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首页> 外文期刊>American Journal of Physiology >Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943.
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Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943.

机译：大鼠心脏中地高辛动力学和变力反应的系统分析：钙和KB-R7943的作用。

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摘要

To gain more insight into the mechanistic processes controlling the kinetics of inotropic response of digoxin in the perfused whole heart, an integrated kinetic model was developed incorporating digoxin uptake, receptor binding (Na(+)-K(+)-ATPase inhibition), and cellular events linking receptor occupation and response. The model was applied to data obtained in the single-pass Langendorff-perfused rat heart for external [Ca(2+)] of 0.5 and 1.5 mM under control conditions and in the presence of the reverse-mode Na(+)/Ca(2+) exchange inhibitor KB-R7943 (0.1 microM) in perfusate. Outflow concentration and left ventricular developed pressure data measured for three consecutive doses (15, 30, and 45 microg) in each heart were analyzed simultaneously. While disposition kinetics of digoxin was determined by interaction with a heterogeneous receptor population consisting of a high-affinity/low-capacity and a low-affinity/high- capacity binding site, response generation was >80% mediated by binding to the high-affinity receptor. Digoxin sensitivity increased at lower external [Ca(2+)] due to higher stimulus amplification. Coadministration of KB-R7943 significantly reduced the positive inotropic effect of digoxin at higher doses (30 and 45 microg) and led to a saturated and delayed receptor occupancy-response relationship in the cellular effectuation model. The results provide further evidence for the functional heterogeneity of the Na(+)-K(+)-ATPase and suggest that in the presence of KB-R7943 a reduction of the Ca(2+) influx rate via the reverse mode Na(+)/Ca(2+) exchanger might become the limiting factor in digoxin response generation.
机译：为了深入了解控制地高辛在灌注的整个心脏中的正性肌力反应动力学的机制过程，开发了一个集成动力学模型，该模型整合了地高辛摄取，受体结合（Na（+）-K（+）-ATPase抑制）和连接受体占领和反应的细胞事件。该模型适用于在控制条件下和存在反向模式Na（+）/ Ca（的情况下）在单次Langendorff灌注大鼠心脏中获得的外部[Ca（2+）]为0.5和1.5 mM的数据。 2+）灌注液中的交换抑制剂KB-R7943（0.1 microM）。同时分析每个心脏中三个连续剂量（15、30和45微克）的流出浓度和左心室形成的压力数据。虽然地高辛的配置动力学是通过与由高亲和力/低容量和低亲和力/高容量结合位点组成的异质受体群体相互作用来确定的，但响应产生是通过与高亲和力的结合介导的> 80％受体。由于较高的刺激放大作用，地高辛的敏感性在较低的外部[Ca（2+）]下增加。在较高剂量（30和45微克）下，KB-R7943的共同给药显着降低了地高辛的正性肌力作用，并在细胞激活模型中导致饱和和延迟的受体占用-反应关系。结果为Na（+）-K（+）-ATPase的功能异质性提供了进一步的证据，并表明在存在KB-R7943的情况下，通过逆向模式Na（+ ）/ Ca（2+）交换子可能成为地高辛反应产生的限制因素。

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