RGD Reference Report - 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.

General

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.
Authors:	Baek, M Weiss, M
Citation:	Baek M and Weiss M, J Pharmacol Exp Ther. 2005 May;313(2):731-9. Epub 2005 Jan 11.
RGD ID:	6903354
Pubmed:	PMID:15644428 (View Abstract at PubMed)
DOI:	DOI:10.1124/jpet.104.078345 (Journal Full-text)
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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
Cardiomegaly		ISO	Atp1a2 (Rattus norvegicus)	6903354; 6903354		RGD
Cardiomegaly		IDA		6903354		RGD

Objects Annotated

Genes (Rattus norvegicus)

Atp1a2 (ATPase Na+/K+ transporting subunit alpha 2)

Genes (Mus musculus)

Atp1a2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide)

Genes (Homo sapiens)

ATP1A2 (ATPase Na+/K+ transporting subunit alpha 2)

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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.