Ishikawa Tetsuya, Mochizuki Seibu, Kurihara Satoshi
Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Circ J. 2006 Apr;70(4):489-94. doi: 10.1253/circj.70.489.
We hypothesized that the negative inotropic effect of nifedipine (Nif) on cardiac ventricular muscle is partly due to the cross-bridge-dependent decrease of Ca2+ sensitivity of the myofilaments as well as the decrease in Ca2+ influx.
We used aequorin-injected ferret papillary muscles and measured the slope of the extra-Ca(2+)-tension relation which expresses the change in the Ca2+ sensitivity through the feedback from the cross-bridges. Twitch tension was decreased significantly by 0.5 micromol/L Nif accompanying a significant reduction of the Ca2+ transient peak. When Nif (0.2-0.5 micromol/L) was added to the solution with 8 mmol/L Ca2+, the slope of the extra-Ca2+-tension relation became steeper in a concentration-dependent manner, which was similar to the change in the slope when the concentration of Ca2+ was decreased from 8 to 1 mmol/L in the absence of Nif. BAY-K 8644 (0.3 micromol/L), a dihydropyridine receptor agonist, showed the opposite effect on the slope of the extra-Ca2+-tension relation to that observed in Nif. However, 2,3-butanedione monoxime (3 mmol/L), an inhibitor of the active cross-bridges, antagonized the effect of BAY-K 8644.
Nif exerts its negative inotropic effect on cardiac muscle by suppressing Ca2+ binding to troponin C via the inhibition of the L-type Ca2+ channel, and by the cross-bridge-dependent decrease in the Ca2+ sensitivity, as in low extracellular Ca2+ concentration.
我们推测硝苯地平(Nif)对心室肌的负性肌力作用部分归因于肌丝横桥依赖性钙敏感性降低以及钙内流减少。
我们使用注射水母发光蛋白的雪貂乳头肌,测量了细胞外钙 - 张力关系的斜率,该斜率通过横桥反馈来表达钙敏感性的变化。0.5微摩尔/升的Nif使强直收缩张力显著降低,同时钙瞬变峰值也显著降低。当在含有8毫摩尔/升钙的溶液中加入Nif(0.2 - 0.5微摩尔/升)时,细胞外钙 - 张力关系的斜率以浓度依赖性方式变得更陡,这与在无Nif情况下将钙浓度从8毫摩尔/升降至1毫摩尔/升时斜率的变化相似。二氢吡啶受体激动剂BAY - K 8644(0.3微摩尔/升)对细胞外钙 - 张力关系斜率的影响与Nif相反。然而,活性横桥抑制剂2,3 - 丁二酮单肟(3毫摩尔/升)可拮抗BAY - K 8644的作用。
Nif对心肌发挥负性肌力作用的机制是通过抑制L型钙通道来抑制钙与肌钙蛋白C的结合,并通过横桥依赖性降低钙敏感性,如同在低细胞外钙浓度时一样。