Cardiac glycosides have been used for decades to treat
congestive heart failure. The recent identification of
cardiotonic steroids such as
ouabain,
digoxin,
marinobufagenin, and
telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of
heart failure and arterial
hypertension. Biosynthesis of
ouabain and
digoxin occurs in adrenal glands and is under the control of
angiotensin II,
endothelin, and
epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body's K(+) content. Rapid changes of endogenous
ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the
sodium pump lag hypothesis, this may be accomplished by partial inhibition of the
sodium pump and Ca(2+) influx via the
Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-
ATPase signalosome complex, generating intracellular calcium oscillations,
reactive oxygen species, and gene activation via
nuclear factor-kappaB or
extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous
ouabain and
marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous
ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction,
hypertrophy, and arterial
hypertension; (iii) about 40% of Europeans with uncomplicated
essential hypertension show increased concentrations of endogenous
ouabain associated with reduced heart rate and
cardiac hypertrophy; (iv) in patients with advanced arterial
hypertension, circulating levels of endogenous
ouabain correlate with BP and total peripheral resistance; (v) among patients with
idiopathic dilated cardiomyopathy, high circulating levels of endogenous
ouabain and
marinobufagenin identify those individuals who are predisposed to progressing more rapidly to
heart failure, suggesting that endogenous
ouabain (and
marinobufagenin) may contribute to toxicity upon
digoxin therapy. In contrast to endogenous
ouabain, endogenous
marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the
ouabain-insensitive alpha(1)
isoform of Na(+)/K(+)-
ATPase of rat kidney tubular cells and its levels are increased in volume expansion and
pre-eclampsia.
Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of
ouabain in rats, as do
antibodies against
ouabain, for example, (
Digibind) and
rostafuroxin (
PST 2238), a selective
ouabain antagonist. It lowers BP in
ouabain- and
adducin-dependent
hypertension in rats and is a promising new class of
antihypertensive medication in humans.