Role of Tyrosine Kinase in Serotonin-Induced
Constriction of the Basilar Artery In Vivo
Takanari Kitazono, MD; Setsuro Ibayashi, MD; Tetsuhiko Nagao, MD; Tomoko Kagiyama, MD;
Jiro Kitayama, MD; Masatoshi Fujishima, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Serotonin is one of the most potent constrictors of cerebral blood vessels and is implicated in
several pathological conditions, including migraine and cerebral ischemia. Recent evidence has suggested that tyrosine
kinase is involved in vasocontractile responses. The objective of this study was to test the hypothesis that activation of
tyrosine kinase contributes to serotonin-induced constriction of the basilar artery in vivo.
Methods—Using a cranial window in anesthetized Sprague-Dawley rats, we examined effects of inhibitors of tyrosine kinase
and tyrosine phosphatase on constrictor responses of the basilar artery to serotonin in vivo.
Results—Serotonin (1028, 1027, and 1026 mol/L) produced constriction of the basilar artery by 1262%, 2762%, and 3763%,
respectively. Genistein (331026 mol/L), an inhibitor of tyrosine kinase, did not affect baseline diameter of the basilar artery
but attenuated serotonin-induced vasoconstriction (P,.05 versus control responses). Daidzein, an inactive analogue of
genistein, did not affect serotonin-induced constriction of the basilar artery. Tyrphostin 47 (1025 mol/L), another inhibitor
of tyrosine kinase, also attenuated serotonin-induced vasoconstriction, and tyrphostin 63, an inactive analogue of
tyrphostin 47, did not affect the vasoconstriction. Sodium orthovanadate (1025 mol/L), an inhibitor of tyrosine
phosphatase, enhanced serotonin-induced vasoconstriction. Phorbol 12,13-dibutyrate, a direct activator of protein kinase
C, also caused constriction of the basilar artery, which was not affected by genistein or sodium orthovanadate.
Conclusions—These results suggest that serotonin-induced constriction of the basilar artery is mediated, at least in part, by
activation of tyrosine kinase in vivo. (Stroke. 1998;29:494-498.)
Key Words: cerebral arteries n genistein n protein kinase C n tyrphostin
C
erebral blood vessels are richly innervated by serotonergic
nerve fibers.1 Although serotonin causes dilatation of small
cerebral arterioles,1 it has potent constrictive actions on large
cerebral arteries such as basilar artery.1–5 It is also suggested that
serotonin has an important role in several pathological conditions including migraine, cerebral vasospasm, and cerebral
ischemia.1 Murray et al2,3 have found a role of calcium and
protein kinase C in serotonin-induced constriction of the
basilar artery.2,3 However, the precise mechanism by which
serotonin produces constriction of the basilar artery is not fully
understood.
Activity of tyrosine kinase appears to be an important
determinant of cell growth and oncogenesis.6 Recent evidence
has suggested that the activity of tyrosine kinase has a major
influence on the contractility of vascular smooth muscle in
vitro.5,7–10 There are no data, however, regarding the role of
tyrosine kinase in constrictor responses of cerebral arteries in
vivo. Because vascular responses in vivo may not be same as
those in vitro, it is valuable to study the mechanisms of vascular
responses in vivo. Thus, the goal of the present study was to
response to serotonin is mediated by activation of tyrosine
kinase in vivo. For this purpose, we tested the effects of
test the hypothesis that constriction of the basilar artery in
See Editorial Comment, page 498
inhibitors of tyrosine kinase, genistein11,12 and tyrphostin 47,12
on serotonin-induced vasoconstriction using a cranial window
technique.
