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This Article Full Text Full Text (PDF) All Versions of this Article: 287/4/H1857    most recent 01121.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Weiss, M. Articles by Kang, W. Search for Related Content PubMed PubMed Citation Articles by Weiss, M. Articles by Kang, W.

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany

Submitted 25 November 2003 ; accepted in final form 29 April 2004

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 [Ca²⁺] of 0.5 and 1.5 mM under control conditions and in the presence of the reverse-mode Na⁺/Ca²⁺ exchange inhibitor KB-R7943 (0.1 µM) in perfusate. Outflow concentration and left ventricular developed pressure data measured for three consecutive doses (15, 30, and 45 µg) 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 [Ca²⁺] due to higher stimulus amplification. Coadministration of KB-R7943 significantly reduced the positive inotropic effect of digoxin at higher doses (30 and 45 µg) 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 Ca²⁺ influx rate via the reverse mode Na⁺/Ca²⁺ exchanger might become the limiting factor in digoxin response generation.

Na⁺-K⁺-ATPase; Na⁺/Ca²⁺ exchanger; cardiac glycosides; mathematical modeling

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