The search for endogenous digitalis has led to the isolation of
ouabain as well as several additional
cardiotonic steroids of the
cardenolide and
bufadienolide type from blood, adrenals, and hypothalamus. The concentration of endogenous
ouabain is elevated in blood upon increased Na(+) uptake,
hypoxia, and physical exercise. Changes in blood levels of
ouabain upon physical exercise occur rapidly. Adrenal cortical cells in tissue culture release
ouabain upon addition of
angiotensin II and
epinephrine, and it is thought that
ouabain is released from adrenal cortex in vivo.
Ouabain levels in blood are elevated in 50% of Caucasians with low-
renin hypertension. Infusion over several weeks of low concentrations of
ouabain, but not of
digoxin, induces
hypertension in rats. A
digoxin-like compound, which has been isolated from human urine and adrenals, as well various other endogenous
cardiac glycosides may counterbalance their actions within a regulatory framework of water and
salt metabolism.
Marinobufagenin, for instance, whose concentration is increased after cardiac
infarction, may show natriuretic properties because it inhibits the alpha1
isoform of Na(+)/K(+)-
ATPase, the main
sodium pump isoform of the kidney, much better than other
sodium pump isoforms. In analogy to other
steroid hormones,
cardiotonic steroid hormones in blood are bound to a specific
cardiac glycoside binding
globulin. The discovery of
ouabain as a new adrenal
hormone affecting Na(+) metabolism and the development of the new
ouabain antagonist
PST 2238 allows for new possibilities for the
therapy of
hypertension and
congestive heart failure. This will lead in turn to a better understanding of the disease on a physiological and endocrinological level and of the action of
ouabain on the cellular level as a signal that is transduced to the plasma membrane as well as to the cell nucleus.