Published online before print February 10, 2003, doi: 10.1161/01.HYP.0000053446.43894.9F
(Hypertension. 2003;41:505.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Myocardial PKC ß2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension
From the Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health (O.V.F., M.I.T., N.I.A., E.G.L., A.Y.B.), Baltimore, Md; and the IPSEN Institute (M.-T.D.-L.), Paris, France.
Correspondence to Alexei Y. Bagrov, Laboratory of Cardiovascular Science, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail BagrovA{at}grc.nia.nih.gov
Marinobufagenin (MBG), an endogenous ligand of 
-1 Na/K-ATPase, becomes elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein kinase C (PKC) phosphorylates -1 Na/K-ATPase and increases its MBG sensitivity. Cicletanine, an antihypertensive compound with PKC-inhibitory activity, reverses MBG-induced Na/K-ATPase inhibition and vasoconstriction. We hypothesized that increased PKC levels in sodium-loaded hypertensive DS would sensitize -1 Na/K-ATPase to MBG and that PKC inhibition by cicletanine would produce an opposite effect. We studied the effects of cicletanine on systolic blood pressure, left ventricular PKC isoforms, cardiac -1 Na/K-ATPase levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg · kg-1 · d-1 cicletanine, and 7 DS received vehicle during 4 weeks of an 8% NaCl diet. Vehicle-treated rats exhibited an increase in blood pressure, left ventricular mass, MBG excretion (74±11 vs 9±1 pmol/24 h, P<0.01), myocardial -1 Na/K-ATPase protein, and PKC ß2 and 
. The sensitivity of Na/K-ATPase to MBG was enhanced at the level of high-affinity binding sites (IC50, 0.8 vs 4.4 nmol/L, P<0.01). Cicletanine-treated rats exhibited a 56-mm Hg reduction in blood pressure (P<0.01) and a 30% reduction in left ventricular weight, whereas cardiac -1 Na/K-ATPase protein and MBG levels were unchanged. In cicletanine-treated rats, PKC ß2 was not increased, the sensitivity of Na/K-ATPase to MBG was decreased (IC50=20 µmol/L), and phorbol diacetate–induced -1 Na/K-ATPase phosphorylation was reduced versus vehicle-treated rats. In vitro cicletanine treatment of sarcolemma from vehicle-treated rats also desensitized Na/K-ATPase to MBG, indicating that this effect was not solely attributable to a reduction in blood pressure. Thus, PKC-induced phosphorylation of cardiac -1 Na/K-ATPase is a likely target for cicletanine treatment.
Key Words: rats, Dahl • Na/K-transporting ATPase • digitalis-like factor • bufanolides • hypertrophy • protein kinases • antihypertensive agents
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