
Inhibitory Drugs Treatment
Protocol
The synthetic serine protease inhibitor
with broad-spectrum FUT-175 (nafamostat
mesylate)18 19 (a
gift from Torii Pharmaceutical Co Ltd, Tokyo, Japan) competitively and
specifically blocks the active sites of multiple serine proteases,
including complement components Clr, Cls, B factor, and D factor; a
component of the coagulation system, thrombin; and a component of the
fibrinolytic system,
plasmin.18 19
The serine protease inhibitor argatroban (a gift from
Mitsubishi Chemical Co, Yokohama, Japan) competitively and selectively
blocks the active site of
thrombin.20 21
Fifty-four rabbits were randomly divided into 9 groups (n=6 each) and
used for experiments 1 and 2.
Experiment 1
FUT-175 (2.5, 5, 10, 20 mg/d) or the same volume (480
µL) of saline (vehicle) was infused intravenously via an
osmotic minipump (Alzet, model 2 ML1) for 48
hours, which was designed to infuse at a speed of 10 µL/h. The
minipump was implanted under the femoral skin with the tip of the
infusion catheter set in the proximal right femoral vein under a
surgical microscope starting 40 minutes after the induction of SAH. No
obstruction of the infusion system was confirmed in each rabbit at the
time of euthanasia on day 2.
Experiment 2
Argatroban (1.25, 2.5, 5 mg/d) or the same volume
(480 µL) of saline (vehicle) was infused with the same
intravenous infusion system described above. Argatroban or
vehicle was infused continuously for 48 hours, and the absence of
catheter obstruction was confirmed at the time of euthanasia on day
2.
In each animal in experiments 1 and 2, the formation of thick SAH around the basilar artery was confirmed at the time of euthanasia. The protocol for FUT-175 or argatroban was designed to inhibit targeted serine proteases in consideration of pharmacological properties and kinetics reported from experimental and human clinical studies.18 19 21 22
Physiological
Parameters During Angiographic Examinations
Physiological
parameters were monitored to confirm that no
parameters were affected by the anesthesia used
for the angiographic examinations or by the drug administrations in a
separate set of 12 animals. Blood pressure, heart rate, blood pH, blood
gases (O2, CO2), and
blood glucose levels were monitored during angiographic examinations
before and at 48 hours after SAH in groups treated with the highest
volumes of FUT-175 (20 mg/d) and argatroban (5 mg/d) and in a group
without drug treatment (n=4 each).
Immunohistochemical Analysis
All SAH rabbits used for angiographic examination and
another 6 normal rabbits were used for immunohistochemical
analysis with the use of the labeled streptavidin-biotin (LASB
kit, Dako) method. Forty-eight hours after SAH, rabbits were deeply
anesthetized and perfused with 500 mL of PBS at a pressure of
110 mm Hg. The brain was removed with vertebrobasilar arteries in
the clot and embedded in methyl Carnoy’s solution (60% methanol, 30%
chloroform, 10% acetic acid). Cross sections of brain stem with
surrounding arteries were processed for immunohistochemistry by
indirect immunoperoxidase with the murine monoclonal antibody PGF-007
(donated by Mochida Pharmaceutical, Tokyo, Japan). The antibody was
produced against PDGF-B
chain.15 23 The
specificity of this antibody for PDGF-BB has been reported
elsewhere.24
Direct Effects of PDGF-BB on Normal Basilar
Arteries In Vivo
In a separate set of 20 rabbits, the effects of
PDGF-BB on the vascular tone of the normal basilar artery were studied.
Five micrograms of recombinant rat PDGF-BB (R&D
Systems, Inc) or vehicle (1 mL of saline), both in 0.2%
rat albumin as a carrier protein for PDGF-BB, was injected into
the cisterna magna (n=10 each). Angiography was performed before and 15
minutes, 1 hour, 6 hours, 24 hours, and 48 hours after the injection of
PDGF-BB with the use of a mobile digital imaging system (series 9600,
OEC Medical Systems Inc). During the angiographic examinations, blood
pressure, blood pH, and blood gases were monitored. The caliber of each
basilar artery was assessed in a blind manner on the angiographic
images with the use of the computer-assisted image analysis
system.
