Myocardial PKC beta2 and the sensitivity of Na/K-ATPase to marinobufagenin are reduced by cicletanine in Dahl hypertension.
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.
Fedorova
Olga V
OV
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA.
Talan
Mark I
MI
Agalakova
Natalia I
NI
Droy-Lefaix
Marie-Therese
MT
Lakatta
Edward G
EG
Bagrov
Alexei Y
AY
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D002018:Bufanolides / Q000037:antagonists & inhibitors* / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000201:enzymology*; D006973:Hypertension / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D012508:Sarcolemma / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000959:Antihypertensive Agents; D002018:Bufanolides; D004791:Enzyme Inhibitors; D011725:Pyridines; C093896:marinobufagenin; C038068:cicletanine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000254:Sodium-Potassium-Exchanging ATPase