Endogenous Digitalislike Factor: An Update

Abstract

bain is the most promising candidate for a circulating hormone to regulate a number of physiological functions, including hypertension, and that other minor substances may also exist as endogenous digitalislike factors. Most of the symposium contributors submitted papers to this journal. I am going to summarize briefly the research history and current research results on endogenous digitalislike factors (EDLF).(Hypertens Res 2000; 23 Suppl: S1-S5)Key Words: endogenous digitalis, ouabain, digoxin, central nervous system, sympathetic activity Identification of Endogenous DigitalisIt has been more than 40 years since researchers suggested that there exists an endogenous digitalis in mammalian species (1). Hamlyn et al. (2) isolated ouabain from a large amount of human plasma and they claimed that ouabain is the endogenous digitalislike factor (EDLF) that had long been sought. However, other EDLFs such as digoxinlike factors (3), bufodienolide derivatives (4-6), and others have been postulated to be the candidate. So far, because of the significant hypertensinogenic actions of ouabain, it seems to be the most probable candidate to fill the putative roles of EDLFs such as water-electrolytes balance maintenance, vasoconstriction, inotropic action on the heart, and hypertension. Endogenous digoxin may also exist. It has been suggested that digoxinlike immunoreactive substances are closely related with hypertension, heart failure, and renal failure. However, because digoxin administered chronically does not elevate blood pressure in humans, it may not be the cardinal endogenous digitalis for blood pressure regulation. Rather, digoxin is found to decrease blood pressure. This points to endogenous ouabain as a possible novel hypertensinogenic hormone. However, there are still concerns to address before reaching this conclusion. One major concern is that ouabain is present in our diets of plant origin (7) and seems to be incorporated in such organs as the adrenal gland, kidney, and brain. In fact, the distribution of ouabainlike and digoxinlike immunoreactivity of high concentration is restricted in those organs; immunohistohemistry with antidigoxin and anti-ouabain antibody have revealed that the immunoreactivity is restricted in neurons of the hypothalamic (8, 9) and medullary nuclei (10) in the brain. In the adrenals, we have found immunoreactivity in the adrenal medulla (11), but others have claimed to find it in the adrenal cortex (12). In any case, digitalislike immunoreactivity found not only in the brain and but also in the adrenals could be of plant origin. However, because plasma concentrations and hypothalamic content of ouabainlike immunoreactivity are markedly reduced by intracerebroventricular (ICV) injections of 6-hydroxydopamine in comparison to amounts in sham-operated rats (13), the existence of endogenously formed ouabain, at least in the brain, is highly probable. Furthermore, some hyperten-

Ouabain, a steroid hormone that signals with slow calcium oscillations

“…It is also locally produced in other tissues, such as the hypothalamus (16,18). Its physiological role has not been clarified (37). It has been suggested that ouabain may act as a natriuretic hormone (22,38), but unlike most other natriuretic factors, it may also have a vasoconstrictive effect (39).…”

Vascular Na+/Ca2+exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension

“…Plasma levels of cardiotonic steroids are also high in several kinds of salt-dependent hypertensive animals (16, 24, 25). Indeed, PST2238, a ouabain antagonist, lowers blood pressure in salt-dependent hypertensive rats and in certain patients with essential hypertension (17,18,91). Thus these cardiotonic steroids may be involved in the etiology of salt-dependent hypertension.…”

“…PST2238 lowers the arterial blood pressure in ouabain-induced hypertensive rats (18) and Milan hypertensive rats (17), in which endogenous ouabain is increased. Recent phase II clinical studies in Europe show that PST2238 effectively lowers blood pressure in essential hypertensive patients (91). On the other hand, thiazide diuretics have been widely used as antihypertensive drugs for a long time.…”

Cardiac Steroids Induce Changes in Recycling of the Plasma Membrane in Human NT2 Cells

“…The structural similarity between the different CS-like compounds identified so far suggests a common precursor and biosynthetic pathway. Numerous studies have shown that the endogenous CS-like compounds are synthesized in and secreted by the adrenal gland (Takahashi, 2000;Schoner, 2002). The level of these endogenous CS-like compounds in human plasma varies between 0.1 and 1 nM (Hamlyn et al, 1996;Goto and Yamada, 1998) and their physiological role, despite extensive research, remains obscure.…”