Myocardial mitogenic effect of erythropoietin through the activation of Na(+)-K(+)-ATPase activity.
Erythropoietin is considered unique among the hematopoietic growth factor with a specific action on the differentiation and proliferation of erythroid progenitor cells. We have observed a dose-dependent modulatory action of human recombinant erythropoietin (rHuEpo) stimulated the rate of cell growth but at higher ones (3-10 U/ml) inhibited it. The mitogenic action of the hormone is correlated with cardiac membrane Na(+)-K(+)-ATPase activity since concentrations of rHuEpo that increased cell growth stimulated paranitrophenilphosphatase (pNPPase) activity, while those concentrations that inhibit the enzyme markedly bloqued its mitogenic action. Moreover, ouabain (10(-5) M), concentration that inhibits Na(+)-K(+)-ATPase activity, blunted the stimulatory action of rHuEpo on cell proliferation. We also demonstrated that rHuEpo while activated the cardiac membrane Na(+)-K(+)-ATPase was able to alter the contractile action of ouabain on isolated neonatal rat atria. Indeed rHuEpo (1 U/ml) enhanced the non toxic action of the cardiac glycoside attenuating and delaying the onset of the toxic effect of the drug. These results show that rHuEpo has a non hematopoietic cardiac effect, associated with the cardiac Na(+)-K(+)-ATPase activity, that regulates the myocytes growth and the biological action of cardiac glycosides on isolated rat myocardium.
Sterin-Borda
L
L
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina.
Wald
M
M
Gutnisky
A
A
Casanova
M
M
Arana
R
R
Borda
E
E
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D011994:Recombinant Proteins; D004921:Erythropoietin; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase