Telmisartan, an angiotensin II type 1 receptor antagonist, attenuates T-type Ca2+ channel expression in neonatal rat cardiomyocytes.
Telmisartan, an angiotensin II type 1 receptor antagonist, attenuates T-type Ca2+ channel expression in neonatal rat cardiomyocytes.
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DOI：
10.1016/j.ejphar.2009.03.024
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发表时间：
2009-05
影响因子：
5
通讯作者：
M. Morishima;Yan Wang;Yuko Akiyoshi;S. Miyamoto;K. Ono
中科院分区：
文献类型：
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作者：
M. Morishima;Yan Wang;Yuko Akiyoshi;S. Miyamoto;K. Ono
最近发现，血管紧张素II 1型受体(AT1)拮抗剂具有抗心律失常的作用，而T型钙通道在心律失常中起重要作用。然而，T型钙通道表达系统如何参与血管紧张素II介导的心肌细胞心律失常尚不清楚。在本研究中，我们观察了AT1受体拮抗剂替米沙坦对新生大鼠心肌细胞T型钙通道亚型(Cav3.1和Cav3.2)转录调控和心肌收缩功能的影响。用替米沙坦和/或血管紧张素II刺激培养的心肌细胞24小时后，用膜片钳技术检测心肌细胞的T型钙电流(ICa.T)，用实时定量聚合酶链式反应检测Cav3.1和Cav3.2的表达。长期应用血管紧张素II(24 H)后，心肌细胞Cav3.1和Cav3.2的表达及ICa电流密度显著增加，同时伴有细胞外信号调节激酶(ERK)1/2和p38丝裂原活化蛋白激酶(MAPK)的磷酸化。相反，替米沙坦降低Cav3.1和Cav3.2的表达，并呈剂量依赖关系。此外，在没有血管紧张素II的情况下，替米沙坦可降低p38MAPK的基础磷酸化水平，而不是ERK1/2的基础磷酸化水平。AT1受体拮抗剂valsartan不能模拟替米沙坦的作用，而替米沙坦的作用可被valsartan完全阻断。这些结果表明替米沙坦可能通过非激动剂依赖的p38MAPK活性抑制T型钙通道的表达，提示替米沙坦有一种新的药理作用。
Recently, it has been revealed that angiotensin II type 1 receptor (AT1) antagonists act as antiarrhythmic agents and that the T-type Ca2+channel plays an important role in arrhythmia. However, it remains unclear how the T-type Ca2+channel expression system is involved in angiotensin II-mediated arrhythmogenesis in cardiomyocytes. In this study, we investigated the effect of telmisartan, an AT1receptor antagonist, on transcriptional regulation of T-type Ca2+channel isoform (Cav3.1 and Cav3.2) expression and cardiac contractility using rat neonatal cardiomyocytes. Cultured cardiomyocytes were stimulated with telmisartan and/or angiotensin II for 24 h. T-type Ca2+currents (ICa.T) were then measured with the patch clamp technique, while Cav3.1 and Cav3.2 mRNA expression were assessed by real-time PCR. Expression of Cav3.1 and Cav3.2 mRNA as well as ICa.Tcurrent density in cardiomyocytes increased significantly after long-term application of angiotensin II (24 h), which was accompanied by extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation. In contrast, telmisartan decreased Cav3.1 and Cav3.2 mRNA expression as well as ICa.Tin a dose-dependent manner in the absence of angiotensin II. In addition, the basal phosphorylation level of p38MAPK but not ERK1/2 was decreased by telmisartan in the absence of angiotensin II. Valsartan, an AT1receptor antagonist, did not mimic the action of telmisartan, while the action of telmisartan was completely blocked by valsartan. These results indicate that telmisartan attenuates T-type Ca2+channel expression likely through p38MAPK activity in an agonist-independent manner, which suggests a novel pharmacological action of telmisartan.