Sphingosine 1-phosphate contracts canine basilar arteries in vitro and in vivo: possible role in pathogenesis of cerebral vasospasm.
OBJECTIVE
Sphingosine 1-phosphate (S1P) is a platelet-derived bioactive lipid that exerts a variety of biological responses, including vasocontraction. To understand the involvement of S1P in cerebral vasospasm, we investigated the effect of S1P on vasocontraction of the canine basilar artery in vitro and in vivo.


METHODS
We recorded isometric tension in basilar arterial rings from dogs in vitro and estimated time-course changes in the diameter of canine basilar arteries and the S1P concentration in cerebrospinal fluid (CSF) by angiography and radioreceptor assays, respectively, after administering S1P into the cisterna magna. Changes in the supernatant S1P concentration during clot formation were monitored by using the in vitro subarachnoid hemorrhage model, in which blood is mixed with CSF.


RESULTS
At concentrations ranging between 100 nmol/L and 10 micromol/L, S1P induced a dose-dependent contraction of the basilar artery in vitro. This effect was significantly inhibited by Y-27632, a highly selective Rho-kinase inhibitor. The administration of S1P into the CSF induced a 60% to 70% decrease in the arterial diameter within 15 minutes, and vasocontraction continued for 2 days thereafter. The concentration of S1P in the supernatant during clot formation in vitro reached approximately 300 nmol/L.


CONCLUSIONS
S1P induces vasocontraction in the canine basilar artery in vitro and in vivo, possibly through a mechanism involving activation of the Rho/Rho-kinase pathway. Thus, S1P might be considered as a novel spasmogenic substance involved in cerebral vasospasm after subarachnoid hemorrhage.
Tosaka
M
M
Department of Neurosurgery, Gunma University School of Medicine, the Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan. nstosaka@med.gunma-u.ac.jp
Okajima
F
F
Hashiba
Y
Y
Saito
N
N
Nagano
T
T
Watanabe
T
T
Kimura
T
T
Sasaki
T
T
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D001769:Blood / Q000378:metabolism; D002533:Cerebral Angiography; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008246:Lysophospholipids; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014654:Vascular Patency / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D020301:Vasospasm, Intracranial / Q000175:diagnosis / Q000209:etiology; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D011725:Pyridines; C108830:Y 27632; C060506:sphingosine 1-phosphate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D013110:Sphingosine