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(Stroke. 1998;29:1924-1929.)
© 1998 American Heart Association, Inc.

Original Contributions

Endothelin B Receptor Antagonists Attenuate Subarachnoid Hemorrhage–Induced Cerebral Vasospasm

Mario Zuccarello, MD; Riccardo Boccaletti, MD; Alberto Romano, MD; Robert M. Rapoport, PhD

From the Departments of Neurosurgery (M.Z., R.B., A.R.) and Pharmacology and Cell Biophysics (R.B., R.M.R.), University of Cincinnati College of Medicine, and Veterans Affairs Medical Center, Cincinnati, Ohio.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
Background and Purpose—While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET_A receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET_A and ET_B receptors, there are no reports on the possible attenuation of the spasm by selective ET_B receptor antagonists. The purpose of this study was to investigate whether (1) ET_B receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET_B (ET_B2) receptor–mediated constriction and/or endothelial ET_B (ET_B1) receptor– mediated ET-1–induced ET-1 release.

Methods—SAH-induced spasm of the rabbit basilar artery was induced with the use of a double hemorrhage model. In vivo effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 µL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window.

Results—SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 µmol/L BQ788, an ET_B1/B2 receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET_B1 receptor–mediated ET-1–induced ET-1 release, as opposed to ET_B2 receptor–mediated constriction, we tested whether ET_B1 receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 µmol/L RES-701-1, a selective ET_B1 receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 µmol/L BQ788 reversed the spasm by 40%, and 1 µmol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1–induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor.

Conclusions—These results demonstrate that ET_B receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET_B1 receptor–mediated ET-1–induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET_B1 receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1–induced ET-1 release.

Key Words: basilar artery • cerebral ischemia, transient • endothelins • vasodilation

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET_A receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET_A and ET_B receptors,^{1 2 3 4 5 6 7 8 9 10 11} there are no reports on the possible attenuation of the spasm by selective ET_B receptor antagonists. This lack of inquiry presumably reflects the considerations that ET-1 constriction of the cerebral vasculature is largely ET_A receptor mediated^{12 13 14 15 16 17 18 19} and that ET_B receptor blockade might actually enhance the spasm by prevention of ET_B receptor–mediated nitric oxide release.^{11 20}

However, there is also some evidence to suggest that ET_B receptor blockade may decrease the spasm. First, the ET-1– dependent spasm may be mediated not only by ET_A receptor activation but also by ET_B receptor activation. This suggestion is supported by our previous demonstration in situ that spasm of the rabbit basilar artery was only partially reversed by a selective ET_A receptor antagonist, and subsequent addition of an ET_A/B receptor antagonist was required to induce complete relaxation.²¹ Also consistent with the involvement of smooth muscle ET_B receptor activation in the spasm is the possible induction of functional ET_B receptors following SAH, as demonstrated by increased ET_B receptor binding and mRNA levels.^{7 22}

Second, we recently suggested that endothelial ET_B receptor activation maintains the spasm by the further release of ET-1.²³ This suggestion was based on the demonstration that intracisternal infusion of ET-1, and then cessation of the infusion, still induced ET-1–dependent spasm of the rabbit basilar artery.²³ Lending support to the possibility that endothelial ET_B receptor activation causes further ET-1 release²³ are reports of ET_B receptor–mediated ET-1/ET-3–induced ET-1 release/preproET-1 mRNA expression in cultured endothelial and mesangial cells.^{24 25 26 27} Therefore, the purpose of this study was to investigate whether (1) ET_B receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET_B (ET_B2) receptor– mediated constriction and/or endothelial ET_B (ET_B1) receptor– mediated ET-1–induced ET-1 release. Some of these results have appeared in abstract form.²⁸

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
Anesthesia
Procedures were approved by the Institutional Animal Care and Use Committee. A total of 69 New Zealand White male rabbits (weight, 3 to 4 kg) were used. Anesthesia was induced with ketamine HCl (30 mg/kg IM) and xylazine (6 mg/kg IM) and was maintained with sodium pentobarbital (25 mg/kg) administered through a catheter inserted into the subclavian artery (in vivo studies) or femoral vein (in situ studies).