Effects of Drug Administrations on Normal Cerebral
Arteries
The effects of the chronic drug administrations on
the vascular tone of normal basilar arteries were studied in a separate
set of 8 animals. The highest volumes of FUT-175 (20 mg/d) or
argatroban (5 mg/d) were administered for 48 hours by the method
described above, and angiographic examinations were performed with
physiological monitoring before and after drug
administration for 48 hours in the absence of SAH (n=4
each).
Statistical Analysis
The data were analyzed by 1-way ANOVA. If
multiple comparisons were indicated, the Student-Newman-Keuls test was
applied. To compare 2 groups at the same time point, the unpaired
2-tailed t test was used. The
results are presented as mean±SEM. The difference was
considered significant at
P<0.05.
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Results |
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Angiographic Examination
Experiment 1
Two days after SAH in the vehicle-treated group, the mean caliber of the basilar artery decreased to 52±5.0% of the baseline value (Figure 1
, left paired panel, and
Figure 2). In the groups treated with the larger 3
doses of FUT-175 (5, 10, or 20 mg/d), there were significant
differences in the calibers of basilar arteries compared with those of
the vehicle-treated groups on day 2
(P<0.05)
(Figure 1, right 3 paired panels, and
Figure 2). There were no significant differences between the
vehicle-treated group and the group treated with the lowest dose of
FUT-175 (2.5 mg/d)
(Figure 2).
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Experiment 2
Two days after SAH in the vehicle-treated group, the
mean caliber of the basilar artery decreased to 52±6.4% of the
control value
(Figure 3, left paired panel, and
Figure 4). In argatroban-treated groups on day 2,
there were significant differences in the calibers of basilar arteries
in the medium- to high-dose (2.5 to 5 mg/d) groups but not in the
low-dose (1.25 mg/d) group
(P<0.05)
(Figure 3, right 3 paired panels, and
Figure 4).
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Physiological
Parameters During Angiographic Examinations
Physiological
parameters monitored during angiographic examinations are
shown in
Table 1. There were no significant differences in any
of the parameters between the groups on day 2 and between
before and 2 days after SAH.
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Immunohistochemical Analysis
Figure 5 shows the results of
immunostaining for PDGF-BB on the cross sections of
basilar arteries 2 days after or without SAH (normal control). Two days
after SAH, strong immunoreactivity for PDGF-BB was observed in all
layers: the endothelial cell, smooth muscle cell, and
adventitial cell layer in the vehicle-treated SAH group
(Figure 5, top panel). In contrast, in normal basilar artery,
there was faint or no immunoreactivity detected for PDGF-BB
(Figure 5, bottom panel). The enhanced immunoreactivity was
observed mainly in the nuclei of endothelial and smooth
muscle cells. In contrast, in groups treated with 3 different doses of
FUT-175
(Figure 6), the immunoreactivity in the
endothelial and smooth muscle cells was weakly positive
compared with that of vehicle-treated vessels
(Figure 5, top panel, and
Figure 6). Furthermore, the level of immunoreactivity in the
smooth muscle cells correlated well with the degree of vascular
constriction indicated by corrugation of the internal elastic lamina
(Figure 6).
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Figure 7 shows the immunostaining in
the argatroban-treated groups. The level of immunoreactivity for
PDGF-BB was highest in the low-dose (1.25 mg/d) and lowest in the
high-dose (5 mg/d) argatroban-treated group. The immunoreactivity for
PDGF-BB in the endothelial and smooth muscle cells
correlated well with the degree of vascular constriction and also
correlated well with the degree of vasoconstriction demonstrated on
angiographic examinations
(Figure 7). Replacing the primary antibody with nonimmune
murine IgG completely abolished the positive
immunostaining (data not shown).