Materials and Methods
Animal Preparation
Experiments were performed on male Sprague-Dawley rats
(mean6SEM weight, 35469 g; mean6SEM age, 3.760.1 month;
n536) anesthetized with amobarbital (50 mg/kg IP). Anesthesia was
supplemented intravenously at 20 to 25 mg/kg per hour. The trachea
was cannulated, and the animals were mechanically ventilated with
room air and supplemental oxygen. Skeletal muscle paralysis was
produced with d-tubocurarine chloride (2 mg/kg). Depth of anesthesia was evaluated by applying pressure to a paw or the tail and
observing changes in heart rate or blood pressure. When such changes
occurred, additional anesthetic was administered. Catheters were
placed in both femoral arteries to measure systemic arterial pressure
and to obtain arterial blood samples. A femoral vein was cannulated for
infusion of drugs.
A craniotomy was prepared over the ventral brain stem as previously described in detail.13 After a part of the dura was opened, the
cranial window was suffused with artificial cerebrospinal fluid
(temperature537°C; ionic composition [in mmol/L]: 132 NaCl, 2.95
KCl, 1.71 CaCl2, 0.65 MgCl2, 24.6 NaHCO3, 3.69 D-glucose) that
Received July 22, 1997; final revision received October 14, 1997; accepted November 20, 1997.
From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Correspondence to Takanari Kitazono, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3–1-1,
Higashi-ku, Fukuoka 812, Japan. E-mail [email protected]
© 1998 American Heart Association, Inc.
494
Kitazono et al
495
was bubbled continuously with 5% CO2 and 95% N2. Cerebrospinal
fluid sampled from the cranial window had a pH of 7.4260.01, a PCO2
of 3661 mm Hg, and a PO2 of 10963 mm Hg. The diameter of the
blood vessel was measured with a microscope equipped with a
television camera coupled to an autowidth analyzer (C3161,
Hamamatsu Photonics K.K.).
After a craniotomy was prepared, pH, PCO2, and PO2 of arterial
blood were adjusted by changing rate and volume of the respirator and
the oxygen content of inspiratory air. Arterial blood gas monitored
during the experiments had a pH of 7.4460.01, a PCO2 of
3761 mm Hg, and a PO2 of 11966 mm Hg.
Experimental Protocol
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
We examined responses of the basilar artery to topical application of
serotonin (1028 to 1026 mol/L). Serotonin was mixed in artificial
cerebrospinal fluid and suffused over the craniotomy for 5 minutes.
Diameters of the basilar artery were measured immediately before and
during the last minute of application of the agonist. We used two
different inhibitors of tyrosine kinase11,12: genistein and tyrphostin 47.
To show specificity of these inhibitors, we used daidzein, an inactive
analogue of genistein,14 and tyrphostin 63, an inactive analogue of
tyrphostin 47.12 We also used sodium orthovanadate, an inhibitor of
tyrosine phosphatase.15 Genistein, daidzein, and tyrphostins were
dissolved in dimethyl sulfoxide (DMSO). The maximum final concentration of DMSO was 0.05%, and the concentration of DMSO did
not cause any significant changes in diameter of the basilar artery (data
not shown). Sodium orthovanadate was dissolved in saline. Inhibitors
were suffused starting from 15 minutes before and during application
of the agonist. Topical application of these agents did not cause any
changes in systemic arterial pressure (data not shown).
We next examined responses of the basilar artery to phorbol
12,13-dibutyrate (PDBu) (1028 to 1027 mol/L), a direct activator of
protein kinase C.16 PDBu was mixed in DMSO and suffused over the
craniotomy for 15 minutes. Because phorbol esters are metabolized
slowly, they persist in the cell membrane for long periods of time.17
For this reason, PDBu was applied to the basilar artery only once
during an experiment, either in the absence or the presence of
inhibitors. The maximum final concentration of DMSO was 0.1% in
these experiments. The concentration of DMSO did not cause any
significant changes in diameter of the basilar artery (data not shown).
Statistical Analysis
All values were expressed as mean6SEM. One-way repeatedmeasures ANOVA was used to compare concentration-dependent
responses to vasoconstrictors. Two-way repeated-measures ANOVA
was used to compare responses under control conditions and during
interventions. When a significant F value was found, post hoc analysis
was made with Wilcoxon’s test for responses to serotonin and
Mann-Whiteny’s U test for responses to PDBu. A value of P,.05 was
considered significant.
