Morishima Masaki, Wang Yan, Akiyoshi Yuko, Miyamoto Shinji, Ono Katsushige
Department of Pathophysiology, Oita University School of Medicine, Oita 879-5593, Japan.
Eur J Pharmacol. 2009 May 1;609(1-3):105-12. doi: 10.1016/j.ejphar.2009.03.024. Epub 2009 Mar 16.
Recently, it has been revealed that angiotensin II type 1 receptor (AT(1)) 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 AT(1) receptor antagonist, on transcriptional regulation of T-type Ca2+ channel isoform (Ca(v)3.1 and Ca(v)3.2) 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 (I(Ca.T)) were then measured with the patch clamp technique, while Ca(v)3.1 and Ca(v)3.2 mRNA expression were assessed by real-time PCR. Expression of Ca(v)3.1 and Ca(v)3.2 mRNA as well as I(Ca.T) current 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 Ca(v)3.1 and Ca(v)3.2 mRNA expression as well as I(Ca.T) in 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 AT(1) receptor 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.
最近，有研究表明血管紧张素II 1型受体（AT(1)）拮抗剂具有抗心律失常作用，且T型Ca2+通道在心律失常中起重要作用。然而，T型Ca2+通道表达系统如何参与心肌细胞中血管紧张素II介导的心律失常发生仍不清楚。在本研究中，我们使用大鼠新生心肌细胞，研究了AT(1)受体拮抗剂替米沙坦对T型Ca2+通道亚型（Ca(v)3.1和Ca(v)3.2）表达的转录调控及心脏收缩性的影响。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。然后用膜片钳技术测量T型Ca2+电流（I(Ca.T)），同时通过实时PCR评估Ca(v)3.1和Ca(v)3.2 mRNA表达。长期应用血管紧张素II（24小时）后，心肌细胞中Ca(v)3.1和Ca(v)3.2 mRNA表达以及I(Ca.T)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）磷酸化。相反，在无血管紧张素II的情况下，替米沙坦以剂量依赖方式降低Ca(v)3.1和Ca(v)3.2 mRNA表达以及I(Ca.T)。此外，在无血管紧张素II的情况下，替米沙坦降低了p38MAPK的基础磷酸化水平，但未降低ERK1/2的基础磷酸化水平。AT(1)受体拮抗剂缬沙坦不能模拟替米沙坦的作用，而替米沙坦的作用被缬沙坦完全阻断。这些结果表明，替米沙坦可能通过p38MAPK活性以非激动剂依赖方式减弱T型Ca2+通道表达，这提示了替米沙坦一种新的药理作用。
