Endogenous cardiotonic steroids and salt-sensitive hypertension

Abstract

Endogenous cardiotonic steroids (CTS), also called digitalis like factors, have been postulated to play important roles in pathogenesis of hypertension for nearly half of a century. For the past 50 years biomedical scientists have been in quest of an unidentified factor or hormone that both increases blood pressure and renal sodium excretion; this "natriuretic hormone" was, in fact, postulated to interact with the Na/K-ATPase. Recent discoveries have led to the identification of steroid molecules which are present in humans, rodents and amphibians, and which, in a complex manner, interact with each other and with the other systems that regulate renal salt handling and contribute to the salt-sensitivity of blood pressure. Recent findings include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of mechanisms by which CTS can signal through the Na/K-ATPase. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the central regulation of blood pressure and regulation of cell growth, and development of cardiovascular and renal fibrosis in particular.

Figure 1. Transient response of endogenous ouabain precedes sustained increase in MBG excretion during high NaCl intake

Similar patterns of renal excretion of endogenous cardiotonic steroids during chronic NaCl loading of Dahl-S rats (administration of 8% NaCl diet) (A and B) and subacute dietry NaCl supplementation of normotensive human subjects (280 vs. 50 mmol NaCl per day) (C and D). By one-way ANOVA and Newman-Keuls test: *-P<0.05; **-P<0.01 vs. day 0. Adapted from references and .

Figure 2. Interactions between brain endogenous ouabain, renin-angiotensin system, and marinobufagenin in pathogenesis of NaCl-sensitive hypertension

In NaCl-loaded Dahl salt-sensitive rats, in the presence of impaired renal sodium transport, sodium retention stimulates endogenous ouabain in the hippocampus, hypothalamus and pituitary. Brain endogenous ouabain stimulates renin-angiotensin system in the hypothalamus and pituitary, and activates sympathetic nervous system. These events stimulate renin-angiotensin system in the adrenal cortex, and activate adrenocortical production of marinobufagenin (MBG). MBG, a natriuretic and a vasoconstrictor, is produced with a primarily adaptive aim, to induce natriuresis via inhibition of renotubular Na/K-ATPase. An excessive MBG elaboration, however, induces a maladaptive effect and leads to the inhibition of the Na/K-ATPase in vascular smooth muscle cells and potentiates vasoconstriction.

Figure 3. Salt, hypertension and renal failure. Trade off of CTS effects?

The schema illustrates how CTS may be the molecular link explaining how long exposure to a high salt diet may produce hypertension and cardiovascular disease. Specifically, we propose that the profibrotic effects of CTS may, as a trade off for maintaining sodium homeostasis, initially sub-clinically injure the renal parenchyma and in this manner, shift the relationship between blood pressure and sodium. Because of this, patients might be expected to develop hypertension which may, in and of itself, increase circulating CTS levels and synergistically injure organs including the heart and kidney.