Results
Effects of Genistein on
Serotonin-Induced Vasoconstriction
Under control conditions, the diameter of the basilar artery
was 25565 mm (n536). Topical application of serotonin
(1028, 1027, and 1026 mol/L) produced constriction of the
basilar artery by 1262%, 2762%, and 3763%, respectively
(Fig 1). Serotonin-induced vasoconstriction was reproducible,
since there was no significant attenuation of the response
during repeated application of serotonin (n56, data not
shown). Genistein (331026 mol/L), an inhibitor of tyrosine
kinase,11 had no effect on baseline diameter of the basilar artery
but attenuated serotonin-induced vasoconstriction (Fig 1). In
the presence of 331026 mol/L genistein, serotonin (1028 and
1027 mol/L) produced constriction of the artery by 361% and
1562%, respectively (P,.05 versus control responses, Fig 1).
Figure 1. Effects of genistein on serotonin-induced vasoconstriction. Changes in diameter of the basilar artery were measured in response to serotonin (1028 to 1026 mol/L) under control conditions and in the presence of genistein (331026 mol/L).
Baseline diameters in the absence and the presence of
genistein were 248614 and 255612 mm, respectively. Values
are mean6SEM (n56). *P,.05 vs control response.
Serotonin (1026 mol/L) caused constriction of the basilar artery
by 3062% in the presence of genistein, which is similar to
control responses. Daidzein, an inactive analogue of
genistein,14 did not affect serotonin-induced constriction of the
basilar artery. In the presence of 331026 mol/L daidzein,
serotonin (1028, 1027, and 1026 mol/L) produced constriction
of the basilar artery by 1062%, 2562%, and 3762%,
respectively.
Effects of Tyrphostin 47 on
Serotonin-Induced Vasoconstriction
We also tested the effects of tyrphostin 47, another inhibitor of
tyrosine kinase, on serotonin-induced vasoconstriction. Under
control conditions, serotonin (1028, 1027, and 1026 mol/L)
produced constriction of the basilar artery by 1161%, 2461%,
and 3863%, respectively (Fig 2). Tyrphostin 47 (1025 mol/L)
did not affect the baseline diameter of the basilar artery but
inhibited serotonin-induced constriction of the basilar artery
(P,.05) (Fig 2). In the presence of 1025 mol/L tyrphostin 47,
serotonin (1028, 1027, and 1026 mol/L) produced constriction
of the artery by 462%, 1161%, and 2061%, respectively
(P,.05 versus control responses) (Fig 2). Tyrphostin 63, an
inactive analogue of tyrphostin 47, did not affect serotonininduced constriction of the basilar artery. In the presence of
1025 mol/L tyrphostin 63, serotonin (1028, 1027, and 1026
mol/L) produced constriction of the basilar artery by 1161%,
2563%, and 3864%, respectively. Thus, constrictor responses
of the basilar artery to serotonin are mediated, at least in part,
by activation of tyrosine kinase in vivo.
Effects of Sodium Orthovanadate on
Serotonin-Induced Vasoconstriction
We next tested effects of sodium orthovanadate, an inhibitor of
tyrosine phosphatase,15 on serotonin-induced constriction of
the basilar artery. Under control conditions, serotonin (1028,
1027, and 1026 mol/L) produced constriction of the basilar
496
Tyrosine Kinase and Vasoconstriction In Vivo
Effects of Genistein and Sodium Orthovanadate on
PDBu-Induced Vasoconstriction
PDBu (log mol/L)
28
27.5
27
Control
21262
22163
23064
Genistein
21062
22064
22764
Sodium orthovanadate
21563
22063
22965
Changes in diameter of the basilar artery were measured in response to phorbol
12,13-dibutyrate (PDBu) (1028 to 1027 mol/L) under control conditions and in the
presence of genistein (331026 mol/L) and sodium orthovanadate (1025 mol/L).
