Rho激酶抑制剂DL0805对血管紧张素Ⅱ刺激的大鼠离体胸主动脉环的舒张作用及机制研究

Vasorelaxant effect of Rho kinase inhibitor DL0805 on isolated rat thoracic aortic rings stimulated by angiotensin Ⅱ and its underlying mechanisms

目的探讨Rho激酶抑制剂DL0805对血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)刺激的大鼠离体胸主动脉环的舒张作用与机制。方法制备SD大鼠胸主动脉环,测定离体血管张力,观察DL0805对AngⅡ收缩血管作用及量效曲线的影响;Western blot检测大鼠离体胸主动脉环肌球蛋白轻链(myosin light chain 2,MLC2)蛋白磷酸化水平。结果DL0805对AngⅡ(100 nmol·L-1)收缩的血管环具有浓度依赖性的舒张作用,其舒张血管作用部分依赖于内皮。25、50μmol·L-1的DL0805使AngⅡ量效曲线呈非平行右移,最大反应压低,pD'2为4.65±0.04。DL0805(25、50μmol·L-1)抑制AngⅡ(100 nmol·L-1)引起的MLC2磷酸化水平增加。结论 DL0805呈浓度依赖性地舒张AngⅡ收缩的大鼠离体胸主动脉环,其机制可能与拮抗血管紧张素Ⅱ1型受体(angiotensinⅡtype 1 receptor,AT1R),抑制AngⅡ引起的MLC2磷酸化水平增加有关。

Aim To investigate the vasorelaxant effect of DL0805, a Rho kinase inhibitor, on the rat thoracic aortic rings stimulated by angiotensin Ⅱ （Ang Ⅱ ） and to explore its underlying mechanisms. Methods The isotonic contractions of the thoracic aortic rings from SD rats were recorded, and the effects of DL0805 on the single dose and concentration cumulative response curves of Ang II were recorded. Phosphorylations of myosin light chain 2 （MLC2） in rat aortic rings were detected by Western blot. Results DI33805 exerted vasorelaxation in a dose-dependent manner in Ang Ⅱ （100 nmol ·L^-1）-induced contraction and partial loss of the vasorelaxation in endothelium-denuded rings. DL0805 （25,50μmol·L^-1 ） shifted the concentra- tion-response curve of Ang Ⅱ to right with non-parallel manner. The maximal response to Ang Ⅱ was depressed progressively and the pD＇2 value was 4.65 ± 0.04. DL0 8 0 5 （ 2 5 , 5 0 μmol·L^-1） significantly attenuated the increased MLC2 phosphorylation level in the aortic rings stimulated by Ang Ⅱ （100 nmol ·L^-1）. Con- clusion DL0805 induces relaxation in the rat aortic rings stimulated by Ang Ⅱ and the mechanism involvesthe inhibition of Ang Ⅱ-induced MLC2 activation via blocking angiotensin Ⅱ type 1 receptor （ATIR）