bufadienolide and Hypertension

Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, have been postulated to play important roles in health and disease for nearly half a century. Recent discoveries, which include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of an alternative mechanism by which CTS can signal through the Na(+)/K(+)-ATPase, have increased the interest in this field substantially. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the regulation of cell growth, differentiation, apoptosis, and fibrosis, the modulation of immunity and of carbohydrate metabolism, and the control of various central nervous functions and even behavior. This review focuses on the physiological interactions between CTS and other regulatory systems that may be important in the pathophysiology of essential hypertension, preeclampsia, end-stage renal disease, congestive heart failure, and diabetes mellitus. Based on our increasing understanding of the regulation of CTS as well as the molecular mechanisms of these hormone increases, we also discuss potential therapeutic strategies.

Topics: Animals; Blood Pressure; Bufanolides; Cardiac Glycosides; Cardiotonic Agents; Diabetes Mellitus; Enzyme Inhibitors; Female; Heart Failure; Humans; Hypertension; Ouabain; Pre-Eclampsia; Pregnancy; Signal Transduction; Sodium-Potassium-Exchanging ATPase

For the past 50 years biomedical scientists have been in quest of an unidentified factor (hormone) that elevates blood pressure and regulates renal sodium transport, i.e., natriuretic hormone. Recent discoveries have led to the identification of such factors which are present in humans, rodents and amphibians, and which, in a complex manner, interact with each other and with the other regulatory systems. In experimental NaCl sensitive hypertension brain endogenous ouabain, via activation of renin-angiotensin system and of sympathetic nervous system, stimulates adrenocortical production of marinobufagenin, a natriuretic and a vasoconstrictor. The combined effects of these endogenous factors may account for the classical properties attributed by Dahl, deWardener and others to the hypothetical "natriuretic hormone".

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bufanolides; Cardenolides; Humans; Hypertension; Ligands; Ouabain; Rats; Rats, Inbred Dahl; Renin-Angiotensin System; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Endogenous digitalis-like factors in humans are presumably cardenolides and bufadienolides. To test whether bufadienolide-like substances may circulate in human blood, we used antibodies from rabbits against the bufadienolide proscillaridin A to measure the concentration of cross-reacting material in human plasma with an indirect enzyme-linked immunosorbent assay. IgG had an apparent affinity of 2 x 10(-9) mol/L for proscillaridin A. It was specific for bufadienolides and did not cross-react with cardenolides or several steroid hormones. Extraction of human plasma with ethanol and fractionation of this extract over a high-performance liquid chromatographic reverse-phase C18 column with a propanol/isopropanol gradient resulted in the separation of three peaks of increasing hydrophobicity (ED1, ED2, ED3) that inhibited the sodium pump of human red blood cells and cross-reacted with proscillaridin A antibodies. The concentration of the proscillaridin A immunoreactivity ED1 in normotensive subjects had a geometric mean of 0.1 nmol/L, with a dispersion factor of 8.77. ED1 correlated positively in a group of 60 normotensive subjects, 22 patients with hypertension, and 19 patients with chronic renal failure with mean arterial blood pressure (log ED1 [nmol/L] = 0.013 x mm Hg-2.17, r = .25, P < .05), systolic pressure (log ED1 [nmol/L] = 0.010 x mm Hg-2.23, r = .32, P < .01), and pulse pressure (log ED1 [nmol/L] = 0.019 x mm Hg-1.80, r = .38, P < .0001). There was no correlation with other parameters of the donors. We conclude that several substances cross-reacting with proscillaridin A antibodies and inhibiting the sodium pump of human red blood cells circulate in human blood. The level of one of these substances (ED1) correlates with mean arterial and pulse pressures.

Topics: Adult; Animals; Blood Pressure; Bufanolides; Cholenes; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Proscillaridin; Rabbits; Reference Values; Systole