Zhao T, Zhang H, Jin C, Qiu F, Wu Y, Shi L
Department of Exercise PhysiologyBeijing Sport University, Beijing, China.
Department of Exercise PhysiologyBeijing Sport University, Beijing, China
J Mol Endocrinol. 2017 Oct;59(3):219-233. doi: 10.1530/JME-17-0028. Epub 2017 Jul 4.
Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large-conductance Ca-activated K (BK) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. This study explored the mechanisms of myocyte BK channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of -nitro-l-arginine methyl ester (l-NAME), a potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC The effect of melatonin was significantly attenuated in the presence of BK channel blocker iberiotoxin or MT1/MT2 receptor antagonist luzindole in both (+) l-NAME and (-) l-NAME groups. In the (+) l-NAME group, iberiotoxin caused a parallel rightward shift of the melatonin concentration-relaxation curve, with pIC lower than that of luzindole. Both inside-out and cell-attached patch-clamp recordings showed that melatonin significantly increased the open probability, mean open time and voltage sensitivity of BK channels. In a cell-attached patch-clamp configuration, the melatonin-induced enhancement of BK channel activity was significantly suppressed by luzindole. These findings indicate that in addition to the activation of eNOS, melatonin-induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BK channels on mesenteric arterial myocytes.
褪黑素主要由松果体合成，是一种具有高膜通透性的神经内分泌激素。褪黑素的血管效应，包括血管收缩和血管舒张，已在众多研究中得到证实。然而，这些效应背后的机制尚未完全明确。大电导钙激活钾（BK）通道广泛表达于平滑肌细胞，在血管张力调节中发挥重要作用。本研究探讨了肠系膜动脉（MA）中肌细胞BK通道和内皮因子在褪黑素作用中的机制。对Wistar大鼠MA的肌细胞进行了血管收缩性和膜片钳研究。褪黑素对MA有显著的血管舒张作用。在存在强效内皮型一氧化氮合酶（eNOS）抑制剂L-硝基-精氨酸甲酯（L-NAME）的情况下，褪黑素引起浓度依赖性舒张，pIC降低。在（+）L-NAME组和（-）L-NAME组中，BK通道阻滞剂iberiotoxin或MT1/MT2受体拮抗剂鲁辛朵尔存在时，褪黑素的作用均显著减弱。在（+）L-NAME组中，iberiotoxin使褪黑素浓度-舒张曲线平行右移，pIC低于鲁辛朵尔。内面向外和细胞贴附式膜片钳记录均显示，褪黑素显著增加了BK通道的开放概率、平均开放时间和电压敏感性。在细胞贴附式膜片钳配置中，鲁辛朵尔显著抑制了褪黑素诱导的BK通道活性增强。这些发现表明，除了激活eNOS外，褪黑素诱导的MA血管舒张部分归因于其对肠系膜动脉肌细胞BK通道的直接（穿过细胞膜）和间接（通过MT1/MT2受体）激活。
