(Stroke. 2000;31:526.)
© 2000 American Heart Association, Inc.
Original Contributions |
Mechanism of Endothelin-1–Induced Contraction in Rabbit Basilar Artery
From the Department of Neurosurgery, University of Mississippi Medical Center, Jackson.
Correspondence to John Zhang, MD, PhD, Department of Neurosurgery, University Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail jzhang{at}neurosurgery.umsmed.edu
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Abstract |
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Background and Purpose—Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1–induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1–induced contraction.
Methods—PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1–induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1–stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot.
Results—(1) ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in rabbit basilar artery by activation of ETA but not ETB receptors. (2) MAPK inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1–induced contraction. (3) The Src tyrosine kinase inhibitor damnacanthal, the phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine kinase2 inhibitor AG-490 abolished ET-1–induced contraction. (4) The PKC inhibitor staurosporine but not calphostin C abolished ET-1–induced contraction, and the PTK inhibitor genistein partially reduced ET-1–induced contraction. (5) In arteries precontracted by ET-1, PD-98059, U-0126, wortmannin, AG-490, genistein, and staurosporine produced concentration-dependent relaxation. (6) ET-1 induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U-0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin, abolished the effect of ET-1 on MAPK immunoreactivity.
Conclusions—This study demonstrated that MAPK may be involved in ET-1–induced contraction in rabbit basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The possible involvement of PKC in ET-1–induced contraction requires further investigation. Inhibition of these pathways may offer alternative treatment for ET-1–induced contraction and cerebral vasospasm.
Key Words: cerebral vasospasm • endothelins • protein kinases • rabbits
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Endothelin-1 (ET-1) is a major cause of cerebral vasospasm after subarachnoid hemorrhage (SAH).1 The level of ET-1 in bloody cerebrospinal fluid is elevated in patients with SAH.1 ET-1 produces a potent and long-lasting vasoconstriction of cerebral arteries.1 In animals, intracisternal injection of ET-1 induces cerebral vasospasm that resembles the vasospasm in humans. Endothelin receptor antagonists, endothelin-converting enzyme inhibitors, and ET-1 antisense oligonucleotide prevent cerebral vasospasm in animal models.1
However, the mechanism of ET-1–induced contraction of cerebral arteries remains unclear. In peripheral arteries, ET-1 has been reported to act as an agonist for the G-protein–coupled receptors and the growth factor receptors.1 Thus, signals from both pathways may be involved in ET-1–induced contraction. We examined the effect of ET-1 in rabbit basilar artery using different inhibitors of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) as well as MAPK antibody in this study.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Materials
PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were purchased from BIOMOL. Endothelin-1, BQ-610, and BQ-788 were purchased from Calbiochem-Novabiochem Corp. U-0126 was purchased from Promega. Anti-MAPK (ERK1/ERK2) antibodies were purchased from Zymed Laboratories. Other chemicals were purchased from Sigma.
Isometric Tension
New Zealand White rabbits (n=45), of either sex and weighing 5
to 6 pounds, were anesthetized with an injection of thiopental
(20 mg/kg IV) and euthanatized by exsanguination. The basilar arteries
were removed and cut into 3-mm rings in a dissecting chamber filled
with modified Krebs-Henseleit bicarbonate solution, bubbled with 95%
O2/5% CO2. No attempt was
made to remove endothelial cells. The modified
Krebs-Henseleit solution contained the following (mmol/L): NaCl 120,
KCl 4.5, MgSO4 1, NaHCO3
27, KH2PO4 1,
CaCl2 2.5, and dextrose 10. All procedures were
approved by the Animal Care and Use Committee at the University of
Mississippi Medical Center.
