Inhibitory effects of eicosapentaenoic acid on chronic cerebral vasospasm after subarachnoid hemorrhage: possible involvement of a sphingosylphosphorylcholine-rho-kinase pathway.
OBJECTIVE
Rho-kinase (ROK)-mediated Ca2+ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca2+ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca2+ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH).


METHODS
Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated.


RESULTS
At cerebrospinal fluid concentrations of 100 and 300 micromol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 micromol/l): 61.8 +/- 8.2%), which was markedly reversed by Y27632 (96.3 +/- 4.4%) or EPA (92.6 +/- 12.8%). SAH caused severe vasospasm on day 7 (67.6 +/- 7.8%), which was significantly blocked by Y27632 (95.5 +/- 10.6%) or EPA (90.0 +/- 4.4%).


CONCLUSIONS
SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV.
Shirao
Satoshi
S
Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan. shirao@yamaguchi-u.ac.jp
Fujisawa
Hirosuke
H
Kudo
Akira
A
Kurokawa
Tetsu
T
Yoneda
Hiroshi
H
Kunitsugu
Ichiro
I
Ogasawara
Kuniaki
K
Soma
Masaaki
M
Kobayashi
Sei
S
Ogawa
Akira
A
Suzuki
Michiyasu
M
D000818:Animals; D001488:Basilar Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology; D001578:Benzopyrans / Q000494:pharmacology; D002533:Cerebral Angiography; D002946:Cisterna Magna / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004285:Dogs; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007267:Injections; D008297:Male; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D015118:Eicosapentaenoic Acid; D054460:rho-Associated Kinases; D013110:Sphingosine; C074338:Y 26763