Angiography
Vertebrobasilar angiograms were obtained on day 0 (pre-SAH) and on day 7 as follows. The left or right subclavian artery was catheterized, and the tip of a 5F catheter was directed toward the ipsilateral vertebral artery to obtain a selective injection of the vertebrobasilar system. Contrast medium (Angiovist 282) was injected (5 mL/s for 5 seconds), and images (4° left anterior oblique angle) of the vertebrobasilar system were obtained at 2 per second for 14 seconds with a rapid sequential angiographic technique. Digital subtraction analysis was performed with the small focal spot at 60 kV and 0.8 mA. Basilar artery diameter was measured by image analysis (ImagePro). Images were collected by placement of angiograms on a light box fixed with a video camera. Three measurements were made at levels just below the basilar-posterior cerebral artery junction, just above the basilar-vertebral artery junction, and midway between these locations, and these 9 values were averaged. Constriction was expressed as a percentage of the basilar artery diameter on day 7 relative to day 0.

Mini Osmotic Pump
Immediately after the day 0 angiogram, a mini osmotic pump (10 µL/h; Alza) containing either 10 µmol/L BQ788, an ET_B1/B2 receptor antagonist,²⁹ RES-701-1, an ET_B1 receptor antagonist,^{30 31 32 33} or vehicle was implanted in the neck, with the catheter placed into the cisterna magna.

Subarachnoid Hemorrhage
On days 1 and 3 after angiography, arterial blood was withdrawn from the central ear artery and injected (0.75 mL/kg) into the cisterna magna over 3 minutes through an additional catheter. For the in situ studies (no angiography or mini osmotic pump implantation), on days 0 and 2, blood was injected through a 21-gauge butterfly needle into the cisterna magna. Similar magnitudes of spasm were induced by blood injected through a catheter or needle inserted into the cisterna magna, as measured 6 days after the initial injection (see Results).

In Situ Studies
Rabbits were intubated and mechanically ventilated with room air supplemented with O₂. The respiratory rate and tidal volume were adjusted to maintain expiratory PCO₂ between 35 and 37 mm Hg. Heart rate and systemic pressure were measured with the use of a femoral artery catheter. Arterial PO₂ and PCO₂ were monitored and maintained within normal levels by adjusting the respiratory rate and/or tidal volume. Core body temperature was monitored rectally and maintained at 37°C with a heating pad.

To prepare the basilar artery cranial window, rabbits were placed in a head holder in the supine position, the clivus was exposed by blunt dissection between the carotid sheath and trachea, and the trachea and esophagus were retracted laterally. Compression of the carotid arteries and the descending vagus nerves was avoided. The muscle covering the basioccipital bone was removed by electrocautery. A rectangular osteotomy (4 to 5 mm wide) was then made at the base of the skull between the tympanic bullae with the use of a microdrill and microrongeur under an operating microscope. After a perfect hemostasis was achieved, the dura was opened and excised with microscissors, and the basilar artery was exposed. The blood clot was gently removed with microforceps. The surgical field was illuminated with a 100-W halogen lamp, which was fitted with a heat filter to avoid warming the cranial window, and was visualized through a trinocular microscope. Head temperature was monitored with a needle inserted in the residual longus colli muscle and was maintained at 37°C to 38°C.

The cranial window was suffused (1 mL/min) with artificial cerebrospinal fluid (mmol/L: NaCl 121.8, KCl 3.2, CaCl₂ 2.5, MgCl₂ 1.26, NaHCO₃ 25.0, D-glucose 3.7, urea 6.0), maintained at 37°C, and gassed with 7% O₂/6% CO₂/87% N₂. Vessel diameter, blood pressure, heart rate, and arterial PO₂ and PCO₂ stabilized within 45 minutes after suffusion with artificial cerebrospinal fluid, and agents were then suffused over the craniotomy. Basilar artery diameter, measured by image analysis with a video camera mounted on the phototube of the microscope, was recorded at the time of the plateau response to each agent.