The rings were suspended at 500 mg resting tension (Radnoti transducer, Radnoti Glass) between stainless steel hooks in 10-mL water-jacketed tissue baths (Radnoti Glass). The tissue bath was filled with modified Krebs-Henseleit buffer and bubbled with 95% O2/5% CO2 at 37°C. Rings were equilibrated for 90 minutes, and the bath solution was changed every 20 minutes. After equilibration, tissues were challenged with KCl (90 mmol/L) 2 times at 30-minute intervals to obtain stable contractions. Only data with recovery of 90% to 110% of the initial contraction by KCl (90 mmol/L) were included. Tension was recorded continuously with a force-displacement transducer, as described previously.2
Western Blot
The basilar arteries were removed from the base of the brain and
incubated with ET-1 (1 µmol/L) for 1, 3, 5, 10, 30, 60, and 120
minutes in Krebs-Henseleit buffer. Some arteries were treated with
specific antagonists for 30 minutes (see Materials) before
being treated with ET-1. After treatment, the arteries were immediately
frozen in liquid nitrogen. The arteries were homogenized
for 20 minutes at 4°C in the following (mmol/L): Tris-HCl (pH 7.5)
50, NaCl 100, EDTA 5, phenylmethylsulfonyl fluoride 1, and
IGEPAL CA-630 100 µL. The insoluble materials were removed by
centrifugation (13 000g, 10 minutes,
4°C). The samples (30 µg protein) were applied to 12.5% SDS-PAGE.
After electrophoretic transfer of the separated polypeptides to
nitrocellulose membrane, the membranes were blotted with 8% nonfat
milk in Tris-buffered PBS for 1 hour. The membranes were washed with
Tris-buffered PBS and incubated at 4°C overnight in a 1:5000 dilution
of mouse anti-MAPK antibodies (ERK1/ERK2, monoclonal mouse antibody,
Zymed Laboratories). These antibodies recognize both
phosphorylated and nonphosphorylated
MAPK. The nitrocellulose membranes were later washed with Tris-buffered
PBS and incubated with a 1:5000 dilution of goat anti-mouse IgG
antibody, linked with horseradish peroxidase. The enhanced
chemiluminescence system (Amersham) was used for visualization of
protein bands. The results were quantified by SigmaGel software (SPSS
Inc).
Data Analysis
Data are expressed as mean±SEM. Statistical differences between
the control and other groups were compared by 1-way ANOVA and then
Tukey-Kramer multiple comparison procedure (95% CI) if significant
variance was found. A value of P<0.05 was considered
statistically significant.
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Results |
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Effect of ET-1 on Contraction and MAPK Immunoprecipitation
The initial contraction was observed with 10-9 mmol/L ET-1, and the maximum contraction was not obtained even at 10-6 mmol/L of ET-1 in rabbit basilar artery (Figure 1
). Since the maximum contraction to ET-1
was not obtained, we could not calculate the pA2
values.
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Preincubation of the arteries with a selective
ETA receptor antagonist BQ-610
(10-6 mmol/L) significantly inhibited
ET-1–induced contraction (Figure 1A
). The selective
ETB receptor antagonist BQ-788
(10-6 mmol/L) was used in the same fashion
as BQ-610 but failed to reduce the effect of ET-1 (Figure 1B).
None of the inhibitors changed the resting tension
alone.
Five minutes of treatment with ET-1 (10-6
mmol/L) produced a significant elevation of MAPK immunoprecipitation in
the rabbit basilar artery samples (Figure 2). Pretreatment of tissues (30
minutes) with BQ-610 (10-6 mmol/L) but not
BQ-788 (10-6 mmol/L) prevented the
enhancement of MAPK immunoprecipitation induced by ET-1 (Figure 2).
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Effect of Inhibitors on ET-1–Induced
Contraction
MAPK inhibitors PD-98059 and U-0126 (100
µmol/L), preincubated with arteries for 30 minutes, significantly
reduced ET-1–induced contraction (Figure 3) (P<0.005 to
P<0.001, ANOVA). At a lower concentration (30
µmol/L), U-0126 but not PD-98059 produced significant inhibition
(P<0.05, ANOVA).
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The Src tyrosine kinase inhibitor damnacanthal, the
phosphatidylinositol-3 kinase (PI-3K) inhibitor wortmannin,
and the Janus tyrosine kinase (JAK2)
inhibitor AG-490 (30 µmol/L) were used in the same
manner as MAPK inhibitions and were found to abolish the contractile
effect of ET-1 (Figure 4).
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The PKC inhibitors calphostin C and
staurosporine and the PTK inhibitor genistein
were tested. Calphostin C inhibits both phorbol ester binding and
phosphotransferase activity of the PKC by binding to the regulatory
domain at the diacylglycerol/phorbol ester binding site.3
Staurosporine, a microbial alkaloid, interacts with the
catalytic moiety of the PKC. Calphostin C
(5x10-7 mmol/L) failed to reduce
ET-1–induced contraction, while staurosporine
(2x10-7 mmol/L) completely abolished it
(P<0.001, ANOVA) (Figure 5A and 5B). The PTK inhibitor genistein
(10-4 mmol/L), preincubated for 30 minutes,
produced partial inhibition of ET-1–induced contraction
(P<0.05, ANOVA) (Figure 5C).
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In another study the rings of rabbit basilar artery were precontracted
with ET-1 (10-6 mmol/L), and once a stable
contraction was obtained, cumulative concentrations of PD-98059,
U-0126, AG-490, wortmannin, damnacanthal, genistein
(10-6 to 10-4
mmol/L), and staurosporine (10-8 to
2x10-7 mmol/L) were applied. All agents
fully relaxed the sustained contraction induced by ET-1
(10-6 mmol/L) (Figure 6). Calphostin C was not used
because it failed to inhibit ET-1–induced contraction (Figure 5A).
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Effect of Inhibitors on MAPK
Immunoprecipitation
Endothelin-1 (10-6 mmol/L) produced a
time-dependent MAPK immunoprecipitation in rabbit basilar artery. The
effect of ET-1 was observed at 3 minutes, peaked between 5 and 30
minutes, decayed at 60 minutes, and was reelevated at 2 to 4 hours
(Figure 7).
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In another study inhibitors were applied for 30
minutes before the arteries were treated with ET-1
(10-6 mmol/L, 5 minutes). PD-98059, U-0126,
damnacanthal, AG-490 (3x10-5 mmol/L), and
genistein (10-4 mmol/L), but not
staurosporine (2x 10-7 mmol/L)
or wortmannin (3x10-5 mmol/L), abolished
the effect of ET-1 on MAPK immunoprecipitation (Figure 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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We have demonstrated the following: (1) ET-1 produced concentration-dependent contractions and MAPK immunoprecipitation in rabbit basilar arteries by activation of ETA but not ETB receptors. (2) The effects of ET-1 on contraction and MAPK immunoprecipitation were abolished by PTK-Src-JAK-MAPK inhibitors. PI-3K inhibitor abolished ET-1–induced contraction but not MAPK immunoprecipitation. (3) The contractile effect of ET-1 was probably mediated by multiple signaling pathways, ie, the PTK-Src-JAK-MAPK pathway and the PI-3K pathway, since inhibitors of all these pathways abolished the contractile effect of ET-1. (4) The possible involvement of the PKC pathway in ET-1–induced contraction requires further investigation.
Role of Endothelin in Cerebral Vasospasm
The role of ET-1 in cerebral vasospasm has been studied in the
following 4 directions: (1) Elevation of ET-1 was found in bloody
cerebrospinal fluid from vasospasm patients.1 The mean
concentration of ET-1 in cerebrospinal fluid obtained from SAH patients
was significantly higher than in healthy individuals.1
Plasma ET-1 concentrations at the onset of SAH in the patients with
vasospasm were significantly higher than those of healthy individuals,
and the high levels persisted for 3 to 14 days.1 (2) ET-1
produced a prolonged contraction of cerebral arteries. In isolated
middle cerebral arteries of the goat, ET-1 induced
Ca2+-dependent contraction. In addition, the
constrictor effect of ET-1 was enhanced after SAH.4
(3) ET-1 induced vasospasm in animal models. In the canine basilar
artery, ET-1 induced dose-dependent angiographic constriction after
intracisternal injection. By day 3, the diameter of the basilar artery
had diminished to 76% of the value seen in the control
group.5 (4) Endothelin receptor antagonists
prevented vasospasm.1 The nonselective endothelin receptor
antagonist bosentan reversed vasospasm in rabbit
single-hemorrhage and dog double-hemorrhage
models.6 In the monkey SAH model, BQ-123
(ETA receptor antagonist) effectively
prevented cerebral vasospasm.7 The endothelin-converting
enzyme levels increased after SAH,8 and
endothelin-converting enzyme inhibitors also attenuated
vasospasm after SAH.1 Antisense
oligonucleotide DNA therapy prevented vasospasm in a
canine model.9 Thus, even though some controversial
reports indicate a poor correlation between cerebrospinal fluid
endothelin levels and vasospasm10 and the failure of
ETA receptor antagonists to reverse
vasospasm,11 the overall picture supports the indication
that ET-1 is a major cause of cerebral vasospasm.1
Signal Transduction Pathways in ET-1–Induced Contraction
The action of endothelin is mediated by 3 different receptor
subtypes: ETA, ETB1, and
ETB2. The ETA receptor
subtype is localized in vascular smooth muscle cells and mediates the
vasoconstrictive effect of endothelins.1
The ETB1 receptor subtype is present in
vascular endothelial cells and mediates
endothelium-derived relaxation. The
ETB2 receptor subtype is located in smooth muscle
cells and causes vasoconstriction.1 Signal transduction
pathways after ET-1 stimulation were not studied systematically in
cerebral tissues.
In peripheral tissues, ET-1 stimulates pp60 c-Src and pp125 focal adhesion kinase activity, resulting in tyrosine phosphorylation of specific cellular proteins.12 Activation of c-Src by ET-1 might link G-protein–coupled receptors to the primary downstream targets of nonreceptor PTK. Simonson and Herman13 demonstrated that ET-1 caused a marked increase of the level of immunoreactive tyrosine phosphorylated proteins, suggesting that phosphorylation of PTK is a necessary step in the mitogenic response to ET-1. ET-1 activates small GTP-binding protein p21ras and increases the p21ras-associated PI-3K activity.14 Activation of PKC, PTK, PI-3K, and Ras may lead to the activation of MAPK in a variety of cells.15
We have demonstrated in this study that ET-1 produced contraction of rabbit basilar artery by activating ETA receptors. Activating ETA receptors (G-protein–coupled receptors) leads to the activation of phospholipase C and the generation of inositol 1,4,5-triphosphate and diacylglycerol. Diacylglycerol in turn theoretically activates PKC. Thus, it is not surprising that the PKC inhibitor staurosporine abolished the contractile effect of ET-1 in this study. Similar findings were reported in rat basilar and middle cerebral arteries in that H-7, another PKC inhibitor, significantly reduced ET-1–induced contraction, indicating that ET-1 produces contractions by activation of PKC.16 ET-1 induced a transient translocation of PKC activity from the cytosol to the membrane, and staurosporine reduced ET-1–induced contraction in bovine cerebral arteries.17 The failure of calphostin C in reducing ET-1–induced contraction in this study is actually consistent with some previous reports that staurosporine and H-718 but not calphostin C19 attenuated cerebral vasospasm in animal models. However, because of the discrepancy between the effects of staurosporine and calphostin C in this study, the role of PKC in ET-1–induced contraction in rabbit basilar artery remains unconfirmed and requires further investigation.
The contractile effect of ET-1 was either abolished or attenuated by
PTK, PI-3K, JAK2, Src, and MAPK
inhibitors, indicating that ET-1–induced contraction in
rabbit basilar arteries is mediated by multiple signaling pathways.
