Department of General and Cardiothoracic Surgery, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan.
J Thorac Cardiovasc Surg. 2011 Aug;142(2):e59-65. doi: 10.1016/j.jtcvs.2011.01.055. Epub 2011 Mar 12.
Radial arteries are increasingly used as conduits for coronary artery bypass grafts. However, vasospasm continues to be a major concern in radial artery grafts. Rho kinase plays a critical role in vascular contraction through phosphorylation of the regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) of the myosin light chain phosphatase to inhibit myosin light chain phosphatase in vascular smooth muscle. The purpose of this study was to evaluate the inhibitory effects of fasudil, a clinically used Rho kinase inhibitor, on Rho kinase activity, myosin light chain phosphorylation, in vitro contraction, and in situ vasospasm in radial arteries of patients undergoing coronary artery bypass grafting surgery.
The inhibitory efficacy of fasudil on vasoconstrictor-induced contraction and phosphorylation of MYPT1 was examined in radial artery rings. In situ phosphorylation of MYPT1 was evaluated in nonspastic and spastic radial arteries, and the effects of intraluminal administration of fasudil and verapamil-glyceryl trinitrate (VG) on in situ free blood flow and phosphorylation of MYPT1 and myosin light chain were compared in spastic radial arteries.
Both fasudil and VG nearly fully inhibited noradrenaline- and serotonin-induced contraction of radial artery rings. However, fasudil but not VG abolished MYPT1 phosphorylation. In spastic radial arteries phosphorylation of MYPT1 and myosin light chain was increased compared with that seen in nonspastic arteries. Intraradial administration of fasudil induced a much larger increase in in situ free blood flow compared with VG treatment. This antispastic effect of fasudil was accompanied by marked decreases in phosphorylation of MYPT1 and myosin light chain.
Fasudil is a very effective Rho kinase inhibitor that deinhibits myosin light chain phosphatase and powerfully relieves vasospasm in situ in radial arteries.
桡动脉作为冠状动脉旁路移植术的移植物越来越受到关注。然而，桡动脉移植物的血管痉挛仍然是一个主要问题。Rho 激酶通过磷酸化肌球蛋白轻链磷酸酶的调节亚单位肌球蛋白磷酸酶靶向亚单位 1（MYPT1）来抑制血管平滑肌中的肌球蛋白轻链磷酸酶，从而在血管收缩中发挥关键作用。本研究旨在评估 Rho 激酶抑制剂法舒地尔对行冠状动脉旁路移植术患者桡动脉中 Rho 激酶活性、肌球蛋白轻链磷酸化、体外收缩和原位血管痉挛的抑制作用。
在桡动脉环中检测法舒地尔对血管收缩剂诱导的收缩和 MYPT1 磷酸化的抑制作用。评估非痉挛和痉挛桡动脉中 MYPT1 的原位磷酸化，并比较腔内给予法舒地尔和维拉帕米-甘油三硝酸酯（VG）对痉挛桡动脉中原位自由血流和 MYPT1 及肌球蛋白轻链磷酸化的影响。
法舒地尔和 VG 几乎完全抑制去甲肾上腺素和 5-羟色胺诱导的桡动脉环收缩。然而，法舒地尔而非 VG 可消除 MYPT1 磷酸化。与非痉挛动脉相比，痉挛桡动脉中的 MYPT1 和肌球蛋白轻链磷酸化增加。与 VG 治疗相比，腔内给予法舒地尔可引起原位自由血流明显增加。法舒地尔的这种抗痉挛作用伴随着 MYPT1 和肌球蛋白轻链磷酸化的显著降低。
法舒地尔是一种非常有效的 Rho 激酶抑制剂，可使肌球蛋白轻链磷酸酶去抑制，并有力缓解桡动脉中的原位血管痉挛。
