Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Abstract

Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na C /K C ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na C /K C ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na C /K C ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na C /K C ATPase activity, cell signaling, and blood pressure regulation.

A New Animal Model to Study Endogenous Cardiotonic Steroids and the Progression of Cardiovascular Events in Salt-Sensitive Hypertension

“…Our preliminary results in the DS rats exposed to a high salt diet support the evidence suggesting that CTS may be of crucial importance in the high mortality rate associated with increased blood pressure response, salt sensitivity and renal salt handling [17,36]. Considering that high blood pressure is the number one cardiovascular risk factor for cardiac failure and stroke, [37,38] we propose the DSc rat as an experimental model to study these relationships and further define the role of endogenous cardiotonic steroids as potential early diagnostic biomarkers to identify those individuals who are at higher risk.…”

“…In conclusion, the DSc model may help to expand and strengthen our knowledge of the relationship of salt sensitivity of blood pressure as have been discussed in recent studies and reviews [17,18,36,40-43]. Moreover, the DSc model can help advance knowledge of the pathophysiology of ocular pathology in ageing [44].…”

Salt intake in children and its consequences on blood pressure

“…Fluid and sodium balances play a central role in regulating blood pressure and, potentially, in the development of arterial hypertension. Several factors modulate salt handling, such as-among others-activation of the sympathetic nervous system, hyperinsulinemia, hypercalcemia, acid-base balance [8], hyperaldosteronism [8,9], leptin [10], genetic background, and maybe also circulating cardioglycosides [11]. Most of these systems ultimately work through the kidney, with the renin-aldosterone-angiotensin system playing a pivotal role in fluid and sodium homeostasis.…”

Ouabain-Induced Cell Death and Survival. Role of α1-Na,K-ATPase-Mediated Signaling and [Na+]i/[K+]i-Dependent Gene Expression

“…In the end of 20th century, several laboratories demonstrated the presence of compounds identical to cardenolides, namely ouabain ( Schneider et al, 1998b ; Kawamura et al, 1999 ), digoxin ( Goto et al, 1990 ), and bufadienolides, such as bufalin ( Lichtstein et al, 1993 ), marinobufagenin ( Bagrov and Fedorova, 1998 ), telocinobufagin ( Komiyama et al, 2005 ), proscillardin A ( Schneider et al, 1998a ), and 19-norbufalin ( Lichtstein et al, 1993 ), in mammals. Their role in the pathogenesis of hypertension and several other disorders is widely disputed now ( Blaustein, 1996 ; de Wardener, 1996 ; Lopatin et al, 1999 ; Dmitrieva and Doris, 2002 ; Schoner, 2002 ; Bagrov et al, 2005 , 2009 ; Bagrov and Fedorova, 2005 ; Khundmiri, 2014 ; Pavlovic, 2014 ; Hamlyn and Manunta, 2015 ; Paczula et al, 2016 ; Khalaf et al, 2018 , 2019 ; Orlov et al, 2020 ).…”