(Stroke. 1996;27:1629-1633.)
© 1996 American Heart Association, Inc.
Articles |
Effect of BQ-123 and Tissue Plasminogen Activator on Vasospasm After Subarachnoid Hemorrhage in Monkeys
the Section of Neurosurgery, University of Chicago (Ill) Medical Center.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Background and Purpose We aimed to determine the effect of intracisternal administration of an endothelin-A receptor antagonist (BQ-123) against vasospasm in a monkey model and to determine whether this drug would have adverse interactions with intracisternal tissue plasminogen activator (TPA).
Methods Thirty-three monkeys were randomly allocated to undergo baseline cerebral angiography, creation of right subarachnoid hemorrhage (SAH), and intracisternal delivery of (1) placebo (n=10); (2) low-dose BQ-123 (5 mg/kg per day, n=7); (3) high-dose BQ-123 (10 mg/kg per day, n=9); or (4) BQ-123 10 mg/kg per day plus TPA 1 mg every 12 hours for three doses (n=7). Angiography was repeated after 7 days, and animals were killed. Vasospasm was assessed by comparisons of angiograms within groups across time by paired t test and by comparisons across groups at each time by ANOVA.
Results Significant clot remained in the basal cisterns in all groups except those receiving TPA, in whom complete clot clearance was noted. Comparisons of angiograms at baseline and after 7 days showed significant vasospasm of the right middle cerebral artery in animals receiving placebo (mean±SEM reduction in diameter, 36±7%; P<.05) and low- and high-dose BQ-123 (16±4% and 18±7%, respectively). Animals that received TPA did not develop significant right cerebral artery vasospasm. Comparisons of arterial diameters at day 7 revealed significant variance in right middle cerebral artery diameter, with animals in the placebo group having significantly more and animals in the TPA group having significantly less vasospasm than the BQ-123 groups. Histopathological examination of the brains did not show inflammation or pathological change in animals that received BQ-123 or BQ-123 plus TPA.
Conclusions Intracisternal TPA was efficacious against vasospasm in monkeys. Combination therapy with TPA and BQ-123 was not associated with reduction in efficacy of either drug or with evidence of toxicity.
Key Words: subarachnoid hemorrhage • thrombolysis • vasospasm • monkeys
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
The main etiologic factor in the development of vasospasm after aneurysmal SAH is subarachnoid blood clot.1 2 The pathogenetic processes that cause vasospasm do not begin for 2 or 3 days after the hemorrhage, as suggested by clinical and experimental evidence that removal of the subarachnoid clot within this time prevents vasospasm from developing.2 3 4 5 6 Experimental studies have documented that intracisternal administration of recombinant TPA clears subarachnoid clot by fibrinolysis and prevents vasospasm.2 7 8 9 10 11 All experimental studies have not consistently shown this, however, and a randomized, blinded clinical trial of TPA found only trends toward prevention of vasospasm.12 13 The more limited efficacy that some treatments for vasospasm show in clinical studies compared with experimental models suggests that successful treatment of vasospasm in humans may require multiple drugs.
Potent vasoconstricting peptides called ETs have also been implicated in the pathogenesis of vasospasm.14 Three endothelin peptides (ET-1, ET-2, and ET-3) and three receptors (ETA, ETB, and ETC) have been identified.14 Drugs that antagonize the action of ETs on ET receptors prevented vasospasm in dogs, rabbits, and monkeys.15 16 17 A peptide that antagonizes actions of ETs on ETA receptors, BQ-123, almost completely prevented vasospasm in a monkey model, an effect that had not been observed with any pharmacological antagonist in prior experiments.17
Since TPA and BQ-123 were effective in preventing vasospasm in monkeys and might be components of a cocktail of drugs to prevent vasospasm in humans, a randomized, blinded experiment was performed to determine whether both agents were efficacious and to determine whether there was any reduction in efficacy or development of adverse effects if the two drugs were given together. The primary end point was angiographic vasospasm, as determined by comparison of angiograms taken before and 7 days after subarachnoid blood clot placement.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Protocol
Thirty-three cynomolgus monkeys (Macaca fascicularis) were randomly divided into four groups to receive (1) placebo; (2) low-dose BQ-123 (5 mg/kg per day); (3) high-dose BQ-123 (10 mg/kg per day); or (4) BQ-123 10 mg/kg per day plus TPA 3 mg. Animals underwent baseline angiography and induction of SAH on day 0. Subcutaneous pumps and, in some animals, Ommaya reservoirs were placed for drug or placebo administration. Seven days later (day 7), angiography was repeated, and animals were killed.
