Sodium Pump Inhibitors In Blood Pressure Regulation

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Salt-sensitive hypertension accounts for 40% of the hypertensives worldwide. Still, molecular mechanisms of salt-sensitivity are not well understood. One theory attributes endogenous digitalis-like cardiotonic steroids (CTS) a central role in the pathogenesis of salt-sensitive hypertension. Two CTS, endogenous ouabain 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 isoform in the kidney, vascular smooth muscle and adult cardiomyocytes. In Dahl salt-sensitive rats (DS) on a high NaCl intake, brain endogenous ouabain triggers peripheral MBG, which raises the blood pressure. In humans, moderate NaCl-loading causes increase in MBG production. During the past year our research focused on (i) pharmacological analysis of central pro-hypertensive effects of low ouabain concentrations in rat, which mimics salt-loading and initiates the angiotensin II-sensitive pathway of MBG stimulation, (ii) study of the impact of heightened MBG levels on glucose tolerance in experimental salt-sensitive hypertension, and (iii) studies of the role of MBG in blood pressure regulation and natriuresis during moderate NaCl-loading of normotensive humans, focusing on age- and gender-associated differences in salt-sensitivity. (i) Pathogenesis of NaCl-sensitive hypertension. We performed pharmacological analyses of central pro-hypertensive effect of low dose ouabain on adrenocortical MBG production in DS rats. Intra-hippocampal administration of 60 ng of ouabain induced activation of renin-angiotensin system (RAS) in the supraoptical nucleus of hypothalamus, and in the pituitary. This activation caused sympathoactivation, which triggered adrenocortical RAS, followed by increase in MBG production. This sequence of events has been analyzed via pharmacological interventions on several levels via administration of anti-ouabain antibody in the supraoptical nucleus of hypothalamus, central and systemic administration of losartan, and via peripheral adrenoceptor blockade. The results permitted to establish a hierarchy in the complex interactions between brain ouabain, central and peripheral RAS, and sympathetic nervous system, and peripheral CTS, which underlies the onset of salt-sensitive hypertension. (ii) The role of CTS has been studied in two other experimental models of NaCl-sensitive hypertension. It is known, that detoxified alcoholics exhibit renal sodium retention, which is a negative prognostic factor for cardiovascular events in the later life. We hypothesized, that MBG is a mediator of hypertension associated with ethanol withdrawal. In a model of acute ethanol withdrawal in rats, animals exhibited renal sodium retention and pressor response, which was prevented by in vivo administration of anti-MBG antibody. Previously, we have demonstrated, that MBG is implicated in pathogenesis of type 1 diabetes mellitus and in pathogenesis of preesclampsia. In hypertensive pregnant diabetic rats following NaCl-supplementation, elevated MBG levels were associated with an improvement of glucose tolerance. Thus, MBG is a common link in the pathogenesis of diabetes and pregnancy-induced hypertension. (iii) The impact of gender and age on CTS response to NaCl-loading has been studied in normotensive humans in collaboration with Lund University, Malmo (Sweden). In this study, a moderate (150 mmol/day) NaCl-loading resulted in an increase in plasma MBG levels, and a moderate elevation of blood pressure. In men, plasma and urine MBG levels correlated with systolic blood pressure, and baseline MBG levels predicted salt-sensitivity of the blood pressure. In aged women, however, this relationship was opposite. Notably, in healthy subjects of both sexes, levels of MBG declined with age, whereas salt-sensitivity of blood pressure is increased with age. Thus, not only excessive production of MBG, but also a failure in the response of this hormone to NaCl-loading may underlie age-associated increase in salt-sensitivity of blood pressure.