Sphingosine 1-Phosphate Contracts Canine Basilar Arteries In Vitro and In Vivo

Abstract

Background and Purpose-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 mol/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 Ϸ300 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.

Up‐regulation of proteinase‐activated receptor 1 and increased contractile responses to thrombin after subarachnoid haemorrhage

“…Since the heparinized blood (containing 100 U ml À1 heparin) can be assumed to be almost completely devoid of the activity of thrombin and other heparin-sensitive proteinases, the heparin-sensitive proteinases could not account for all mechanisms for the induction of hyper-responsiveness. Known spasmogens such as platelet products (Yanamoto et al, 1992;Tosaka et al, 2001) and free radicals (Macdonald and Weir, 1991) could be other factors contributing to induction of the upregulation of PAR 1 and hyper-contractile responsiveness. Such factors, however, remain to be identified.…”

“…The increased production of spasmogens (Macdonald and Weir, 1991;Tosaka et al, 2001) and/or increased vascular responsiveness (Harder et al, 1987;Todo et al, 1998;Sato et al, 2000) is considered to contribute to the development of vasospasm. A clinical study demonstrated that the incidence of post-haemorrhagic vasospasm correlates with the amount of peri-arterial blood clotting (Fisher et al, 1980).…”

Sphingosine-1-phosphate and modulation of vascular tone

“…70 In cultured smooth muscle cells derived from rat cerebral arteries, S1P activates RhoA. 59 The ROK inhibitor Y-27632 also counteracts S1P-elicited constriction responses in canine basilar arteries 71 as well as in hamster gracilis muscle small resistance arteries. 72 The roles of RhoA/ROK pathway have been documented in several smooth muscle models, but roles of PKC in S1P-dependent contraction remain less completely characterized.…”

“…For example, S1P-induced vasoconstriction was observed in canine basilar arteries, 71 in rodent cerebral arteries, 59,60 and in mesenteric resistance arteries from aged rats. 76 In general, higher concentrations of S1P are required to elicit vasoconstriction (several 100 nanomolar to micromolar) than required for S1P-induced vasorelaxation, which typically shows an EC 50 in the low nanomolar range.…”

“…It is also plausible that smooth muscle S1P receptors may elicit pathological spastic responses in cerebral arteries in the face of brain stroke associated with cerebral haemorrhage. 71 S1P is enriched in HDL fractions of human serum (see review 10 ) and in serum albumin. HDL removes excess cholesterol from the vessel wall and delivers this cholesterol to liver; clinically, higher concentrations of HDL are associated with more favourable outcomes in the patients with cardiovascular diseases.…”