Procedures on animals were approved by the Animal Care and Use Committee of the University of Chicago. They complied with standards set by the US Department of Health and Human Services.
Angiography and SAH
Methods for angiography and SAH in this model have been described in detail.2 17 After sedation with ketamine 10 mg/kg IM, animals were intubated and ventilated on oxygen and 1% to 2% isofluorane with a small-animal respirator (Harvard Apparatus). A peripheral vein catheter was placed. End-tidal PCO2 (pulse oximeter, Nellcor), body temperature (model 43TA, Yellow Springs), arterial PCO2 and PO2 (STAT profile 3 analyzer, Nova Biomedical), blood pressure (Criticon Dynamap), and heart rate were monitored and maintained in the physiological range. Under an operating microscope and sterile conditions, the right axillary artery was exposed and cannulated with a 20-gauge polyethylene catheter. A single midarterial phase, anteroposterior cerebral angiogram was obtained. The same exposure factors and magnification were used for every angiogram. The PaCO2 was lowered to 30 mm Hg, mannitol 0.5 g/kg IV was administered, and a right pterional craniectomy was performed. The arachnoid over the right ICA, MCA, and ACA was opened widely. SAH was simulated by placement of 6 to 7 mL clotted autologous blood over the exposed arteries.
The surgeon was then given an osmotic pump (Alzet model 2ML1, Alza Corp) and, in some animals, an Ommaya reservoir to implant. The surgeon did not know what drugs animals were receiving. The catheter of the pump and reservoir was placed along the right MCA.
After 7 days, angiography was repeated with the animals under general anesthesia as described above. The monkeys were exsanguinated under anesthesia, and the brains were removed. Specimens of MCA and brain were fixed in 10% buffered formalin. Hematoxylin and eosin histological sections of the right (clot side) and left (control side) sides of the brains from three animals in each group were studied for evidence of inflammation or other adverse effects from intracisternal injection of BQ-123 and TPA. Inflammation was indicated by the presence of polymorphonuclear or mononuclear lymphocytes and macrophages. Inflammation was assessed in the subarachnoid space of the sylvian fissure in the area where the blood clot was placed and in the periarterial and adventitial areas of the MCAs. The degree of inflammation was graded on a 3-point scale.
Dose and Administration of Placebo, BQ-123, and TPA
BQ-123 (Banyu Pharmaceutical Co) is a synthetic peptide that antagonizes the action of ET peptides on ETA receptors.4 In previous experiments in monkeys, 5 mg/kg per day administered by continuous intracisternal infusion almost completely prevented vasospasm. In the present experiment the same dose was tested as well as a higher dose to assess toxicity. TPA (Genentech) was administered as three 1-mg intracisternal injections delivered via the Ommaya reservoir every 12 hours starting 24 hours after induction of SAH.
Placebo monkeys received either one or two osmotic pumps and, in some cases, an Ommaya reservoir. All drugs and placebos injected were in physiological saline except TPA, which was reconstituted in sterile water. Three methods of placebo administration were used to account for the different methods of drug administration and to maintain blinding. There were no differences in the degree of vasospasm between the three methods of placebo administration, and the results for these animals are presented as a single group. The sterility of all injected solutions was confirmed by microbiological culture.