Baseline diameters under control conditions and in the presence of genistein and
sodium orthovanadate were 240610, 238614, and 23764 mm, respectively.
Values are mean6SEM, expressed as percentages (n56).
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Figure 2. Effects of tyrphostin 47 on serotonin-induced vasoconstriction. Changes in diameter of the basilar artery were
measured in response to serotonin (1028 to 1026 mol/L) under
control conditions and in the presence of tyrphostin 47 (1025
mol/L). Baseline diameters in the absence and the presence of
tyrphostin 47 were 244610 and 23967 mm, respectively. Values
are mean6SEM.(n56). *P,.05 vs control response.
artery by 661%, 2162%, and 3363%, respectively (Fig 3). In
the presence of 1025 mol/L sodium orthovanadate, serotonin
(1028 and 1027 mol/L) caused vasoconstriction by 1362% and
3165%, respectively (P,.05 versus control responses) (Fig 3).
Serotonin (1026 mol/L) caused constriction of the basilar artery
by 3863% in the presence of sodium orthovanadate, which
was not different from control responses.
Effects of Genistein and Sodium Orthovanadate
on PDBu-Induced Vasoconstriction.
Topical application of PDBu (1028, 331027, and 1027 mol/L)
produced constriction of the basilar artery by 1262%, 2163%,
Figure 3. Effects of sodium orthovanadate on serotonin-induced vasoconstriction. Changes in diameter of the basilar
artery were measured in response to serotonin (1028 to 1026
mol/L) under control conditions and in the presence of sodium
orthovanadate (131025 mol/L). Baseline diameters in the
absence and the presence of sodium orthovanadate were
24766 and 23869 mm, respectively. Values are mean6SEM
(n56). *P,.05 vs control response.
and 3064%, respectively. Neither genistein nor sodium orthovanadate affected PDBu-induced vasoconstriction (Table).
Thus, constriction of the basilar artery to activation of protein
kinase C is not mediated by activation of tyrosine kinase
in vivo.
Discussion
The major new finding in the present study is that constriction
of rat basilar artery in response to serotonin is mediated, at least
in part, by activation of tyrosine kinase in vivo. Because
PDBu-induced vasoconstriction is not affected by genistein or
sodium orthovanadate, activation of tyrosine kinase may not be
involved in protein kinase C– dependent constriction of the
basilar artery in vivo.
The first evidence regarding the role of tyrosine kinase in
vasocontractile responses was based on the observation that
epidermal growth factor (EGF) produces contractile responses
as well as growth of vascular muscle.7 It is well known that the
activity of tyrosine kinase presents in EGF receptors and has a
major influence on cell growth.6,18 Recently, it has also been
reported that tyrosine kinase plays a role in EGF-induced
vasocontraction.7 Toma et al9 have shown that contractile
responses of rat mesenteric arteries to norepinephrine, whose
receptors do not contain the activity of tyrosine kinase and are
coupled to GTP-binding protein,19 are mediated in part by
activation of tyrosine kinase in vitro. Abebe et al8 have also
reported that activation of tyrosine kinase is involved in
norepinephrine-induced contraction of rat aorta in vitro.
Thus, the activity of tyrosine kinase may be one of the major
regulators of vasocontractile responses.
In the present study we have found, using a cranial window
technique, that inhibition of tyrosine kinase markedly attenuates serotonin-induced constriction of the basilar artery and
sodium orthovanadate, an inhibitor of tyrosine phosphatase,
conversely enhances the vasoconstriction. Thus, activation of
tyrosine kinase may also contribute to serotonin-induced
constriction of the basilar artery in vivo. This is the first report
thus far to show the presence of the activity of tyrosine kinase
in cerebral blood vessels in vivo and to show the role of the
kinase in contractile responses of the basilar artery to agonists.