This result differs from our previous observation of hemolysate-induced
contraction in rabbit basilar arteries.2
Hemolysate-induced contraction was attenuated by PTK and MAPK
inhibitors2 20 but not reduced by PI-3K, Src,
or JAK2 inhibitors, indicating that
the signaling pathway for hemolysate is PTK-MAPK. To establish the
relationship between MAPK and other signaling pathways,
inhibitors for those pathways were tested on ET-1–induced
MAPK phosphorylation. ET-1–induced MAPK
immunoprecipitation was reduced by all but PKC and PI-3K
inhibitors (Figure 8), suggesting that ET-1–induced
contraction was mediated by multiple signaling pathways. PTK, Src, and
JAK2 probably mediated ET-1–induced contraction
by activating MAPK. It has been established that activation of PTK or
Src by receptor agonists may activate Ras, leading to the
activation of MAPK in rabbit basilar artery.15
JAK2 is required for MAPK activation by some
growth hormones, more likely through phosphorylation of
Raf-1.15 Growth hormone
receptor/JAK2–mediated activation of MAPK
(ERK1/ERK2) is dependent on both Ras and Raf-1.15 AG-490,
a specific inhibitor of JAK2,
prevents proliferation of vascular smooth muscle cells, complex
formation of JAK2 and Raf-1, tyrosine
phosphorylation of Raf-1, and thus activation of ERK1
in response to either angiotensin II or
platelet-derived growth factor.21 Even though MAPK and
other signaling pathways may be involved in ET-1–induced contraction
in rabbit basilar artery, and this observation is supported by
isometric tension and Western blot studies, these results should be
interpreted carefully because these studies depend heavily on the use
of inhibitors. Inhibitors of MAPK or other
signaling pathways may possess additional or nonspecific actions, and
further studies are needed to clarify the mechanism of ET-1–induced
contraction.
PI-3K may be involved in MAPK-independent ET-1–induced contraction in rabbit basilar arteries, since PI-3K inhibitor abolished ET-1–induced contraction but failed to prevent ET-1–induced MAPK immunoprecipitation. The possible involvement of PKC in ET-1–induced contraction is still debatable, but PKC may not be involved in ET-1–induced MAPK immunoprecipitation, since staurosporine but not calphostin C reduced ET-1–induced contraction and staurosporine failed to reduce ET-1–induced MAPK immunoprecipitation. The relationship between PKC and PI-3K in ET-1–induced contraction is not clear. One study indicated that PI-3K seemed downstream of PKC since the PI-3K inhibitor wortmannin inhibited ET-1–induced mitogenic responses in PKC activator PMA-treated and untreated Chinese hamster ovary cells.22 The role of PI-3K and PKC in ET-1–induced contraction requires further investigation.
Role of PTK, MAPK, and PKC in Cerebral Vasospasm
It has been suggested that PTK regulates intracellular
Ca2+ and contraction of cerebral smooth muscle
cells.20 23 PTK can either increase
Ca2+ release from internal
Ca2+ stores or Ca2+ entry
from external space. PTK may potentiate the sensitivity of contractile
proteins to Ca2+.24 The mechanism
for MAPK-related contraction is probably mediated by
phosphorylation of thin filament–associated proteins
such as caldesmon.25 The 2 isoforms 42 and 44 kDa
(ERK1/ERK2) are the most well-studied MAPK and are activated by
dual phosphorylations of the threonine and tyrosine
residues.15 Both PTK and MAPK have been suggested to be
involved in cerebral vasospasm. PTK is involved in the regulation of
intracellular Ca2+ in cultured
endothelial26 and smooth muscle
cells.23 PTK and MAPK are involved in the contractions of
rabbit basilar arteries by hemolysate.2 20 MAPK activity
was elevated in canine basilar arteries in a double-hemorrhage
model of experimental cerebral vasospasm.27 This study for
the first time demonstrated that PTK and MAPK are involved in
ET-1–induced contraction in cerebral arteries. Since both hemolysate
and ET-1 are extremely important spasmogens for cerebral
vasospasm1 2 and PTK and MAPK are involved in the signal
transduction of both hemolysate2 20 and ET-1 (this study),
PTK and MAPK may be important factors in the pathogenesis of cerebral
vasospasm.