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Direct Effects of PDGF-BB on Normal Basilar
Arteries In Vivo
The caliber of the basilar arteries slowly decreased
after the injection of recombinant PDGF-BB
(Figure 8). There were significant differences in
calibers between the vehicle and PDGF-BB–injected groups at 1 hour, 6
hours, and 24 hours but not at 15 minutes or 48 hours after the
injection. The development of vasoconstriction was delayed and was
gradually enhanced. The peak of the chronic and long-lasting
vasoconstriction was observed 24 hours after the cisternal injection of
recombinant PDGF-BB. Regarding the physiological
parameters, there were no significant differences between
PDGF-BB or vehicle injection
(Table 2).
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Effects of Chronic Drug Administrations on Normal
Cerebral Arteries
After 48 hours of continuous intravenous
administration with 20 mg/d FUT-175 or 5 mg/d argatroban, the calibers
of the basilar arteries were 100±1.8% and 101±1.7%, respectively,
compared with the baseline calibers. Calibers of the basilar arteries
were not affected and remained consistent after the drug
administrations of FUT-175 or argatroban in normal rabbits.
Physiological parameters were within
the normal range and were not significantly different from the values
monitored before drug administration (data not
shown).
Side Effects of Drug Treatment
There were no functional impairments or
mortalities during treatment after SAH. In human clinical studies, the
side effects of these compounds have been fully clarified in the
clinical phase I trials and were within the acceptable range for
clinical use.
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Discussion |
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An inflammatory defense reaction against a coagulated clot (non-self) in the subarachnoid space is differentiated into protein (protease)-based and subsequent infiltrated cells–based inflammation.8 After SAH, the coagulated clot around the cerebral arteries triggers the initial protease-based noncellular inflammation in the subarachnoid space.8 The protease-based inflammation proceeds in spiral and dynamic activations of interrelated multiple cascades of the complement, coagulation, fibrinolytic, and kallikrein-kinin systems.25 26 These closely linked systems that comprise multiple proteases have cascades with which to stimulate and activate each other to exert local inflammatory responses. The levels of activated proteases in these systems reportedly elevate in the CSF during the acute phase after SAH, which is considered to be an etiologic factor of cerebral vasospasm.10 12 13 14 27 FUT-175 inhibits complement factors thrombin and plasmin and suppresses the protease-based inflammation.18 19 FUT-175 has been used for disseminated intravascular coagulation in clinical practice.22 Before the present study, it was reported that intermittent intravenous administration of FUT-175 prevented the development of experimental and clinical vasospasm after SAH17 28 29 ; however, an overdose phenomenon (>4 mg/d) was suggested by the intermittent administration in rabbits.17 The present study examined the effect of FUT-175 using continuous (slow) intravenous administration and demonstrated that larger doses of 5 to 20 mg/d were similarly effective in preventing cerebral vasospasm.
