Down-regulation of Na+ pump alpha 2 isoform in isoprenaline-induced cardiac hypertrophy in rat: evidence for increased receptor binding affinity but reduced inotropic potency of digoxin.
Cardiac hypertrophy in rats induces a down-regulation of Na(+),K(+)-ATPase alpha(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 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange inhibitor 2-[2-[4-(4-nitrobenzyloxyl-)phenyl]ethyl isothiourea methansulfonate] (KB-R7943) (0.1 microM) in perfusate. In hypertrophied hearts, 1) the amount of alpha(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 alpha(1) and alpha(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 microg) 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.
Baek
Myoungki
M
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Germany.
Weiss
Michael
M
D000818:Animals; D004077:Digoxin / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020033:Protein Isoforms; D004077:Digoxin; C498532:Atp1a2 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol