Roles of TRPC channel activation in the induction of ventricular tachycardias

激活G蛋白αq（Gαq- tg； HF模型）在转基因小鼠心脏瞬态表达较多，而在Gαq/ dgk - ζ- tg和野生型（WT）小鼠心脏无明显表达（p<0.01），室性早搏（PVC）和/或室速（VT）较多。典型瞬态受体电位（TRPC）通道阻滞剂SK & F96365可减少Gαq-TG麻醉小鼠的PVC数量，阻止VT发生（p<0.05）。1-油基-2-酰基-sn-甘油（OAG）是二酰基甘油类似物，与WT相比，OAG能增加离体Gαq-TG心脏的PVC数量和诱导Gαq-TG心脏的VT （p<0.01）。即使在OAG存在的情况下，SK和F96365也能降低离体Gαq-TG心脏的PVC数量并阻止VT （p<0.01）。在单个g - α - q- tg心室肌细胞中经常观察到早期去极化后（EAD）诱导的触发活性。此外，SK和F96365阻止了ead诱导的触发活性。这些结果表明，TRPC通道参与了衰竭心脏的室速诱导。慢性尼可地尔给药，atp敏感的K通道打开剂，改善Gαq-TG小鼠心力衰竭，减少PVC数量。但对TRPC通道3和6蛋白表达水平的升高没有改善作用。急性尼可地尔给药可缩短langendorff灌注g - α - q- tg小鼠32周龄心室单相动作电位持续时间。这些结果表明，TRPC通道蛋白表达水平的升高并不一定会诱导VT。与WT心脏相比，Gαq-TG心脏左室舒张末期压（LVEDP）的升高显著增加了离体心脏的PVC数量。即使在LVEDP增加的情况下，SK和F96365也能降低离体g - α - q- tg心脏的PVC数量。这些结果表明，随着LVEDP的增加，TRPC通道参与了衰竭心脏的VT诱导。这项研究为开发一种新的抗心律失常药物提供了新的信息。

Premature ventricular contraction(PVC) and/or VT were frequently observed in transgenic mice with transient cardiac expression of activated G proteinαq(Gαq-TG ; Model of HF) mice but not in Gαq/DGKζ-TG and wild-type(WT) mice(p<0.01). SK & F96365, a canonical transient receptor potential(TRPC) channel blocker, decreased the number of PVC and prevented VT in anesthetized Gαq-TG mice(p<0.05). 1-oleoyl-2-acyl-sn-glycerol(OAG), a diacylglycerol analogue, increased the number of PVC in isolated Gαq-TG hearts compared with WT hearts and induced VT in Gαq-TG hearts(p<0.01). SK & F96365 decreased the number of PVC and prevented VT in isolated Gαq-TG hearts(p<0.01) even in the presence of OAG. Early afterdepolarization(EAD)-induced triggered activity was frequently observed in single Gαq-TG ventricular myocytes. Moreover, SK & F96365 prevented the EAD-induced triggered activity. These results suggest that TRPC channels participate in VT induction in failing hearts. Chronic nicorandil administration, ATP-sensitive K channel opener, improved heart failure and decreased the number of PVC in Gαq-TG mice. However, it did not improve the increased protein expression levels of TRPC channels 3 and 6.Acute nicorandil administration shortened ventricular monophasic action potential duration in Langendorff-perfused Gαq-TG mouse hearts at age of 32 weeks. These results suggest that the increased protein expression levels of TRPC channels do not necessarily induce VT. Increases in left ventricular end-diastolic pressure(LVEDP) significantly increased the number of PVC in isolated Gαq-TG hearts compared with WT hearts. SK & F96365 decreased the number of PVC in isolated Gαq-TG hearts even in the presence of increased LVEDP. These results suggest that TRPC channels participate in VT induction in failing hearts with the increased LVEDP. This study provides new information regarding the possibility of the development of a new anti-arrhythmic drug.