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CARDIOVASCULAR

Down-Regulation of Na⁺ Pump ₂ Isoform in Isoprenaline-Induced Cardiac Hypertrophy in Rat: Evidence for Increased Receptor Binding Affinity but Reduced Inotropic Potency of Digoxin

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

Cardiac hypertrophy in rats induces a down-regulation of Na⁺,K⁺-ATPase ₂ isoform, although its functional consequences are poorly understood. Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding kinetics, and positive inotropism of digoxin in single-pass Langendorff-perfused hearts of vehicle- and isoprenaline-pretreated rats (2.4 mg/kg per day over 4 days). Digoxin outflow concentration and left ventricular developed pressure data were measured for three consecutive doses (15, 30, and 45 µg) in the absence and presence of the reverse mode Na⁺/Ca²⁺ exchange inhibitor 2-[2-[4-(4-nitrobenzyloxyl-)phenyl]ethyl isothiourea methansulfonate] (KB-R7943) (0.1 µM) in perfusate. In hypertrophied hearts, 1) the amount of ₂ receptors was reduced to 52% of control levels; 2) the digoxin binding affinity was increased 12-fold due to a decrease in dissociation rate constants of ₁ and ₂ receptors, and 3) inotropic responsiveness to digoxin the was attenuated on the stimulus-response level, where the coupling ratio of stimulus to response was reduced to 38% of control values. Only in the lowest dose level (15 µg) was this decrease in inotropic potency counterbalanced by the increase in receptor affinity. The Na⁺,K⁺-ATPase isoform shift was not responsible for the diminished inotropic effect of digoxin. Coadministration of KB-R7943 significantly reduced cellular response generation at higher digoxin doses to the same limiting stimulus-response relationship in both the vehicle and isoprenaline group.

Address correspondence to: Dr. Michael Weiss, Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany. E-mail: michael.weiss{at}medizin.uni-halle.de

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