Data Analysis
An optical micrometer was used to measure cerebral arterial diameters at predetermined points along the extradural ICA (C3), intradural ICA (C4), ACA, MCA, and basilar artery. Measurements were conducted by a blinded investigator. Vasospasm was assessed within groups by comparison of angiograms taken before and 7 days after SAH. Vasospasm was classified as none (<10% reduction in diameter), mild (10% to 25% reduction), moderate (>25% to 50% reduction), or severe (>50% reduction). Comparisons within groups across time were by paired t test. Comparisons between groups at days 0 and 7 were by one-way ANOVA followed by a Bonferroni multiple comparison test if significant variance was found. Vasospasm, as assessed with the categorical scale described above, and inflammation were compared between groups at day 7 by Fisher's exact test. Data analysis was performed by a statistician blinded to the identity of the groups, and significance was taken at P<.05. Values are mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Physiological Variables
On day 0 there were no significant differences in physiological variables between the groups (Table 1
). On day 7 there was significant variance in heart rate and PaCO2 between groups, although there were no pairwise differences between groups. When comparisons were made within groups between days 0 and 7, there were significant decreases in weight in animals in the placebo, high-dose BQ-123, and high-dose BQ-123 plus TPA groups (P<.05, paired t test).
|
Angiographic Vasospasm
There were no differences in arterial diameters between the groups at baseline (Table 2, Figs 1 and 2). There was significant variance between groups in the diameters of the right C3 and C4, left C3, right MCA, and right ACA on day 7 (P<.05, ANOVA). Pairwise comparisons showed that the mean diameter of the right MCA was significantly less in the placebo group than in the high-dose BQ-123 plus TPA group.
|
|
|
Comparisons within groups between days 0 and 7 showed that animals in the placebo and high-dose BQ-123 groups developed significant reductions in diameters of the right C4 (-33±5% and -24±8%, P<.0005, respectively, paired t test), MCA (-36±7%, P<.0005 and -18±7%, P<.05, respectively, paired t test), and ACA (-30±5%, P<.0005 and -15±6%, P<.05, respectively, paired t test). Monkeys in the low-dose BQ-123 group had significant reductions in the diameter of the right ACA (-10±4%, P<.05, paired t test) and MCA (-16±4%, P<.01, paired t test). The only significant change in the high-dose BQ-123 plus TPA group was a 25±7% increase in diameter of the left C3 (P<.05).
Clinical and Pathological Findings
There were no differences in the volume of clot placed on day 0 (Table 3). On day 7 there was significantly less clot remaining in the subarachnoid space in monkeys in the high-dose BQ-123 and high-dose BQ-123 plus TPA groups (Table 3). Animals in the latter group had virtually complete clot clearance in all cases.
|
One monkey in the placebo group and two in the high-dose BQ-123 group died suddenly before day 7 angiography. The deaths were attributed to mass effect from the subarachnoid clot. Histopathological examination of the brains and MCAs from animals in groups not receiving TPA showed subarachnoid clot with mild inflammatory cell infiltration. The changes were indistinguishable between placebo and drug-treated animals. The MCAs showed contraction and changes consistent with the degree of vasospasm seen angiographically. There was significantly less inflammation in monkeys receiving TPA (P<.05, Fisher's exact test). There was no subarachnoid clot remaining, and the brain parenchyma and leptomeninges and MCAs appeared normal (Table 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
These results show that TPA is very effective at preventing vasospasm after SAH in monkeys. The combination of BQ-123 at 10 mg/kg per day with TPA was not associated with toxicity. It also resulted in dilation of the extracranial ICA, possibly because of the vasodilating effect of BQ-123 that could occur when blood clot was not present to cause vasospasm. BQ-123 alone reduced the severity of vasospasm to approximately 50% of that seen in placebo animals, although significant vasospasm of the MCA was still present. The prevention of vasospasm by TPA was associated with complete clot clearance on day 7. The infusion of a high dose of BQ-123 in a volume of 4 mL over 7 days also decreased the amount of subarachnoid clot. The degree of vasospasm in the two BQ-123 groups was similar, however, suggesting that clot clearance was not a mechanism of vasospasm prevention by BQ-123.
BQ-123 is a peptide that antagonizes actions of ETs on ETA receptors. In a prior study, monkeys treated with BQ-123 5 mg/kg per day did not develop significant vasospasm compared with placebo-treated animals, whereas animals treated with bosentan, an antagonist of ETA and ETB receptors, did develop vasospasm.17 The difference in receptor affinity may be important in the effects on vasospasm since ETA receptors usually mediate vasoconstriction, whereas ETB receptors usually mediate vasodilation.14 The groups treated with BQ-123 alone in this study showed a statistically insignificant but quite marked approximately 50% reduction in the severity of vasospasm. The reason for the differences between the two studies is unclear. Experimental studies of ET antagonists for prevention of vasospasm have produced conflicting results.15 16 17 18 19 20 21 22 23 24 25 The efficacy of BQ-123 has been variable in dogs and rats and may relate to technical and species differences.15 19 22 Other ET antagonists reduced vasospasm in dogs.20 21 23 24 25 Most of the currently available ET antagonists are not active against vasospasm when administered parenterally and require intracisternal application.
These results confirm prior experiments in monkeys and dogs that showed that intracisternal TPA prevents vasospasm.2 7 8 9 10 Of six experimental studies, only one failed to demonstrate efficacy of TPA for this indication.12 Results of phase 1 and 2 studies in humans were also promising,26 27 28 29 30 although a randomized, blinded trial of intracisternal TPA showed only trends in reduction in vasospasm with TPA.13 The lack of effect of TPA in that study was postulated to be due to a lower rate of clot clearance. The more complex, diffuse nature of the hemorrhage and of the subarachnoid space in humans might mean that multiple doses of TPA or wider opening of the basal cisterns is required to prevent vasospasm in humans. Alternatively, these results suggest that combination therapy with two agents that have shown promise in nonhuman primate models, TPA and the ET antagonist BQ-123, would be safe and possibly effective in humans.
In summary, TPA prevents vasospasm after SAH in monkeys. BQ-123, a peptide ET antagonist, also reduces the severity of vasospasm in this model and does not appear to interact with TPA. Combined therapy for vasospasm with TPA and an ET antagonist such as BQ-123 is feasible and may be worth assessing in humans.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by US Public Health Service National Institutes of Health grant NS25946-07. We thank Genentech, Inc for supplying TPA and Banyu Pharmaceutical Co for supplying BQ-123.
|
Footnotes |
|---|
Reprint requests to R.L. Macdonald, MD, Section of Neurosurgery, MC3026, University of Chicago Medical Center, 5841 S Maryland Ave, Chicago, IL 60637. E mail lmacdona@surgery.bsd.uchicago.edu.
Received March 11, 1996; revision received May 7, 1996; accepted May 22, 1996.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Duff TA, Louie J, Feilbach JA, Scott G. Erythrocytes are essential for development of cerebral vasculopathy resulting from subarachnoid hemorrhage in cats. Stroke. 1988;19:68-72.
2. Findlay JM, Weir BKA, Kanamaru K, Grace M, Gordon P, Baughman R, Howarth A. Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature. Can J Neurol Sci. 1989;16:28-40.[Medline] [Order article via Infotrieve]
3. Inagawa T, Yamamoto M, Kamiya K. Effect of clot removal on vasospasm. J Neurosurg. 1990;72:224-230.[Medline] [Order article via Infotrieve]
4. Mayberg MR, Okada T, Bark DH. The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage. J Neurosurg. 1990;72:634-640.[Medline] [Order article via Infotrieve]
5. Mizukami M, Kawase T, Usami T, Tazawa T. Prevention of vasospasm by early operation with removal of subarachnoid blood. Neurosurgery. 1982;10:301-307.[Medline] [Order article via Infotrieve]
6. Suzuki J, Onuma T, Yoshimoto T. Results of early operations on cerebral aneurysms. Surg Neurol. 1979;11:407-412.[Medline] [Order article via Infotrieve]
7. Findlay JM, Weir BKA, Steinke D, Tanabe T, Gordon P, Grace M. Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg. 1988;69:723-735.[Medline] [Order article via Infotrieve]
8. Findlay JM, Weir BKA, Gordon P, Grace M, Baughman R. Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm. Neurosurgery. 1989;24:491-498.[Medline] [Order article via Infotrieve]
9. Findlay JM, Weir BKA, Kanamaru K, Grace M, Baughman R. The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage. Neurosurgery. 1990;26:201-206.[Medline] [Order article via Infotrieve]
10. Peterson EW, Choo SH, Lewis AJ, Lach B, Bormanis J. Lysis of blood clot and experimental treatment of subarachnoid hemorrhage. In: Wilkins RH, ed. Cerebral Arterial Spasm. Baltimore, Md: Williams and Wilkins; 1980:625-627.
