Mechanism of suppression of cardiac L-type Ca(2+) currents by the phospholipase A(2) inhibitor mepacrine.
Mechanism of suppression of cardiac L-type Ca(2+) currents by the phospholipase A(2) inhibitor mepacrine.
复制标题
磷脂酶 A(2) 抑制剂 mepacrine 抑制心脏 L 型 Ca(2) 电流的机制。
DOI：
10.1016/s0014-2999(00)00366-6
复制
发表时间：
2000
影响因子：
5
通讯作者：
Morgan,JP
中科院分区：
文献类型：
--
作者：
Xiao,YF;Zeind,AJ;Kaushik,V;Perreault-Micale,CL;Morgan,JP
Phospholipase A2plays a crucial role in the release of arachidonic acid (AA) from membrane phospholipids and in myocardial injury during ischemia and reperfusion. Mepacrine, a phospholipase A2inhibitor, has been shown to protect the heart from ischemic injury. In order to examine the mechanism of this protection, we investigated the effects of mepacrine on the L-type Ca2+current (ICa,L) in rat single ventricular myocytes. Extracellular application of mepacrine significantly inhibited ICa,Lin a tonic- and use-dependent manner. The inhibition was also concentration-dependent with an IC50of 5.2 μM. Neither the activation nor the steady-state inactivation of ICa,Lwas altered by mepacrine. The mepacrine-induced inhibition of ICa,Lwas reversible after washout of the inhibitor. Addition of 1 μM AA partially reversed the mepacrine-induced inhibition of ICa,L. Intracellular dialysis, with 2 mM cAMP, significantly increased ICa,L, but did not prevent the mepacrine-induced inhibition of ICa,L. In addition, extracellular application of isoproterenol or membrane permeable db-cAMP did not reverse the mepacrine-induced inhibition of ICa,L. Biochemical measurement revealed that incubation of ventricular myocytes with mepacrine significantly reduced intracellular cAMP levels. The mepacrine-induced reduction of cAMP production was abolished by addition of AA. Our results demonstrate that mepacrine strongly inhibits cardiac ICa,L. While mepacrine is a phospholipase A2inhibitor and reduces cAMP production, its inhibitory effect on ICa,Lmainly results from a direct block of the channel. Therefore, we speculate that the protective effect of mepacrine during myocardial ischemia and reperfusion mostly relates to its blockade of Ca2+channels.
