Räcke H F, Koppers D, Lemke P, Casaretto H, Hauswirth O
Physiologisches Institut II, Bonn, Germany.
Cardiovasc Res. 1994 Feb;28(2):201-8. doi: 10.1093/cvr/28.2.201.
The aim was to study the effect of fosinoprilate, a new ACE inhibitor, on the action potential and plateau currents of cardiac muscle.
Whole cell patch technique was used to record action potentials (n = 6), the L-type iCa (iCaL; n = 5), in some cases (n = 4) also using Cs+ loaded pipettes; with 5 mM Co2+, the time dependent K+ current (IK) underlying delayed rectification was analysed in guinea pig ventricular myocytes (n = 3).
Fosinoprilate prolonged the 50% repolarisation (APD50) from 440(SEM 50) ms to 485(48) ms (0.1 microM), to 525(46) ms (0.3 microM), to 632(58) ms (1 microM), and to 702(69) ms (3.0 microM). The APD90 was delayed from 510(63) ms to 540(45) ms (0.1 microM), to 583(42) ms (0.3 microM), to 702(62) ms (1.0 microM), and to 765(72) ms (3.0 microM). Higher concentrations (10-100 microM) caused early afterdepolarisations, very long action potentials, and irregular oscillations. ICaL was enhanced by up to 183%, showing a Kd of 0.2 microM; in contrast to the steady state activation (d infinity), the inactivation curve f infinity was shifted in the depolarising direction, considerably enlarging the Ca2+ window. Slow inactivation time course was unchanged, whereas the fast time constant (tau f) was accelerated. Fosinoprilate reduced the outward current during depolarising clamps from 1.7(0.2) nA to 1.41(0.11) nA with a 0.1 microM dose, and to 0.54(0.14) nA with a 1.0 microM dose; the tails were decreased from 0.39(0.03) nA to 0.27(0.03) nA with 0.1 microM and to 0.13(0.02) nA with 1.0 microM. Kinetics of IK were unaltered. Computer simulations based on these data using the OXSOFT-HEART program mimicked the results rather closely.
The results suggest that fosinoprilate prolongs the plateau due to a partial block of iK and an extension of the Ca2+ window by 10 mV, causing a class III antiarrhythmic effect. High concentrations further open the Ca2+ window resulting in early afterdepolarisations and plateau oscillations and may cause an inward transport of Ca2+ ions by the Na-Ca exchange.
研究新型血管紧张素转换酶抑制剂福辛普利拉对心肌动作电位和平台电流的影响。
采用全细胞膜片钳技术记录动作电位（n = 6）、L型钙电流（iCaL；n = 5），部分实验（n = 4）还使用了加载铯离子的微电极；加入5 mM Co2+，分析豚鼠心室肌细胞中延迟整流钾电流（IK）的时间依赖性（n = 3）。
福辛普利拉使50%复极化时间（APD50）从440（标准误50）ms延长至485（48）ms（0.1 μM）、525（46）ms（0.3 μM）、632（58）ms（1 μM）和702（69）ms（3.0 μM）。APD90从510（63）ms延迟至540（45）ms（0.1 μM）、583（42）ms（0.3 μM）、702（62）ms（1.0 μM）和765（72）ms（3.0 μM）。更高浓度（10 - 100 μM）可引起早期后去极化、极长动作电位和不规则振荡。iCaL增强高达183%，解离常数Kd为0.2 μM；与稳态激活（d∞）相反，失活曲线f∞向去极化方向移动，显著扩大了钙窗。慢失活时间进程未改变，而快时间常数（τf）加快。福辛普利拉在去极化钳制时使外向电流从1.7（0.2）nA降至1.41（0.11）nA（0.1 μM剂量），降至0.54（0.14）nA（1.0 μM剂量）；尾电流从0.39（0.03）nA降至0.27（0.03）nA（0.1 μM）和0.13（0.02）nA（1.0 μM）。IK的动力学未改变。基于这些数据使用OXSOFT - HEART程序进行的计算机模拟结果与之非常接近。
结果表明，福辛普利拉通过部分阻断IK和使钙窗扩展10 mV来延长平台期，产生Ⅲ类抗心律失常作用。高浓度进一步打开钙窗，导致早期后去极化和平台期振荡，并可能通过钠 - 钙交换引起钙离子内流。
