Abstract：
Background Cardiac hypertrophy is associated with abnormal electrophysiology and increased arrhythmia risk. This study assessed whether candesartan cilexetil, an angiotensin II type 1 receptor blocker, could suppress arrhythmogenecity by attenuating cardiac electrical remodeling and calcium mishandling in rats with pressure-overload hypertrophy. Methods and Results Male Sprague-Dawley rats were randomly subjected to abdominal aorta banding or sham procedure and received either candesartan cilexetil (3.0 mg/kg per day) or vehicle by gavage for 5 weeks. Pressure overload was characterized by compensated left ventricular (LV) hypertrophy and fibrosis, increased LV pressure and its decay time, and prolonged corrected QT interval, all of which were attenuated by candesartan cilexetil treatment. Candesartan cilexetil-treated banded rat hearts displayed shorter QT intervals and lower vulnerability to atrial and ventricular tachyarrhythmias than vehicle-treated banded hearts. Candesartan cilexetil prevented banding-induced prolonged action potential duration and reduced the occurrence of triggered activity in LV papillary muscles. In addition, the prolonged time to 50% cell relengthening and calcium transient decay time were normalized in LV myocytes from candesartan cilexetil-treated banded rats, along with a normalization of decreased SERCA2a (sarco[endo]plasmic reticulum calcium-ATPase) expression in LV tissues. Furthermore, candesartan cilexetil normalized depressed transient outward potassium current densities and protein and mRNA levels of both voltage-gated potassium 4.2 and 4.3 channel subunits (Kv4.2 and Kv4.3) in banded rats. Conclusions Candesartan cilexetil protects the heart from pressure overload-induced adverse electrical remodeling by preserving potassium channel densities. In addition, calcium handling and its molecular regulation also improved after treatment. These beneficial effects may contribute to a lower susceptibility to arrhythmias in hearts from candesartan cilexetil-treated pressure-overloaded rats.
摘要：
背景心脏肥大与异常电生理和心律失常风险增加有关。这项研究评估了坎地沙坦西酯，血管紧张素II1型受体阻滞剂，可以通过减轻压力超负荷肥大大鼠的心脏电重构和钙错误处理来抑制心律失常的发生。方法和结果雄性Sprague-Dawley大鼠随机接受腹主动脉束带或假手术，并通过管饲法接受坎地沙坦酯（每天3.0mg/kg）或赋形剂5周。压力超负荷的特点是代偿性左心室（LV）肥大和纤维化，低压压力增加及其衰减时间，和延长的校正QT间期，所有这些都通过坎地沙坦西酯治疗减毒。与媒介物处理的带状心脏相比，坎地沙坦酯处理的带状大鼠心脏显示出较短的QT间隔和较低的心房和心室快速性心律失常的脆弱性。坎地沙坦西酯可防止条带引起的动作电位持续时间延长，并减少LV乳头状肌触发活动的发生。此外,在坎地沙坦西酯处理的带状大鼠的LV心肌细胞中，延长的50％细胞再生时间和钙瞬变衰减时间被标准化，随着LV组织中SERCA2a（sarco[endo]质网钙-ATPase）表达降低的正常化。此外，坎地沙坦西酯使带状大鼠中电压门控钾4.2和4.3通道亚基（Kv4.2和Kv4.3）的瞬时外向钾电流密度以及蛋白质和mRNA水平恢复正常。结论坎地沙坦酯通过保留钾通道密度保护心脏免受压力超负荷引起的不良电重构。此外,钙处理及其分子调控也在治疗后得到改善。这些有益作用可能有助于降低坎地沙坦西酯治疗的压力超负荷大鼠对心脏心律失常的敏感性。
