This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fedorova, O. V. Articles by Bagrov, A. Y. Search for Related Content PubMed PubMed Citation Articles by Fedorova, O. V. Articles by Bagrov, A. Y. Related Collections Cardiovascular Pharmacology Cell signalling/signal transduction Hypertension - basic studies Ion channels/membrane transport

(Hypertension. 2002;39:298.)
© 2002 American Heart Association, Inc.

Scientific Contributions

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

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

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.

Correspondence to Alexei Bagrov, Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail BagrovA{at}grc.nia.nih.gov

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 ₁-NKA–selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the 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 ₁-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the ₃-NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains 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 ₃-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC₅₀, 17±6 nmol/L versus 150±40 nmol/L; P<0.01). Our results suggest that 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.

Key Words: drug therapy • ouabain • Na⁺-K⁺-exchanging ATPase • vasoconstriction • protein kinases • blood pressure • bufanolides

This article has been cited by other articles:

				D. E. Anderson, O. V. Fedorova, C. H. Morrell, D. L. Longo, V. A. Kashkin, J. D. Metzler, A. Y. Bagrov, and E. G. Lakatta Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1248 - R1254. [Abstract] [Full Text] [PDF]

				V. M. Buckalew Atrial Peptides Modify the Effect of Marinobufagenin on Sodium Pumps: Implications for Blood Pressure Control Hypertension, December 1, 2006; 48(6): 1029 - 1030. [Full Text] [PDF]

				O. V. Fedorova, N. I. Agalakova, C. H. Morrell, E. G. Lakatta, and A. Y. Bagrov ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta Hypertension, December 1, 2006; 48(6): 1160 - 1168. [Abstract] [Full Text] [PDF]

				O. Kotova, L. Al-Khalili, S. Talia, C. Hooke, O. V. Fedorova, A. Y. Bagrov, and A. V. Chibalin Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism J. Biol. Chem., July 21, 2006; 281(29): 20085 - 20094. [Abstract] [Full Text] [PDF]

				O. A. Akimova, A. Y. Bagrov, O. D. Lopina, A. V. Kamernitsky, J. Tremblay, P. Hamet, and S. N. Orlov Cardiotonic Steroids Differentially Affect Intracellular Na+ and [Na+]i/[K+]i-independent Signaling in C7-MDCK Cells J. Biol. Chem., January 7, 2005; 280(1): 832 - 839. [Abstract] [Full Text] [PDF]

				A. Y. Bagrov and E. G. Lakatta The Dietary Sodium-Blood Pressure Plot "Stiffens" Hypertension, July 1, 2004; 44(1): 22 - 24. [Full Text] [PDF]

				J. Abramowitz, C. Dai, K. K. Hirschi, R. I. Dmitrieva, P. A. Doris, L. Liu, and J. C. Allen Ouabain- and Marinobufagenin-Induced Proliferation of Human Umbilical Vein Smooth Muscle Cells and a Rat Vascular Smooth Muscle Cell Line, A7r5 Circulation, December 16, 2003; 108(24): 3048 - 3053. [Abstract] [Full Text] [PDF]

				O. V. Fedorova, M. I. Talan, N. I. Agalakova, M.-T. Droy-Lefaix, E. G. Lakatta, and A. Y. Bagrov Myocardial PKC {beta}2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension Hypertension, March 1, 2003; 41(3): 505 - 511. [Abstract] [Full Text] [PDF]