Zobel C, Brixius K, Frank K, Schwinger R H
Klinik III für Innere Medizin der Universität zu Köln, Laboratory of Muscle Research and Molecular Cardiology, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 May;357(5):532-9. doi: 10.1007/pl00005204.
The present study aimed to investigate the inotropic effect of the Na+-channel modulator BDF 9148 in hypertrophic myocardium compared to control tissue. Thus, TG(mREN2)27 rats (TGR), a model with hypertension induced cardiac hypertrophy, was compared with age matched Sprague-Dawley rats (SPDR). The effect of BDF 9148 (0.01-10 microM) on force of contraction (1 Hz, 37 degrees C), the force-frequency relationship (0.5-7 Hz) and the frequency-dependent diastolic tension (0.5-7 Hz) was studied on left ventricular papillary muscles from SPDR and TGR. Chemically skinned muscle fibers of the same hearts were used to examine the influence of BDF 9148 on the Ca2+-sensitivity of the contractile proteins. For control the Ca2+-sensitizer EMD 57033 was examined. In addition the Na+/K+-ATPase activity was measured in both, SPDR and TGR. BDF 9148 showed a concentration dependent positive inotropic effect in SPDR and TGR cardiac preparations. Comparing SPDR and TGR, a higher effectiveness of BDF 9148 on TGR was found, while the potency was unchanged. With increasing stimulation rates a significant higher decrease in force of contraction in TGR compared to SPDR was observed. In addition, a significant higher increase in diastolic tension was found in TGR. After exposure to 1 microM BDF 9148 the decrease in force of contraction was significantly reduced in both SPDR and TGR, while only in TGR the increase in diastolic tension was reduced. BDF 9148 had no effect on the Ca2+-sensitivity or maximal developed tension of skinned fiber preparations from SPDR or TGR. In contrast, the Ca2+-sensitizer EMD 57033 increased the Ca2+-sensitivity. The activity of the Na+/K+-ATPase was significantly reduced in TGR compared to controls.
The Na+-channel modulator BDF 9148 was more effective in hypertrophic compared to control myocardium in increasing force of contraction, enhancing frequency-dependent force generation and reducing diastolic tension. These effects were not mediated via interaction with the contractile apparatus. The enhanced effectiveness of Na+-channel modulation in hypertrophic myocardium could result from alterations of the Na+ homeostasis, i. e. a reduced Na+/K+-ATPase activity.
本研究旨在探究钠通道调节剂BDF 9148在肥厚心肌中与对照组织相比的变力作用。因此，将TG(mREN2)27大鼠（TGR），一种高血压诱导的心脏肥大模型，与年龄匹配的Sprague-Dawley大鼠（SPDR）进行比较。研究了BDF 9148（0.01 - 10微摩尔）对SPDR和TGR左心室乳头肌收缩力（1赫兹，37摄氏度）、力-频率关系（0.5 - 7赫兹）和频率依赖性舒张张力（0.5 - 7赫兹）的影响。使用相同心脏的化学去表皮肌纤维来检查BDF 9148对收缩蛋白钙敏感性的影响。作为对照，检测了钙敏化剂EMD 57033。此外，还测量了SPDR和TGR两者的钠钾ATP酶活性。BDF 9148在SPDR和TGR心脏制剂中显示出浓度依赖性正性变力作用。比较SPDR和TGR，发现BDF 9148对TGR的有效性更高，而效价不变。随着刺激频率增加，与SPDR相比，TGR的收缩力显著下降更多。此外，在TGR中发现舒张张力显著增加更多。暴露于1微摩尔BDF 9148后，SPDR和TGR的收缩力下降均显著减少，而仅在TGR中舒张张力的增加减少。BDF 9148对SPDR或TGR的去表皮纤维制剂的钙敏感性或最大舒张张力没有影响。相反，钙敏化剂EMD 57033增加了钙敏感性。与对照组相比，TGR中的钠钾ATP酶活性显著降低。
与对照心肌相比，钠通道调节剂BDF 9148在肥厚心肌中增加收缩力、增强频率依赖性力产生和降低舒张张力方面更有效。这些作用不是通过与收缩装置相互作用介导的。肥厚心肌中钠通道调节有效性的增强可能源于钠稳态的改变，即钠钾ATP酶活性降低。
