Document Detail


Myocardial PKC beta2 and the sensitivity of Na/K-ATPase to marinobufagenin are reduced by cicletanine in Dahl hypertension.
MedLine Citation:
PMID:  12623951     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Olga V Fedorova; Mark I Talan; Natalia I Agalakova; Marie-Therese Droy-Lefaix; Edward G Lakatta; Alexei Y Bagrov
Publication Detail:
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:
Title:  Hypertension     Volume:  41     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-03-07     Completed Date:  2003-04-11     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  505-11     Citation Subset:  IM    
Affiliation:
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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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