A major concern regarding the findings mentioned above
might be specificity of the inhibitors. In the present study both
331026 mol/L genistein and 1025 mol/L tyrphostin 47 had
good inhibitory effects on the vasoconstriction, and these
Kitazono et al
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
concentrations are very close to half-maximum concentrations
for inhibition of tyrosine kinase.11,12 Moreover, daidzein and
tyrphostin 63, inactive analogues of genistein14 and tyrphostin
47,12 did not affect serotonin-induced vasoconstriction. Thus,
the inhibitory effects of genistein and tyrphostin 47 are likely to
be specific for tyrosine kinase. The finding that genistein did
not affect PDBu-induced constriction of the basilar artery may
also support our interpretation that the inhibitory action of
genistein and tyrphostin 47 on vasoconstriction may be specific
for tyrosine kinase. The concentration of sodium orthovanadate (1025 mol/L) is also very close to half-maximum concentration for inhibition of tyrosine phosphatase.15 The finding
that the concentration of sodium orthovanadate did not affect
PDBu-induced vasoconstriction may also support the interpretation that the inhibitory effects of sodium orthovanadate may
not be nonspecific.
Serotonin appears to activate phospholipase C through
GTP-binding protein and thereby produces inositol 1,4,5trisphosphate and diacylglycerol.20 Inositol 1,4,5-trisphosphate
increases cytoplasmic Ca21 level by means of activation of
intracellular Ca21stores,21 and diacylglycerol activates protein
kinase C.16,21 It is reported that serotonin-induced constriction
of the basilar artery is mediated in part by activation of protein
kinase C in vivo.2,3 Thus, we next tested the role of tyrosine
kinase in constriction of the basilar artery produced by activation of protein kinase C. PDBu, a direct activator of protein
kinase C,16 produced constriction of the basilar artery, which
was not affected by genistein or sodium orthovanadate. Thus,
PDBu-induced constriction of the basilar artery may not be
mediated by activation of tyrosine kinase in vivo. The findings
are similar to the recent studies of noncerebral blood vessels.5,8
It is reported that tyrosine kinase inhibitors attenuate agonistinduced increase in the cytoplasmic Ca21 level of vascular
muscle.9,22 Thus, it may be possible that tyrosine kinase has a
role in calcium signaling of the basilar arterial muscle in vivo.
Masumoto et al10 have reported that activation of tyrosine
kinase is involved in pressure-induced contraction of rat
cerebral artery in vitro. Thus, it may be possible that inhibition
of tyrosine kinase affected the resting (myogenic) tone of the
basilar artery. In the present study, however, neither genistein
nor tyrphostin 47 affected the baseline diameter of the basilar
artery. Activation of tyrosine kinase appears to be involved in
nitric oxide production of vascular endothelial cells.23 Thus,
inhibition of tyrosine kinase may have attenuated dilator
responses as well as constrictor responses of the basilar artery
and thereby masked the inhibitory effects of tyrosine kinase
inhibitors on myogenic tone under control conditions. Another possibility may be that some compensatory mechanisms
may have counteracted the inhibitory actions of genistein and
tyrphostin 47 on myogenic tone under control conditions
in vivo.
In summary, activation of tyrosine kinase may be involved
in constrictor responses of rat basilar artery to serotonin in
vivo. Protein kinase C– dependent constriction of the basilar
artery may not be mediated by activation of tyrosine kinase.
497
Acknowledgments
This study was supported by a research grant for cardiovascular diseases
(6A-3) from the Ministry of Health and Welfare and a grant from
Sankyo Foundation of Life Sciences.
References
1. Bonvento G, MacKenzie ET, Edvinsson L. Serotonergic innervation of the
cerebral vasculature: relevance to migraine and ischemia. Brain Res
Rev. 1991;16:257–263.
