Zhao Zhen, Wang Jinxin, Huo Zhijun, Wang Zhiyong, Mei Qibing
State Key Laboratory of New Drug & Pharmaceutical Process Shanghai Institute of Pharmaceutical Industry Shanghai 200437 China.
Pharmacol Res Perspect. 2017 Apr 17;5(3):e00308. doi: 10.1002/prp2.308. eCollection 2017 Jun.
Sphingosine 1-phosphate (S1P) is an important signaling sphingolipid involved in the pathogenesis of various cardio cerebral vascular diseases such as ischemic stroke. In particular, the S1P mimetic FTY720 is protective for brain against ischemic conditions. However, whether and how FTY720 can modulate vascular tone and blood pressure remains to be determined. We showed that FTY720 (1 mg/kg) enhanced the contractile response of rat thoracic aortic rings induced by high potassium and phenylephrine, respectively. This enhancement involves the activation of extracellular signal-regulated kinase (ERK) since ERK phosphorylation was also enhanced and application of PD98059 (10 mol/L), an inhibitor of ERK activation abrogated the aforementioned enhanced response by FTY720. In parallel, FTY720 (1 mg/kg) led to a modest elevation of blood pressure in rats, effects also being prevented by PD98059. In contrast, FTY720 decreased the high potassium-induced contractile response in basilarartery preparations from rabbits, an effect blocked by PD98059. Together, FTY720-induced an enhanced response of artery contractility in aorta and in arterial pressure involving ERK activation, with an attenuation in basilarartery contractility. This action property of FTY720 would be endowed with a potential of facilitating more blood flow perfusion to the brain and improving blood supply to the ischemic brain region and could be useful as an adjuvant in the treatment of ischemic stroke in the clinics.
鞘氨醇-1-磷酸（S1P）是一种重要的信号鞘脂，参与多种心脑血管疾病如缺血性中风的发病机制。特别是，S1P模拟物FTY720对脑缺血具有保护作用。然而，FTY720是否以及如何调节血管张力和血压仍有待确定。我们发现，FTY720（1mg/kg）分别增强了高钾和去氧肾上腺素诱导的大鼠胸主动脉环的收缩反应。这种增强涉及细胞外信号调节激酶（ERK）的激活，因为ERK磷酸化也增强了，并且应用ERK激活抑制剂PD98059（10μmol/L）可消除FTY720上述增强的反应。同时，FTY720（1mg/kg）使大鼠血压适度升高，PD98059也可阻止这种作用。相反，FTY720降低了兔基底动脉制剂中高钾诱导的收缩反应，该作用被PD98059阻断。总之，FTY720通过激活ERK诱导主动脉和动脉压中动脉收缩力增强，同时减弱基底动脉收缩力。FTY720的这种作用特性可能具有促进更多血流灌注到脑并改善缺血脑区血液供应的潜力，在临床上可作为缺血性中风治疗的辅助药物。