11. Seifert V, Eisert W, Stolke D, Goetz C. Efficacy of single intracisternal bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery. 1989;25:590-598.[Medline] [Order article via Infotrieve]
12. Hariton GB, Findlay JM, Weir BKA, Kasuya H, Grace MGA, Mielke BW. Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. Neurosurgery. 1993;33:691-697.[Medline] [Order article via Infotrieve]
13. Findlay JM, Kassell NF, Weir BKA, Haley EC Jr, Kongable G, Germanson T, Truskowski L, Alves WM, Holness RO, Knuckey NW, Yonas H, Steinberg GK, West M, Winn HR, Ferguson G. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995;37:168-178.[Medline] [Order article via Infotrieve]
14. Cosentino F, Katusic ZS. Does endothelin-1 play a role in the pathogenesis of cerebral vasospasm? Stroke. 1994;25:904-908.[Abstract]
15. Clozel M, Watanabe H. BQ-123, a peptidic endothelin ETA receptor antagonist, prevents the early cerebral vasospasm following subarachnoid hemorrhage after intracisternal but not intravenous injection. Life Sciences. 1993;52:825-834.[Medline] [Order article via Infotrieve]
16. Foley PL, Caner HH, Kassell NF, Lee KS. Reversal of subarachnoid hemorrhage-induced vasoconstriction with an endothelin-receptor antagonist. Neurosurgery. 1994;34:108-113.[Medline] [Order article via Infotrieve]
17. Hino A, Weir BKA, Macdonald RL, Thisted RA, Kim CJ, Johns LM. Prospective, randomized, double-blind trial of BQ-123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys. J Neurosurg. 1995;83:503-509.[Medline] [Order article via Infotrieve]
18. Matsumura Y, Ikegawa R, Suzuki Y, Takaoka M, Uchida T, Kido H, Shinyama H, Hayashi K, Watanabe M, Morimoto S. Phosphoramidon prevents cerebral vasospasm following subarachnoid hemorrhage in dogs: the relationship to endothelin-1 levels in the cerebrospinal fluid. Life Sci. 1991;49:841-848.[Medline] [Order article via Infotrieve]
19. Cosentino F, McMahon EG, Carter JS, Katusic ZS. Effect of endothelinA-receptor antagonist BQ-123 and phosphoramidon on cerebral vasospasm. J Cardiovasc Pharmacol. 1993;22(suppl 8):S332-S335.
20. Nirei H, Hamada K, Shoubo M, Sogabe K, Notsu Y, Ono T. An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs. Life Sci. 1993;52:1869-1874.[Medline] [Order article via Infotrieve]
21. Itoh S, Sasaki T, Ide K, Ishikawa K, Nishikibe M, Yano M. A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental cerebral vasospasm in dogs. Biochem Biophys Res Commun.. 1993;195:969-975.[Medline] [Order article via Infotrieve]
22. Itoh S, Sasaki T, Asai A, Kuchino Y. Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change in ETA receptor mRNA expression in a canine subarachnoid hemorrhage model. J Neurosurg. 1994;81:759-764.[Medline] [Order article via Infotrieve]
23. Willette RN, Zhang H, Mitchell MP, Sauermelch CF, Ohlstein EH, Sulpizio AC. Nonpeptide endothelin antagonist: cerebrovascular characterization and effects on delayed cerebral vasospasm. Stroke. 1994;25:2450-2456.[Abstract]
24. Roux S, Loffler BM, Gray GA, Sprecher U, Clozel M, Clozel JP. The role of endothelin in experimental cerebral vasospasm. Neurosurgery. 1995;37:78-86.[Medline] [Order article via Infotrieve]
25. Shigeno T, Clozel M, Sakai S, Saito A, Goto K. The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm. Neurosurgery. 1995;37:87-91.[Medline] [Order article via Infotrieve]
26. Findlay JM, Weir BKA, Kassell NF, Disney LB, Grace MGA. Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1991;75:181-188.[Medline] [Order article via Infotrieve]
27. Mizoi K, Yoshimoto T, Takahashi A, Fujiwara S, Koshu K, Sugawara T. Prospective study on the prevention of cerebral vasospasm by intrathecal fibrinolytic therapy with tissue-type plasminogen activator. J Neurosurg. 1993;78:430-437.[Medline] [Order article via Infotrieve]
28. Ohman J, Servo A, Heiskanen O. Effect of intrathecal fibrinolytic therapy on clot lysis and vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 1991;75:197-201.[Medline] [Order article via Infotrieve]
29. Stolke D, Seifert V. Single intracisternal bolus of recombinant tissue plasminogen activator in patients with aneurysmal subarachnoid hemorrhage: preliminary assessment of efficacy and safety in an open clinical study. Neurosurgery. 1992;30:877-881.[Medline] [Order article via Infotrieve]
