Phorbol Diacetate Potentiates Na + -K + ATPase Inhibition by a Putative Endogenous Ligand, Marinobufagenin

Author:

Fedorova Olga V.1,Dorofeeva Natalia A.1,Lopatin Denis A.1,Lakatta Edward G.1,Bagrov Alexei Y.1

Affiliation:

1. From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health (O.V.F., E.G.L., A.Y.B.), Baltimore, Md; and Laboratory of Pharmacology, Sechenov Institute of Evolutionary Physiology and Biochemistry (N.A.D., D.A.L., A.Y.B.), St Petersburg, Russia.

Abstract

Several vasoconstrictor agents can regulate the phosphorylation status of the Na + -K + ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like α 1 -NKA–selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the α 1 -NKA isoform, the major isoform in vascular smooth muscle, kidney, and heart cells. We hypothesized that protein kinase C–induced phosphorylation of NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can occur in an NKA isoform–specific fashion. A protein kinase C activator, phorbol 12,13-diacetate (PDA, 50 nmol/L), induced phosphorylation of the α 1 -NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the α 3 -NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains α 1 -NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05±0.03 nmol/L versus 4.0±1.7 nmol/L, P <0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an α 3 -NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC 50 , 17±6 nmol/L versus 150±40 nmol/L; P <0.01). Our results suggest that α 1 -isoform–specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C. Thus, an interaction of protein kinase C–dependent phosphorylation and MBG on NKA activity may underlie the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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