Myocardial PKC 2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

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 2 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 2 was not increased, the sensitivity of Na/K-ATPase to MBG was decreased (IC50 20 mol/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. (Hypertension. 2003;41:505-511.)