30. Zabramski JM, Spetzler RF, Lee KS, Papadopoulos SM, Bovill E, Zimmerman RS, Bederson JS. Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 1991;75:189-196.[Medline] [Order article via Infotrieve]
Editorial Comment
Department of PharmacologySmooth Muscle Ion Channel GroupUniversity of Vermont Medical Research FacilityColchester, Vt
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
The study by Kim et al attempted to explore the role of ET-1 and ETA receptors in the evolution of cerebral vasospasm after SAH (induced by autologous blood) in the monkey. SAH is still a high-morbidity and -mortality medical problem that has not yet gained adequate preventive and therapeutic progress. Clot removal by TPA seems to provide significant therapeutic possibilities if early treatment can be delivered locally, as shown in many experimental and human studies in the past 5 years. However, cisternal or intrathecal administration of TPA is not a desired mode of drug delivery in severe neurological emergencies such as SAH. In addition, the delicate balance between thrombolysis and bleeding may force limited efficacy, leaving room for adjunct therapy that could maximize the prevention of cerebrovascular vasospasm. In this light, the study, as several other studies in the past,1R draws attention to ET-1, a potent vasoconstrictor peptide released from endothelium in response to stimuli such as free hemoglobin. ET-1, probably via ETA receptors, induces long-lasting vasospasm and mitogenic activity in blood vessels. By using a selective ETA receptor antagonist, BQ-123, delivered intracisternally, the authors were able to demonstrate less severe cerebral vasospasm; in fact, the combination of TPA and BQ-123 completely blocked the cerebrovasospasm. A straightforward interpretation of the data would suggest that indeed ET-1 via ETA receptors contributes to the evolution of cerebrovasospasm after SAH, and therefore an agent that blocks ETA receptors could eventually aid in treatment of SAH complications. It is, however, unfortunate that the study by Kim et al used a limited dose range of TPA (only one dose), which does not allow for gauging the contribution of benefits by TPA alone vis-a-vis possible liabilities and the possibility that extended efficacy could be sustained by combination therapy (TPA+ETA receptor antagonist) with superior therapeutic index. Such studies are highly warranted since more potent, nonpeptide, and orally bioavailable ETA receptor antagonists are now available (eg, SB21724) that allow for systemic (intravenous) or oral administration. In summary, there is an apparent rationale for combination therapy for prevention of cerebrovasospasm after SAH; a thrombolytic coupled to an antagonist of a potent cerebral vessel constrictor such as ET-1 makes perfect sense.
|
Selected Abbreviations and Acronyms |
|---|
|
Values are number of animals exhibiting the indicated degree of inflammation. There was significantly less inflammation in the right subarachnoid space and MCA of the high-dose BQ-123+TPA group compared with the other groups (P<.05).
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1R. Shigeno T, Clozel M, Sakai S, Saito A, Goto K. The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm. Neurosurgery.. 1995;37:87-90.
This article has been cited by other articles:
 |
|
 |
|
  L. N. Pierre, A. P. Davenport, and Z. S. Katusic Blockade and Reversal of Endothelin-Induced Constriction in Pial Arteries From Human Brain • Editorial Comment Stroke, March 1, 1999; 30(3): 638 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zuccarello, R. Boccaletti, A. Romano, R. M. Rapoport, and J. P. Muizelaar Endothelin B Receptor Antagonists Attenuate Subarachnoid Hemorrhage–Induced Cerebral Vasospasm • Editorial Comment Stroke, September 1, 1998; 29(9): 1924 - 1929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. FARACI and D. D. HEISTAD Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels Physiol Rev, January 1, 1998; 78(1): 53 - 97. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||