Each value of vessel diameter was the mean of 13 consecutive measurements taken at approximately 10-second intervals. The magnitude of constriction was expressed as a percentage of basal diameter, measured in micrometers. The basal diameter used to calculate the magnitude of SAH-induced spasm was the mean of 156 measurements from present and historic non-SAH vessels and was 831 µm (SEM=7). The magnitude of relaxation was expressed as a percentage of the constriction, the latter measured as the difference in micrometers between basal and agonist-induced tone.

Statistical Methods
Statistical significance between 2 means and multiple means was determined with Student's unpaired t test and ANOVA, respectively. Significance was accepted at the 0.05 level of probability. Values are expressed as mean±SEM; n represents the number of animals.

Materials
Reagent sources were as follows: American Peptide Company for ET-1 and RES-701-1; Henry Schein for ketamine and xylazine; and Peptides International, Inc for BQ610, BQ788, and phosphoramidon. RES-701-1 was also obtained from Kyowa Hakko Kogyo Company, Ltd (gift), and PD145065 was obtained from Parke-Davis (gift).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
In Vivo Studies
SAH decreased basilar artery diameter by 30% (Figure 1). To test whether ET_B receptor blockade prevented the spasm, the selective ET_B receptor antagonist BQ788²⁹ was infused intracisternally in rabbits subjected to SAH. Indeed, BQ788 infusion (10 µmol/L; 10 µL/h) decreased the magnitude of spasm to 10% (Figure 1). BQ788 infusion in the absence of SAH did not alter basal diameter (Figure 1). Vehicle infusion also did not alter basal diameter or the magnitude of SAH-induced spasm (data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 1. Effects of ETB receptor antagonists on SAH-induced spasm of the rabbit basilar artery in vivo. Rabbits were subjected to SAH and, in some cases, with intracisternal infusions (via mini osmotic pump) of 10 µmol/L BQ788 or RES-701-1. Basilar artery diameter was measured with angiography. The magnitude of constriction is expressed as a percentage of the pre-SAH value. Values shown are mean±SEM; n, indicated in parentheses, represents the number of rabbits. *Significantly less than SAH and greater than BQ788 and RES-701-1 in the absence of SAH. Significantly less than BQ788 and RES-701-1 in the absence of SAH and significantly less than SAH.

To test whether the ability of BQ788 to prevent the spasm resulted from inhibition of ET-1–induced (1) constriction, due to blockade of smooth muscle ET_B (ET_B2) receptors, or (2) ET-1 release, due to blockade of endothelial ET_B (ET_B1) receptors, we utilized the ET_B1 selective antagonist RES-701-1.^{30 31 32 33} Intracisternal infusion of RES-701-1 (10 µmol/L; 10 µL/h) in rabbits subjected to SAH also decreased the spasm to 10% (Figure 1). RES-701-1 infusion in the absence of SAH did not alter basal diameter (Figure 1). Systolic and diastolic pressures of rabbits subjected to SAH were not altered by BQ788 and RES-701-1 (data not shown).

In Situ Studies
We then investigated whether ET_B receptor antagonists also reversed the spasm due to SAH. Thus, we tested whether BQ788 and RES-701-1 relaxed the spasm in situ. SAH induced 28% constriction (Figure 2), which was a magnitude of constriction similar to the spasm observed in vivo (Figure 1). BQ788 and RES-701-1 (1 µmol/L) in situ relaxed the spasm by 39% and 52%, respectively, and these magnitudes of relaxation were not significantly different (Figure 2).