2. Murray MA, Faraci FM, Heistad DD. Role of protein kinase C in constrictor responses of the rat basilar artery in vivo. J Physiol (Lond). 1992;
445:169 –179.
3. Murray MA, Faraci FM, Heistad DD. Signal transduction pathways in
constriction of the basilar artery in vivo. Hypertension. 1992;19:739 –742.
4. Nishimura Y. Characterization of 5-hydroxytryptamine receptors
mediating contractions in basilar arteries from stroke-prone spontaneously
hypertensive rats. Br J Pharmacol. 1996;117:1325–1333.
5. Watts SW, Yeum CH, Campbell G, Webb RC. Serotonin stimulates
protein tyrosyl phosphorylation and vascular contraction via tyrosine
kinase. J Vasc Res. 1996;33:288 –298.
6. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient
versus sustained extracellular signal-regulated kinase activation. Cell. 1995;
80:179 –185.
7. Hollenberg MD. Tyrosine kinase pathways and the regulation of smooth
muscle contractility. Trends Pharmacol Sci. 1994;15:108 –114.
8. Abebe W, Agrawal DK. Role of tyrosine kinases in norepinephrineinduced contraction of vascular smooth muscle. J Cardiovasc Pharmacol.
1995;26:153–159.
9. Toma C, Jensen PE, Prieto D, Hughes A, Mulvany MJ, Aalkjaer C. Effects
of tyrosine kinase inhibitors on contractility of rat mesenteric resistance
arteries. Br J Pharmacol. 1995;114:1266 –1272.
10. Masumoto N, Nakayama K, Oyabe A, Uchino M, Ishii K, Obara K,
Tanabee Y. Specific attenuation of the pressure-induced contraction of rat
cerebral artery by herbimycin A. Eur J Pharmacol. 1997;330:55– 63.
11. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N,
Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific
protein kinase. J Biol Chem. 1987;262:5592–5595.
12. Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug
development. Science. 1995;267:1782–1787.
13. Faraci FM, Heistad DD, Mayhan WG. Role of large arteries in regulation
of blood flow to brain stem in cats. J Physiol (Lond). 1987;387:15–23.
14. Sargeant P, Farndale RW, Sage SO. ADP- and thapsigargin-evoked Ca21
entry and protein tyrosine phosphorylation are inhibited by the tyrosine
kinase inhibitors, genistein and 2,5-dihydroxycinnamate in fura2-loaded
human platelets. J Biol Chem. 1993;268:18151–18156.
15. Alexander DR. The role of phosphatases in signal transduction. New Biol.
1990;2:1049 –1053.
16. Nishizuka Y. The role of protein kinase C in cell surface signal transduction
and tumor promotion. Nature. 1984;308:693– 698.
17. Bell RM. Protein kinase C activation by diacylglycerol second messengers.
Cell. 1986;45:631– 632.
18. Malarkey K, Belham CM, Paul A, Graham A, McLees A, Scott PH, Plevin
R. The regulation of tyrosine kinase signaling pathways by growth factor
and G-protein-coupled receptors. Biochem J. 1995;309:361–375.
19. Lomasney JW, Cotecchia S, Lefkowitz RJ, Caron MG. Molecular biology
of a-adrenergic receptors: implication for receptor classification and for
structure-function relationships. Biochim Biophys Acta. 1991;1095:127–139.
20. Roth BL, Nakaki T, Chuang DM, Costa E. Aortic recognition sites for
serotonin (5-HT2) are coupled to phospholipase C and modulate phosphoinositol turnover. Neuropharmacology. 1984;23:1223–1225.
21. Berridge MJ. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984;220:345–360.
22. Gould EM, Rembold CM, Murphy RA. Genistein, a tyrosine kinase
inhibitor, reduces Ca21 mobilization in swine carotid media. Am J Physiol.
1995;268:C1425–C1429.
23. Fleming I, Fisslthaler B, Busse R. Calcium signaling in endothelial cells
involves activation of tyrosine kinase and leads to activation of mitogenactivated protein kinase. Circ Res. 1995;76:522–529.
