Our 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 last year our research efforts concentrated on the studies of: (i) relationship between central and peripheral SPL during the establishment of Dahl hypertension, and (ii) pathogenetic role of MBG in preeclampsia, and (iii) changes in SPLs and their receptors, NKA isoforms, during cardiac remodeling in NaCl-sensitive hypertension. (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), and, via activation of sympathetic nervous system activates renin-angiotensin system in the adrenal cortex. Adrenocortical ATII acting through AT1 receptors stimulates production of MBG. An increase in MBG production induces inhibition of the sodium pump in renal tubules and in cardiovascular tissues. The later contributes to the chronic blood pressure elevation induced by a sustained high NaCl intake. Intrahippocampal administration of low concentrations of ouabain to NaCl naive rats mimics the effects of NaCl loading, i.e. stimulates MBG production, induces natriuretic and pressor responses and sustained inhibition of renal sodium pump. These effects of central ouabain administration are prevented by peripheral administration of anti-MBG antibody. Thus, MBG, an effector of NaCl induced natriuresis and blood pressure elevation, plays a key role in the complex sequence of events, which underlies the onset of NaCl sensitive hypertension. (ii) Preeclampsia. Previously we have shown that dramatic increases in plasma MBG accompany preeclampsia. 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 that of EO. Administration of specific antibodies to MBG to pregnant hypertensive rats lowers the blood pressure and restores the activity of vascular NKA, a target enzyme for MBG. In patients with preeclampsia activity of the NKA in erythrocytes is inhibited by 40%, which is accompanied by a rise in plasma MBG levels. In vitro treatment of erythrocytes obtained from preeclamptic patients with anti-MBG antibody restored the enzyme activity to the levels observed in normal pregnancy. These findings provide further evidence that MBG is a target for therapy in preeclampsia. (iii) Left ventricular remodeling in NaCl-sensitive hypertension. On an 8% NaCl intake within 4 weeks DS develop compensated left ventricular hypertrophy, which progresses to heart failure at 8-12 weeks. The hypertrophic stage is associated with increased plasma MBG (1.22?0.22 nmol/L vs. 0.31?0.03 nmol/L; P<0.01), increased sensitivity of NKA from left ventricular sarcolemma to MBG, and an increased abundance of alpha-1 NKA. Plasma levels of EO do not change, and the sensitivity of NKA to ouabain decreases. The transition to heart failure is accompanied by a decrease in alpha-1 NKA, a reduction in plasma MBG, decreased sensitivity of NKA to MBG, increased abundance of ouabain-sensitive alpha-3 NKA, 3-fold rise in plasma EO (1.01?0.13 nmol/L vs. 0.27?0.06 nmol/L), and a 7-fold increase in ouabain sensitivity of NKA compared to control. One of the factors, which sensitizes cardiac NKA to MBG, is PKC-dependent NKA phosphorylation. Chronic administration of cicletanine, an antihypertensive compound which inhibits PKC, to NaCl loaded DS, reduces pressor response to heightened NaCl intake, reduces left ventricular weight, prevents up-regulation of alpha-1 NKA and beta 2- and delta-PKC isoforms in myocardiocytes, and desensitizes cardiac NKA to MBG. Endogenous NKA inhibitors function through differential binding to multiple NKA isoforms that are differentially expressed at different stages of hypertensive heart disease. Thus, alterations in the levels and types of NKA isoforms may alter the responsiveness to cardiovascular tissues to SPL, and the interaction of MBG and PKC on the cardiovascular NKA, i.e., PKC induced sensitization of cardiac alpha-1 NKA to MBG via its phosphorylation, is a target for therapy of hypertensive heart disease. Taken together, these findings demonstrate that MBG is an important factor in pathogenesis of hypertension, and open new pharmacological possibilities in the treatment of hypertension, including blockade of circulating MBG with a specific antibody, attenuation of NKA inhibitory effect of MBG on cardiac NKA by inhibition of PKC, and inhibition of adrenocortical MBG production by ATII receptor blockade.
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