View larger version (39K): [in this window] [in a new window]   Figure 2. Effects of ET receptor antagonists and phosphoramidon on SAH-induced spasm of the rabbit basilar artery in situ. Rabbits were subjected to SAH, and the resulting spastic vessels were challenged in situ with 1 µmol/L BQ788, 1 µmol/L RES-701-1 (synthetic and natural product), 1 µmol/L PD145065, or 100 µmol/L phosphoramidon. Constriction was calculated as a percentage of the non-SAH vessel baseline diameter (see Materials and Methods), and relaxation was calculated as a percentage of the constriction. Values shown are mean±SEM; n, indicated in parentheses, represents the number of rabbits. *Significantly greater than BQ788 and RES-701-1.

To further investigate whether the ability of the ET_B receptor antagonists to prevent as well as reverse the spasm resulted from inhibition of ET-1–induced (1) constriction, due to blockade of smooth muscle ET_B (ET_B2) receptors, or (2) ET-1 release, due to blockade of endothelial ET_B (ET_B1) receptors, we tested whether BQ788 and RES-701-1 also relaxed the constriction due to exogenous ET-1. That is, if the attenuation of the spasm by the ET_B receptor antagonists was the result of blockade of ET_B2-receptor–mediated constriction, then the ET_B receptor antagonists would also be predicted to relax the constriction elicited by exogenous ET-1.

Importantly, this test needed to be performed in vessels from rabbits subjected to SAH, since there is some evidence to suggest that SAH causes the induction of ET_B receptors.^{7 22} Thus, it was first necessary to eliminate the spasm associated with SAH, as well as any endogenous ET-1 release, before ET-1 challenge. Thus, we considered that the ET-1 released in spastic vessels was newly synthesized and tested whether spastic vessels were relaxed by phosphoramidon, an ET-converting enzyme inhibitor.³⁴

Phosphoramidon (0.1 mmol/L) relaxed the spasm by 74%. The magnitude of phosphoramidon-induced relaxation was not significantly different from the magnitude of relaxation to the ET_A/B receptor antagonist PD145065 (1 µmol/L; 81%; Figure 2).³⁵ Phosphoramidon-treated spastic vessels were not further relaxed by 1 µmol/L BQ788, RES-701-1, and PD145065 (data not shown). Phosphoramidon (100 µmol/L) did not alter the diameter of basilar artery from non-SAH rabbits (data not shown).

ET-1 constricted phosphoramidon-treated spastic vessels by 26% (Figure 3). In contrast to the relaxation of the spasm by the ET_B receptor antagonists (Figure 2), 1 µmol/L BQ788 and RES-701-1 enhanced the ET-1 constriction elicited in phosphoramidon-treated spastic vessels (51% and 47%, respectively; Figure 3). BQ788 and RES-701-1 (1 µmol/L) also enhanced the ET-1 constriction elicited in non-SAH vessels unexposed to phosphoramidon (M. Zuccarello, MD, et al, unpublished data, 1998).

View larger version (49K): [in this window] [in a new window]   Figure 3. Effects of ETB receptor antagonists on the ET-1 constriction elicited in phosphoramidon-treated spastic rabbit basilar artery in situ. Rabbits were subjected to SAH, and the resulting spasm was relaxed with 100 µmol/L phosphoramidon in situ (see Figure 2). In the continued presence of phosphoramidon, the vessels were reconstricted with 3 nmol/L ET-1, followed by 1 µmol/L BQ788 or 1 µmol/L RES-701-1 (synthetic and natural product). Constriction was calculated as a percentage of the baseline diameter observed in the presence of phosphoramidon, and relaxation was calculated as a percentage of the ET-1 constriction. Values shown are mean±SEM; n, indicated in parentheses, represents the number of rabbits.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
Spasm Attenuation
The present results represent the first demonstration that selective ET_B receptor antagonists attenuate SAH-induced cerebral vasospasm. Approximately two thirds of the spasm was prevented by intracisternal treatment with BQ788 and RES-701-1, ie, the spasm of 30% was reduced to 10% (Figure 1). A similar magnitude of protection was observed in this model after oral administration of the selective ET_A receptor antagonist PD155080 and the ET_A/B receptor antagonist bosentan.¹⁰

