Sodium Pump Inhibitors In Blood Pressure Regulation

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Previous studies demonstrated that two endogenous sodium pump ligands (SPL), endogenous ouabain (EO) and marinobufagenin (MBG), coexist in mammalian tissues. MBG acts as a selective inhibitor of ouabain resistant alpha-1 isoform of Na/K-ATPase (NKA), the main sodium pump isoform in the kidney, vascular smooth muscle and adult myocardiocytes. In Dahl salt-sensitive rats (DS), in which the defect of alpha-1 NKA underlies development of NaCl sensitive hypertension, brain EO triggers peripheral MBG, which raises the blood pressure. In vivo administration of MBG antibody to hypertensive DS lowered the blood pressure. During the past year, our research focused on: (i) studies of relationship between central and peripheral SPL during establishment of Dahl hypertension, (ii) studies of interaction of SPL and protein kinases on renal and cardiovascular NKA, and (iii) investigations of the pathogenic role of MBG in preeclampsia. (i) Pathogenesis of NaCl sensitive hypertension. In the course of development of NaCl hypertension in DS, an initial transient rise of EO in the hippocampus and amygdala, followed by an increase in EO in the supraoptic nucleus of the hypothalamus and pituitary, stimulates pituitary angiotensin II (ATII), which stimulates adrenocortical production of MBG via an ATII sensitive pathway. A sustained increase in MBG production occurs, and induces inhibition of the sodium pump in renal tubules and in cardiovascular tissues. The latter contributes to a chronic blood pressure elevation induced by sustained high NaCl intake. The complex mechanism by which MBG inhibits sodium transport in renal tubules involves internalization of the NKA. Bilateral administration of low concentration of ouabain mimics the effects of NaCl loading and results in increased levels of MBG, and natriuretic and pressor responses. These effects of central ouabain administration are prevented by in vivo administration of anti-MBG antibody. Thus, two SPL, MBG and EO, play an important role in this vicious circle, which may underlie the pathogenesis of NaCl sensitive hypertension. (ii) Protein kinases modulate MBG induced NKA inhibition. Protein kinases phosphorylate/dephosphorylate the NKA and alter its sensitivity to digitalis-like ligands. In rat aorta, ANP at nanomolar concentration dephosphorylates alpha-1 NKA and markedly reduces the sensitivity of the sodium pump to MBG. In contrast, in renal medulla, ANP induces alpha-1 NKA phosphorylation and potentiates MBG induced inhibition of the sodium pump. These effects of ANP are mimicked by an activator of protein kinase G, 8-Br-PET-cGMP. Since kidney and vascular smooth muscle cells express type 2 and type 1 isoforms of the PKG, respectively, these two isoforms are likely to exhibit opposite effects on the sensitivity of NKA to MBG. The concurrent production of a vasorelaxant, ANP, and a vasoconstrictor, MBG, which occurs in NaCl sensitive hypertension and in congestive heart failure, results in the potentiation of their natriuretic effects, while ANP peptides may offset the deleterious vasoconstrictor effect of MBG. Therefore, prohypertensive cardiovascular effects of MBG may be antagonized via cGMP/PKG dependent mechanisms. In hypertensive Dahl rats, enhanced sensitivity of cardiac NKA to MBG is associated with upregulation of beta2 and delta PKC in the myocardium. Chronic treatment of Dahl rats with cicletanine, an antihypertensive compound, which inhibits the PKC, lowers the blood pressure, desensitizes cardiac NKA to MBG and decreases its phosphorylation, and prevents increases in PKC in myocardial sarcolemma. Thus, interaction of SPL and protein kinases on cardiovascular NKA is a novel target for therapy of hypertension. (iii) Preeclampsia. Previously we have shown that dramatic increases in plasma MBG accompany preeclampsia. Interestingly, antibodies to digoxin (DIGIBIND), due to their ability to bind SPL are used in the treatment of preeclampsia clinically. In two rat models of preeclampsia (NaCl supplementation of pregnant with and without administration of deoxycorticosterone acetate- DOCA) elevations of blood pressure are associated with sustained increases in the levels of MBG, but not EO. Furthermore, DOCA+NaCl treatment of pregnant rats is associated with a dramatic increase in the sensitivity of uterine vasculature to constrictor effect of MBG. Administration of polyclonal and monoclonal antibodies to MBG to pregnant hypertensive rats lowers the blood pressure and restores the activity of vascular NKA. These data make MBG a potential target for therapy in patients with preeclampsia. Taken together, these findings demonstrate that MBG is a novel factor in the pathogenesis of hypertension, and may open new pharmacological possibilities in the treatment of hypertension, including blockade of circulating MBG with specific antibodies in preeclampsia, attenuation of NKA inhibitory effect of MBG on cardiovascualar NKA by inhibition of protein kinase C and resulting desensitization of the sodium pump to MBG, and inhibition of adrenocortical MBG production by ACE inhibitors and/or angiotensin II receptor blockers.