Published Online
on October 16, 2006

A more recent version of this article appeared on December 1, 2006

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Submitted on October 26, 2005
Revised on November 14, 2005

ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta

Olga V. Fedorova; Natalia I. Agalakova; Christopher H. Morrell; Edward G. Lakatta; and Alexei Y. Bagrov^*

From the Laboratory of Cardiovascular Science (O.V.F., N.I.A., C.H.M., E.G.L., A.Y.B.), National Institute on Aging, National Institutes of Health, Baltimore, Md; and Loyola College in Maryland (C.H.M.), Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: BagrovA{at}mail.nih.gov.

Abstract--NaCl loading and plasma volume expansion stimulate 2 natriuretic systems, vasoconstrictor, digitalis-like Na/K-ATPase inhibitors and vasorelaxant ANP peptides. Several hormones, including ANP, regulate activity of the Na/K-ATPase by modulation of its phosphorylation state. We studied effects of ANP on Na/K-ATPase phosphorylation and inhibition by an endogenous sodium pump ligand, marinobufagenin, in the aorta and renal medulla from male Sprague-Dawley rats. Marinobufagenin dose-dependently inhibited the Na/K-ATPase in renal and vascular membranes at the level of higher (nanomolar) and lower affinity (micromolar) binding sites. Marinobufagenin (1 nmol/L) inhibited Na/K-ATPase in aortic sarcolemma (18%) and in renal medulla (19%). prepro-ANP 104 to 123 (ppANP) and -human ANP ([-hANP] both 1 nmol/L) potentiated marinobufagenin-induced Na/K-ATPase inhibition in the kidney, but reversed the effect of marinobufagenin in the aorta. Similarly, ppANP and -hANP modulated the sodium pump (ouabain-sensitive ⁸⁶Rb uptake) inhibitory effects of marinobufagenin in the aorta and renal medulla. In renal medulla, ppANP and -hANP induced -1 Na/K-ATPase phosphorylation, whereas in aorta, both peptides dephosphorylated Na/K-ATPase. The effect of ppANP on Na/K-ATPase phosphorylation and inhibition was mimicked by a protein kinase G activator, 8-Br-PET-cGMP (10 µmol/L), and prevented by a protein kinase G inhibitor, KT5823 (60 nmol/L). Our results suggest that -1 Na/K-ATPase inhibition by marinobufagenin in the kidney is enhanced via Na/K-ATPase phosphorylation by ANP, whereas in the aorta, ANP exerts an opposite effect. The concurrent production of a vasorelaxant, ANP, and a vasoconstrictor, marinobufagenin, potentiate each other’s natriuretic effects, but ANP peptides may offset the deleterious vasoconstrictor effect of marinobufagenin.

Key words: sodium-potassium exchanging adenosinetriphosphatase • natriuretic hormones • ANP • ouabain • marinobufagenin • cGMP

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Vardaman M. Buckalew
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