On the Mechanism Underlying the Action of D‐600 on Slow Inward Current and Tension in Mammalian Myocardium
On the Mechanism Underlying the Action of D‐600 on Slow Inward Current and Tension in Mammalian Myocardium
复制标题
D-600 对哺乳动物心肌慢内向电流和张力作用的机制研究
作者：
R. T. Eick;W. Trautwein
D-600是维拉帕米的甲氧基衍生物，据说可以通过降低Ca 2+的膜电导（gsi）来影响心脏收缩力和缓慢内向电流（Isl）。然而，很明显，D-600的许多影响不能仅仅通过对gsi的影响来充分解释。采用单蔗糖间隙电压钳技术，研究了D-600对猫心室乳头肌细胞膜电流和张力的影响。结果表明，D-600不仅降低了最大钙电导，但也取决于浓度和暴露的持续时间，改变了动力学的钙运载系统和稳态外向电流的幅度。稳态激活和失活变量以及Isi失活速率均未发现变化，但在暴露于D-600（0.5 × 10-6至2.0 × 10-6 M）至少20分钟后，观察到Isl达到峰值的时间显著增加，为正常值的7倍。由于D-600诱导的Isl减少约只有75%可归因于gsi（gsi）最大值的变化，因此我们得出结论，达到峰值的时间变化和约25%的Isi减少必须归因于Ca-携带系统的活化动力学变化。计算表明，通过长期暴露于负性肌力浓度的D-600，gsi活化至70%的时间可延长至正常值的10倍。
D-600, the methoxy derivative of verapamil, is said to affect the force of cardiac contraction and the slow inward current (Isl) specifically by reducing the membrane conductance for Ca2+ (gsi). However it is apparent that many effects of D-600 cannot be adequately explained solely by an effect on gsi. We studied the effects of D-600 on membrane current and tension of cat papillary muscle, using a conventional single sucrose gap voltage clamp technique. The results indicate that D-600 not only reduces the maximal Ca conductance but also, depending on concentration and duration of exposure, alters both the kinetics of the Ca-carrying system and the amplitude of the steady state outward current. No changes in the steady state activation and inactivation variables or in the rate of Isi inactivation were found. However, a substantial increase in the time to peak Isl, as much as 7 times normal, was observed after exposure to D-600 (0.S × 10-6 to 2.0 × 10-6 M) for at least 20 minutes. Because approximately only 75% of the reduction in lsl induced by D-600 could be attributed to change in the maximum value of gsi (gsi), we conclude that the change in time to peak and about 25% of the reduction in Isi must be due to a change in the activation kinetics of the Ca-carrying system. Calculations suggest that the time to 70% activation of gsi can be prolonged to as much as 10 times normal by prolonged exposure to negatively inotropic concentrations of D-600.