Argatroban, a selective thrombin inhibitor, effectively inhibits thrombin-induced cleavage of fibrinogen, factor V, factor VIII, and protein C, as well as the initiation of platelet aggregation, and it has been used in the treatment of acute cerebroarterial thrombosis and other chronic vascular occlusive diseases in clinical practice in Japan (the US Food and Drug Administration approved this drug for the treatment of heparin-induced thrombocytopenia in October 2000).30 Thrombin had been considered an enzyme belonging solely to the coagulation system; however, it is now recognized as a multifunctional organizer leading to a healing process from inflammation, and it stimulates vascular endothelial cells, smooth muscle cells, fibroblasts, neutrophils, and macrophages.31 32 33 After SAH, it has been reported that levels of thrombin-antithrombin III complex and F1+2, molecular markers of thrombin activation in the CSF, were elevated and correlated well with the clinical severity of SAH at the onset and occurrence of cerebral vasospasm.11 12 34 35 Recently, it has been reported that intrathecal placement of collagen pellets releasing thrombin inhibitor prevented the development of canine vasospasm.36 Although vascular endothelial and smooth muscle cells are capable of expressing thrombin receptor,37 and thrombin causes the immediate contraction of smooth muscle cells via activated thrombin receptor,38 39 the peak thrombin-antithrombin III complex concentration in the CSF of SAH patients was apparently earlier (on days 2 to 5) than the development of human cerebral vasospasm, which indicated that thrombin activation and its vasoconstrictive effect were not a direct cause of cerebral vasospasm.34 39
In the search for factors downstream to thrombin activation due to SAH, elevated immunoreactivity for PDGF-BB was first demonstrated in the endothelial and smooth muscle cells of the basilar artery after SAH. Regulations of PDGF production in smooth muscle cells by thrombin have been reported.16 40 Furthermore, it has been reported that levels of PDGF-BB concentration in the CSF in the acute phase of SAH patients were significantly higher in patients with rather than without symptomatic vasospasm.41 Direct vasoconstrictive effects on arteries by exogenous PDGF are controversial in the literature. Recombinant PDGF has caused potent concentration-dependent contraction on rat aortic strips within 2 minutes after the application; however, it did not constrict rat intracerebral arterioles (perforating arteries) in vitro.42 43 44 In the present study it was first demonstrated that exogenous PDGF-BB caused delayed and prolonged but not rapid vasoconstriction on cerebral arteries in rabbits. The peak of the vasoconstriction (24 hours) was earlier than that of vasospasm in rabbits (48 hours) caused by blood injection17 ; however, it can be speculated that a time delay of approximately 1 day is due to a phase for the active production of PDGF-BB after thrombin activation in the subarachnoid space or within the vascular wall.
The preventive effects on the developing cerebral vasospasm by intravenous administration of the 2 serine protease inhibitors reduced the immunoreactivity for PDGF-BB in vessel walls as well as cerebral vasospasm. These results were in agreement with the previous study in that an effective inhibition of neointimal formation was achieved by administration of FUT-175, and the preventive effects correlated well with the reduced expression of PDGF-BB in the neointimal as well as smooth muscle cells after balloon (stretching) injury to rat carotid arteries.45 Although the pathophysiology of the proliferative or constricting abnormalities, after injury or bleeding-derived inflammation, is considered different, both of these vascular responses may have a common cascade through PDGF-BB expression linked to a healing process. It was striking that cerebral vasospasm, which normally does not accompany significant proliferation of smooth muscle cells at the peak of vasospasm, expressed strong PDGF-BB–like immunoreactivity in the arterial wall after SAH. In general, growth factors are produced after inflammation to initiate repair injury.31 It is postulated that SAH triggered the activation of a protease cascade, which in turn triggered the production of the growth factor PDGF-BB, and the accumulated PDGF-BB in the smooth muscle cells, via the autocrine or paracrine mechanism,46 47 48 caused delayed and prolonged vasoconstriction. PDGF-BB or its metabolite in smooth muscle cells is a new candidate for spasmogen or inducer of pathological vascular remodeling. This could explain why vascular narrowing is delayed and prolonged. In this context, a significant stretching injury on cerebral arteries, possibly caused by SAH or surgery, may enhance cerebral vasospasm through PDGF-BB production. Cerebral vasospasm was suggested to occur during the healing process in cerebral arteries after SAH.
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Acknowledgments |
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This study was supported by Japan Health Sciences Foundation, Special Coordination Funds for Promoting Science and Technology, and by a grant-in-aid for scientific research from the Ministry of Education, Culture, Science, and Technology of Japan. Dr Zhang was supported in part by Japan-China Sasakawa Medical Fellowship. We acknowledge the valuable assistance of Atsuko Okuno, Tomoko Yasuda, and Mihoko Kurimoto.
Received May 24, 2000; revision received February 27, 2001; accepted March 20, 2001.
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