Natriuretic Hormones, Endogenous Ouabain, and Related Sodium Transport Inhibitors

Abstract

The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NHs). In addition to the atrial peptides (APs), the circulation contains unidentified physiologically relevant NHs. One NH is controlled by the central nervous system (CNS) and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide (NO). Both NHs have short (<35 min) circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS) including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress NO in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain-like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority.

Endogenous Cardiotonic Steroids in Kidney Failure: A Review and an Hypothesis

“…Numerous studies showed that the third factor was humoral and it induced natriuresis 2 . This so called natriuretic hormone (NH) has long been associated with the efferent natriuretic response to elevated plasma and intracerebroventricular sodium as well as intravascular volume expansion 3 . Hence, a significant portion of the pioneering work in the search for NHs employed human or experimental animals with chronic kidney disease (CKD) in whom ECFV is expanded.…”

“…Further, elevated levels of an NH might, as a side effect, augment vascular tone and raise blood pressure (BP). Indeed, increased circulating levels of a sodium pump inhibitor were readily detected in low renin (i.e., volume-expanded) hypertension 33 and subsequent work demonstrated multiple natriuretic materials in the circulation and urine 3 . Moreover, in the last decade, several natriuretic materials have been isolated and identified.…”

“…Some inhibit sodium transport and, like the classic cardiotonic steroids (CTS) ouabain and digoxin, inhibit sodium pumps. Yet other identified materials are natriuretic via secondary transport mechanisms 3 . Here, we focus on two endogenous CTS implicated in the pathogenesis of CKD and propose a feed-forward mechanism including specific elements by which one or both CTS become elevated in the circulation, raise BP, and promote renal and cardiac damage.…”

Influence of Endogenous Cardiac Glycosides, Digoxin, and Marinobufagenin in the Physiology of Epithelial Cells

“…It is very interesting that our results seem to support the hypothesis stating that a hormonal role of ECS is to influence renal function. Since decades ago, there has been evidence suggesting that ECS functions as natriuretic agents [90,91], although this hypothesis is still controversial [92][93][94][95][96][97]. Our findings, which have been made in epithelial cells, lead us to propose that the ECS modulates the epithelial phenotype because they influence the crucial properties of this type of tissue.…”

Bufalin Inhibits Proliferation and Induces Apoptosis in Osteosarcoma Cells by Downregulating MicroRNA‐221

“…Thus, it is urgently needed to find alternative anticancer agents that will avoid chemoresistance and improve clinical outcomes. The skin and parotid venom glands of toads have been widely used for centuries in traditional Chinese medicine for the treatment of various ailments such as heart failure, hypertension, cancer, and sores [4–6]. Bufalin is the major component of the Chinese medicine ChanSu, which is obtained from the skin and parotid venom glands of toads.…”