OF WORK Our previous studies demonstrated that two endogenous ligands of Na,K ATPase (NKA), or cardiotonic steroids (CS), ouabain- like compound (OLC) and marinobufagenin (MBG), coexisting in mammalian tissues, are responsive to NaCl loading and plasma volume expansion, differ with respect to effective stimuli that evoke an increased release, and differ in their targets (alpha-3 and alpha-1 isoforms of NKA). For the first time we demonstrated that MBG in the the physiologically realistic concentrations inhibits renal NKA at the level of high-affiniy (nanomolar) binding sites. In the Dahl salt sensitive rats (DS) with mutated alpha-1 NKA gene, high NaCl intake induced transient increase in OLC excretion, whereas progressive increase in plasma and urinary MBG paralleled blood pressure elevation. Acute administration of MBG antibody (but not ouabain antibody) to hypertensive DS exhibited antihypertensive effect. The development of compensatory left ventricular hypertrophy (4 weeks on an 8% NaCl diet) and transition to heart failure after 8 weeks of hypertension in DS, was associated with an upregulation and downregulation of alpha-1 NKA in myocardium, respectively. Upregulation of myocardial alpha-1 NKA was associated with increased NKA sensitivity to MBG. In preeclampsia, e.g. rapidly developing, volume dependent and Na sensitive hypertension, plasma levels of MBG were increased four-fold as compared to that in normotensive pregnancy. MBG immunoreactive material purified from preeclamptic plasma caused inhibition of NKA from human mesenteric arteries at nanomolar range of concentrations. In the course of studies of mechanisms of vasoconstrictor action of MBG and OLC, we have shown for the first time, that the isoform-specific phosphorylation of NKA by protein kinase C (PKC) in cardiovascular tissues increased sensitivity of NKA to CS. This mechanism may play an important role in the action of CS, per se, and in interaction of CS and other hormones on cardiovascular remodeling. Conversely, inhibition of PKC by an antihypertensive compound, cicletanine, in vitro attenuated NKA inhibitor activity of MBG. This mechanism may explain the exaggerated efficacy of cicletanine in Dahl hypertension, where MBG is elevated and contributed to enhanced vascular tone. In summary, our results demonstrate that elevated levels of an endogenous ligand of alpha-1 NKA, MBG, contribute to vasoconstriction in experimental and clinical NaCl sensitive hypertension. Phosphorylation of alpha-1 NKA by PKC is likely to underlie the interaction of CS and other vasoactive hormones on vasoconstriction and cardiovascular remodeling, and represents a target for therapeutic intervention in the hypertensive states where endogenous CS are stimulated. - Hypertension, Dahl rats, sodium chloride, Na,K ATPase, isoforms, inhibitors, protein kinase C
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