Consistent with the in vivo prevention of the spasm by the ET_B receptor antagonists, these antagonists also reversed the spasm in situ (Figure 2). Furthermore, the magnitude of reversal of the spasm in situ was similar to that observed in vivo (Figures 1 and 2), after the apparent magnitude of relaxation of the spasm due to phosphoramidon and PD145065 in situ was taken into account (74% and 81%, respectively; Figure 2).

Mechanism of Spasm Attenuation
The present results further suggest that the mechanism of ET_B receptor antagonist attenuation of the spasm is largely through blockade of ET_B receptor–mediated ET-1–induced ET-1 release, rather than blockade of ET_B receptor–mediated ET-1–induced constriction, as supported by the following (see working model of Figure 4). First, the ET_B receptor antagonists differentially affected the constriction associated with SAH, which is due to ET-1 release,²¹ and the constriction due to exogenous ET-1. Specifically, BQ788 and RES-701-1 relaxed the constriction associated with SAH and enhanced the constriction due to exogenous ET-1 (Figures 2 and 3, respectively). Thus, if an ET-1 release mechanism independent of ET_B receptor activation were not responsible for the SAH-induced spasm, then the ET_B receptor antagonists should have enhanced the constriction resulting from both SAH and exogenous ET-1. It should also be considered that an additional ET-1 release mechanism independent of ET_B receptor activation may be present, since the magnitude of reversal of the spasm by the ET_B receptor antagonists was less than that due to phosphoramidon and PD145065 (Figure 2).

View larger version (14K): [in this window] [in a new window]   Figure 4. Working model of the role of ET-1 in SAH-induced cerebral vasospasm. In response to SAH, numerous factors are released that act on the endothelium to cause the initial release of ET-1. ET-1 then induces (1) spasm through activation of smooth muscle ETA and ETB2 receptors; (2) further ET-1 release through activation of endothelial ETB1 receptors; and (3) nitric oxide (NO) release through activation of endothelial ETB1 receptors. While NO release under normal physiological conditions inhibits both the magnitude of ET-1 constriction and ET-1–induced ET-1 release, initially after SAH these negative modulatory effects are inhibited by the presence of hemoglobin (Hb). Thus, once ET-1–induced ET-1 release is established, the spasm no longer is dependent on the presence of Hb, which results in chronic ET-1–dependent spasm. 5-HT indicates 5-hydroxytryptamine; TGFß1, transforming growth factor-ß1.

A second observation in support of the suggestion that the ET_B receptor antagonist attenuation of the spasm is largely through blockade of ET_B receptor–mediated ET-1–induced ET-1 release is that RES-701-1, a selective ET_B1 receptor antagonist and thus an antagonist of endothelial ET_B receptors,^{30 31 32 33} effectively attenuated the spasm (Figures 1 and 2). RES-701-1 appears selective for the ET_B1 receptor since, in the basilar artery in situ, (1) the ET-1 constriction that remained after exposure to the selective ET_A receptor antagonist BQ610 was enhanced by RES-701-1 but was relaxed by BQ788 and (2) BQ788 relaxed the ET-1 constriction elicited in the presence of BQ610 and RES-701-1 (M. Zuccarello, MD, et al, unpublished data, 1998). However, the presence of ET_B1 as well as ET_B2 receptors in the basilar artery awaits more direct confirmation.

With respect to the selectivity of RES-701-1 as an ET_B1 receptor antagonist, such a selectivity was not observed by others.^{36 37} The inability to demonstrate ET_B1 selectivity for RES-701-1 may have been due to differences in the tertiary structure of the natural compared with the synthetic product.³⁸ In this regard, the present studies were performed with both natural and synthetic RES-701-1 (see Materials and Methods), and similar results were obtained. The apparent ET_B1 receptor selectivity of the currently used synthetic RES-701-1, compared with the synthetic RES-701-1 used by other investigators, may relate to differences in synthetic procedures (S. Lee, PhD, personal communication, 1997; although see Reference 36³⁶ ).