It has been suggested that some upstream regulators such as PI-3K, JAK, and Src may be involved in the activation of MAPK.15 Src family kinases play an important role in relaying signals from both Gq- and Gi-coupled receptors to MAPK.28 It was shown that activating one of the proteins in this family, p56lck, led to a time-dependent activation of phosphotransferase activity of the MAPK in T cells.28 Angiotensin II stimulation was associated with a rapid activation of c-Src and activation of MAPK in vascular smooth muscle cells.29 PI-3K activation may be upstream of Ras activation, and PI-3K may be involved in the function of Src, Shc, and Grb2.30 It has been reported that the p110 subunit of PI-3K binds to an effector domain of Ras in vitro,30 and the PI-3K inhibitor wortmannin reduced insulin-induced MAPK activity.31 The JAK2 family is a key mediator of mRNA expression characterized as "early growth response genes."32 Recent studies have established that JAK2 associates with membrane receptors and, when activated, stimulates tyrosine phosphorylation of a family of transcription factors termed signal transducers and activators of transcription (STAT). STAT proteins translocate to the nucleus, where they stimulate transcription of early growth response genes. JAK2 PTK may represent a common component in the activation of MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with MAPK phosphorylation.25 The role of JAK2 in smooth muscle contraction is unclear, even though activation of 5-HT2A receptor in skeletal muscles triggers a rapid and transient tyrosine phosphorylation of JAK2 kinase. On the basis of the data obtained in this study, it is likely that PTK, JAK, and Src are involved in ET-1–induced contraction and MAPK immunoprecipitation in rabbit basilar arteries. PI-3K, if involved in ET-1–induced contraction, seems to mediate the contractile action of ET-1 by other mechanisms, since wortmannin failed to reduce ET-1–induced MAPK immunoprecipitation. These results are also distinct from those observed previously with hemolysate.2 None of the proteins PI-3K, JAK, and Src were involved in hemolysate-induced contraction of rabbit basilar arteries.
PKC and endothelin are 2 important factors in cerebral vasospasm.1 33 PKC produces prolonged contraction of cerebral arteries and may lead to contraction by activation of PTK and MAPK.32 ET-1 produces prolonged contraction, and endothelin receptor antagonists attenuate cerebral vasospasm in animal models. However, the relationship between endothelin and PKC has not been established. This study failed to confirm this relationship because of the discrepancy in the effectiveness of staurosporine and calphostin C in reducing ET-1–induced contraction. This study, on the other hand, pointed out that ET-1–induced contraction seems to be mediated by multiple signaling pathways, and ET-1–induced MAPK immunoprecipitation may be PKC independent. The effect of staurosporine, which reduced the contraction of ET-1 but failed to decrease MAPK immunoprecipitation, offered some evidence of this.
Conclusion
We have demonstrated that the signal transduction pathways
for ET-1 in rabbit basilar arteries may involve different proteins,
including Src, JAK2, PI-3K, PTK, and MAPK. Among
them, the Src-JAK2-PTK-MAPK pathway seems
connected in contraction and activation of MAPK, and MAPK may serve as
a final common pathway. PI-3K may be involved in ET-1–induced
contraction, although probably by other MAPK-unrelated mechanisms. The
role of PKC is uncertain, but it may not be involved in ET-1–induced
MAPK immunoprecipitation. The role of these proteins in ET-1–induced
contraction and the possible use of these inhibitors in
cerebral vasospasm require further investigation.
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Acknowledgments |
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This work was supported in part by a grant-in-aid to Dr Zhang from the American Heart Association.
Received September 7, 1999; revision received November 15, 1999; accepted November 15, 1999.
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Editorial Comment
Department of Anesthesiology, Baylor College of Medicine, Houston, Texas
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Endothelin (ET), a 21-residue peptide, is the most potent vasoconstrictor currently known.R1 In the human and other mammalian species there are 3 separate isopeptides termed ET-1, ET-2, and ET-3.R2 ET-1 is the only isoform of the peptide produced by the endothelium.R2 R3 R4 The characteristics of the ET-1–produced constrictions make it an ideal candidate as a mediator of vasospasm.R5 Although not without controversy, evidence is mounting for a key role of ET in the development of vasospasm (see the Discussion section of the above article).
This article by Zubkov et al identifies protein kinases likely to be involved with ET-1 constrictions of cerebrovascular smooth muscle and raises the possibility that several pathways are involved in the response. Of significance, the study underscores the complexity of the ET-1 signaling process. This article is significant for 2 reasons. First, it provides important information regarding the signal transduction pathways associated with ET-1 in vascular smooth muscle. Second, it provides a framework around which therapeutic approaches for the clinical treatment of vasospasm can be considered.
Received September 7, 1999; revision received November 15, 1999; accepted November 15, 1999.
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