Chen Yu-Fang, Wang Chen, Zhang Rui, Wang Huan, Ma Rong, Jin Si, Xiang Ji-Zhou, Tang Qiang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Huazhong Univ Sci Technolog Med Sci. 2016 Feb;36(1):8-13. doi: 10.1007/s11596-016-1534-6. Epub 2016 Feb 3.
The present study attempted to test a novel hypothesis that Ca(2+) sparks play an important role in arterial relaxation induced by tacrolimus. Recorded with confocal laser scanning microscopy, tacrolimus (10 µmol/L) increased the frequency of Ca(2+) sparks, which could be reversed by ryanodine (10 µmol/L). Electrophysiological experiments revealed that tacrolimus (10 µmol/L) increased the large-conductance Ca(2+)-activated K(+) currents (BKCa) in rat aortic vascular smooth muscle cells (AVSMCs), which could be blocked by ryanodine (10 µmol/L). Furthermore, tacrolimus (10 and 50 µmol/L) reduced the contractile force induced by norepinephrine (NE) or KCl in aortic vascular smooth muscle in a concentration-dependent manner, which could be also significantly attenuated by iberiotoxin (100 nmol/L) and ryanodine (10 µmol/L) respectively. In conclusion, tacrolimus could indirectly activate BKCa currents by increasing Ca(2+) sparks released from ryanodine receptors, which inhibited the NE- or KCl-induced contraction in rat aorta.
本研究试图验证一个新的假说，即钙火花在他克莫司诱导的动脉舒张中起重要作用。用共聚焦激光扫描显微镜记录发现，他克莫司（10 µmol/L）可增加钙火花的频率，而这一作用可被ryanodine（10 µmol/L）逆转。电生理实验表明，他克莫司（10 µmol/L）可增加大鼠主动脉血管平滑肌细胞（AVSMCs）中的大电导钙激活钾电流（BKCa），这一作用可被ryanodine（10 µmol/L）阻断。此外，他克莫司（10和50 µmol/L）可浓度依赖性地降低去甲肾上腺素（NE）或氯化钾（KCl）诱导的主动脉血管平滑肌收缩力，而iberiotoxin（100 nmol/L）和ryanodine（10 µmol/L）分别可显著减弱这一作用。总之，他克莫司可通过增加ryanodine受体释放的钙火花间接激活BKCa电流，从而抑制大鼠主动脉中NE或KCl诱导的收缩。
