Na Tao, Huang Zhi-Jiang, Dai De-Zai, Zhang Yuan, Dai Yin
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2007 Jun;28(6):773-82. doi: 10.1111/j.1745-7254.2007.00580.x.
The occurrence of ventricular fibrillation (VF) is dependent on the deterioration of channelopathy in the myocardium. It is interesting to investigate molecular changes in relation to abrupt appearance of VF on reperfusion. We aimed to study whether changes in the expression of FKBP12.6 and SERCA2a and the endothelin (ET) system on reperfusion against ischemia were related to the rapid occurrence of VF and whether CPU86017, a class III antiarrhythmic agent which blocks I(Kr), I(Ks), and I(Ca.L), suppressed VF by correcting the molecular changes on reperfusion.
Cardiomyopathy (CM) was produced by 0.4 mg/kg sc L-thyroxin for 10 d in rats, and subjected to 10 min coronary artery ligation/reperfusion on d 11. Expressions of the Ca2+ handling and ET system and calcium transients were conducted and CPU86017 was injected (4 mg/kg, sc) on d 6-10.
A high incidence of VF was found on reperfusion of the rat CM hearts, but there was no VF before reperfusion. The elevation of diastolic calcium was significant in the CM myocytes and exhibited abnormality of the Ca2+ handling system. The rapid downregulation of mRNA and the protein expression of FKBP12.6 and SERCA2a were found on reperfusion in association with the upregulation of the expression of the endothelin-converting enzyme (ECE) and protein kinase A (PKA), in contrast, no change in the ryanodine type 2 receptor (RyR2), phospholamban (PLB), endothelin A receptor (ETAR), and iNOS was found. CPU86017 removed these changes and suppressed VF.
Abrupt changes in the expression of FKBP12.6, SERCA2a, PKA, and ECE on reperfusion against ischemia, which are responsible for the rapid occurrence of VF, have been observed. These changes are effectively prevented by CPU86017.
心室颤动（VF）的发生取决于心肌离子通道病的恶化。研究再灌注时与VF突然出现相关的分子变化很有意思。我们旨在研究再灌注时针对缺血的FKBP12.6和SERCA2a表达变化以及内皮素（ET）系统是否与VF的快速发生有关，以及III类抗心律失常药物CPU86017（可阻断I(Kr)、I(Ks)和I(Ca.L)）是否通过纠正再灌注时的分子变化来抑制VF。
用0.4mg/kg皮下注射L-甲状腺素连续10天在大鼠中诱导心肌病（CM），并在第11天进行10分钟冠状动脉结扎/再灌注。在第6至10天进行钙处理和ET系统的表达以及钙瞬变检测，并注射CPU86017（4mg/kg，皮下注射）。
在大鼠CM心脏再灌注时发现VF的高发生率，但再灌注前无VF。CM心肌细胞舒张期钙升高显著，且表现出钙处理系统异常。再灌注时发现FKBP12.6和SERCA2a的mRNA和蛋白表达迅速下调，同时内皮素转化酶（ECE）和蛋白激酶A（PKA）表达上调，相反，未发现2型兰尼碱受体（RyR2）、受磷蛋白（PLB）、内皮素A受体（ETAR）和诱导型一氧化氮合酶（iNOS）有变化。CPU86017消除了这些变化并抑制了VF。
已观察到再灌注时针对缺血的FKBP12.6、SERCA2a、PKA和ECE表达的突然变化，这些变化是VF快速发生的原因。这些变化可被CPU86017有效预防。