Third and finally, it should be noted that the ability of ET-1 to induce further ET-1 release through activation of ET_B receptors is consistent with several observations in the literature: (1) ET-1 activation of ET_B receptors induced ET-1 release^{24 25 26 27} ; (2) intravenous bolus infusion of ET-1 in rats induced a delayed pressor response that was inhibited by the ET_A receptor antagonist BQ123 and by phosphoramidon³⁴ ; and (3) intravenous bolus infusion of the selective ET_B receptor agonist IRL1620 in guinea pigs induced initial and secondary phases of bronchospasm that were blocked by BQ788, while only the secondary phase was inhibited by BQ123.³⁹

The present results also suggest that newly synthesized ET-1 is released as a result of ET_B1 receptor activation, since phosphoramidon greatly, if not completely, relaxed the vasospasm (Figure 1). It should be noted that these results represent the first demonstration of the reversal of chronic vasospasm through inhibition of ET-1 synthesis and are consistent with previous demonstrations that intraperitoneal infusion or intracisternal injection of ET-converting enzyme inhibitor initiated before SAH prevented the development of spasm in the rabbit and dog basilar artery^{40 41} and the recent demonstration of the reversal of acute spasm in the rabbit basilar artery.⁴²

In summary, these results demonstrate that ET_B receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET_B1 receptor–mediated ET-1–induced ET-1 release of newly synthesized ET-1. Clearly, the direct measurement of ET-1 release would further test this proposed mechanism. These studies provide rationale for the therapeutic use of ET_B1 receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1–induced ET-1 release.

	Acknowledgments

 
This study was supported by grants from the Department of Veterans Affairs and the Department of Neurosurgery, University of Cincinnati, College of Medicine (Ohio).

	Footnotes

 
Reprint requests to Robert M. Rapoport, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Ave, Cincinnati, OH 45267-0575. E-mail Robert.Rapoport@UC.EDU

Received March 11, 1998; revision received May 4, 1998; accepted May 28, 1998.

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Editorial Comment

J. Paul Muizelaar, MD, PhD, Guest Editor

Department of Neurosurgery, University of California, Davis Sacramento, California

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
Like so many other substances implicated in the induction of vasospasm after aneurysmal SAH, the role of ET becomes more and more complicated. The authors describe the roles of three different ET-1 receptors, one of which generates both a positive self-enhancing feedback loop (the ET_B1 receptor–mediated ET-1–induced ET-1 release) and a negative modulating effect through the release of nitric oxide.

The experiments were cleverly designed and well executed.

Although vasospasm in the rabbit basilar artery narrows the lumen by only 30%, which is much less than the clinically manifest vasospasm in aneurysmal SAH and therefore of uncertain significance, there is an interesting aspect to the results described in the accompanying article: Phosphoramide, a blocker of ET-1 synthesis, reversed for a good part the chronic vasospasm in this model. This is, to my knowledge, the first time that any substance has been shown to reverse (not prevent) chronic (not acute) vasospasm in the conducting arteries, and it makes one wonder what parts are played by smooth muscle contraction, vessel wall inflammation and thickening, and collagen lattice contraction in this particular model compared with the human situation.

Despite this encouraging finding, I remain skeptical about the prospect of identifying a single substance that works as a "silver bullet" in the prevention and treatment of aneurysmal vasospasm.

Reprint requests to Robert M. Rapoport, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Ave, Cincinnati, OH 45267-0575. E-mail Robert.Rapoport@UC.EDU

© 1998 American Heart Association, Inc.

Received March 11, 1998; revision received May 4, 1998; accepted May 28, 1998.

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