498
Tyrosine Kinase and Vasoconstriction In Vivo
Editorial Comment
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Although it is well known that serotonin (5-hydroxytryptamine) is a potent constrictor of large cerebral arteries, the
mechanism that mediates the constriction has not been fully
defined. This study provides evidence that tyrosine kinases play
an important role in serotonin-induced constriction of the
basilar artery.
Tyrosine kinases are thought to be a major signal transduction system in a variety of cells, including vascular muscle.1,2
For example, several effects of angiotensin II on vascular
muscle, including contraction, appear to be mediated by
tyrosine kinases.2 The study presented here by Kitazono et al
supports this concept by providing pharmacological evidence
that constriction of the basilar artery in response to serotonin in
vivo is dependent on activation of tyrosine kinases. The
conclusion supports previous work that implicated a role for
these kinases in contraction of cerebral arteries in response to
other stimuli in vitro.3–5
Serotonin has been implicated in cerebral vascular pathophysiology, including conditions involving intravascular activation of platelets. Serotonin-induced contraction of large
cerebral arteries is enhanced under pathophysiological conditions, including chronic hypertension,6 atherosclerosis,7 and
subarachnoid hemorrhage.8 Because activation of tyrosine
kinases appears to be an important mechanism of constriction
of large cerebral arteries under normal conditions, it is tempting to speculate that enhanced activity of tyrosine kinases may
contribute to augmented vasoconstrictor effects of serotonin
under pathophysiological conditions. This study contributes to
our understanding of signaling events in cerebral vascular
muscle and may help provide insight into management of
cerebral vascular disorders, including vasospasm.
Frank M. Faraci, PhD, Guest Editor
Department of Internal Medicine
Cardiovascular Division
University of Iowa College of Medicine
Iowa City, Iowa
References
1. Levitzki A. Signal-transduction therapy: a novel approach to disease management. Eur J Biochem. 1994;226:1–13.
2. Berk BC, Corson MA. Angiotensin II signal transduction in vascular smooth
muscle: role of tyrosine kinases. Circ Res. 1997;80:607– 616.
3. Wagerle LC, Kim SJ, Russo P. Protein tyrosine kinase signaling in coldstimulated contraction of newborn lamb cerebral arteries. Am J Physiol.
1996;270:H645–H650.
4. Sagher O, Huang DL, Webb RC. Induction of hypercontractility in human
cerebral arteries by rewarming following hypothermia: a possible role for
tyrosine kinase. J Neurosurg. 1997;87:431– 435.
5. Masumoto N, Nakayama K, Oyabe A, Uchino M, Ishii K, Obara K, Tanabe
Y. Specific attenuation of the pressure-induced contraction of rat cerebral
artery by herbimycin A. Eur J Pharmacol. 1997;330:55– 63.
6. Mayhan WG, Faraci FM. Cerebral vasoconstrictor responses to serotonin
during chronic hypertension. Hypertension. 1990;15:872– 876.
7. Heistad DD, Breese K, Armstrong M. Cerebral vasoconstrictor responses to
serotonin after dietary treatment of atherosclerosis: implications for transient
ischemic attacks. Stroke. 1987;18:1068 –1073.
8. Vollmer DG, Takayasu M, Dacey RG. An in vitro comparative study of
conducting vessels and penetrating arterioles after experimental subarachnoid hemorrhage in the rabbit. J Neurosurg. 1992;77:113–119.
Role of Tyrosine Kinase in Serotonin-Induced Constriction of the Basilar Artery In Vivo
Takanari Kitazono, Setsuro Ibayashi, Tetsuhiko Nagao, Tomoko Kagiyama, Jiro Kitayama and
Masatoshi Fujishima
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Stroke. 1998;29:494-498
doi: 10.1161/01.STR.29.2.494
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1998 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/29/2/494
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/