| Myocardial PKC beta2 and the sensitivity of Na/K-ATPase to marinobufagenin are reduced by cicletanine in Dahl hypertension. | |
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MedLine Citation:
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PMID: 12623951 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Marinobufagenin (MBG), an endogenous ligand of alpha-1 Na/K-ATPase, becomes elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein kinase C (PKC) phosphorylates alpha-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 alpha-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 alpha-1 Na/K-ATPase levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg x kg(-1) x 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 alpha-1 Na/K-ATPase protein, and PKC beta2 and delta. 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 alpha-1 Na/K-ATPase protein and MBG levels were unchanged. In cicletanine-treated rats, PKC beta2 was not increased, the sensitivity of Na/K-ATPase to MBG was decreased (IC50=20 micromol/L), and phorbol diacetate-induced alpha-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 alpha-1 Na/K-ATPase is a likely target for cicletanine treatment. |
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Authors:
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Olga V Fedorova; Mark I Talan; Natalia I Agalakova; Marie-Therese Droy-Lefaix; Edward G Lakatta; Alexei Y Bagrov |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2003-02-10 |
Journal Detail:
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Title: Hypertension Volume: 41 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2003 Mar |
Date Detail:
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Created Date: 2003-03-07 Completed Date: 2003-04-11 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 505-11 Citation Subset: IM |
Affiliation:
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Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antihypertensive Agents / pharmacology* Binding Sites Blood Pressure / drug effects Bufanolides / antagonists & inhibitors*, blood Enzyme Inhibitors / pharmacology Heart Ventricles / enzymology* Hypertension / enzymology*, metabolism, physiopathology Hypertrophy, Left Ventricular / metabolism, pathology, physiopathology Kidney / metabolism, physiopathology Protein Kinase C / metabolism* Pyridines / pharmacology* Rats Rats, Inbred Dahl Sarcolemma / enzymology Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*, chemistry, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antihypertensive Agents; 0/Bufanolides; 0/Enzyme Inhibitors; 0/Pyridines; 470-42-8/marinobufagenin; 87520-10-3/cycletanide; EC 2.7.1.-/protein kinase C beta; EC 2.7.11.13/Protein Kinase C; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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