Roles of TRPC channel activation in the induction of ventricular tachycardias

在心脏瞬时表达活化G蛋白αq的转基因小鼠（Gαq-TG ; HF模型）中经常观察到室性早搏（PVC）和/或VT，但在Gαq/DGK-TG和野生型（WT）小鼠中未观察到（p<0.01）。经典瞬时受体电位（TRPC）通道阻断剂SK & F96365可减少麻醉Gαq-TG小鼠的PVC数量并防止VT（p<0.05）。1-油酰基-2-酰基-sn-甘油（OAG）是一种甘油二酯类似物，与WT相比，可增加Gαq-TG心脏的PVC数量，并诱导Gαq-TG心脏的VT（p<0.01）。SK & F96365即使在存在OAG的情况下也能减少分离的Gαq-TG心脏中的PVC数量并防止VT（p<0.01）。在单个Gαq-TG心室肌细胞中，常观察到早期后除极（EAD）诱发的触发活动。此外，SK & F96365阻止EAD诱导的触发活动。这些结果表明，TRPC通道参与VT诱导在衰竭的心脏。尼可地尔长期给药（ATP敏感性K通道开放剂）可改善Gαq-TG小鼠的心力衰竭并减少PVC数量。然而，它并没有改善TRPC通道3和6的蛋白表达水平的增加。在32周龄的Langendorff灌注的Gαq-TG小鼠心脏中，急性尼可地尔给药缩短了心室单相动作电位时程。这些结果表明，TRPC通道的蛋白表达水平的增加不一定诱导VT。与WT心脏相比，左心室舒张末期压（LVEDP）的增加显著增加了分离的Gαq-TG心脏中的PVC数量。SK & F96365减少了分离的Gαq-TG心脏中的PVC数量，即使在LVEDP增加的情况下也是如此。这些结果表明，TRPC通道参与VT诱导在衰竭的心脏增加LVEDP。这项研究提供了新的信息，关于开发一种新的抗疟疾药物的可能性。

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.