The evidence that high levels of endogenous
ouabain (EO), a closely related isomer of
ouabain, are implicated in human
hypertension and
cardiac hypertrophy and failure stimulated the pharmacological research for developing novel
anti-hypertensive agents active as
ouabain antagonists. The pathogenetic mechanisms through which increased EO levels affect cardiovascular system involve the modulation of Na-K
ATPase, the key
enzyme responsible for renal tubular
sodium reabsorption and the activation of signalling transduction pathways implicated in growth-related gene transcription. By studying both genetic and experimental rat models of
hypertension and comparing them with humans, our group has demonstrated that elevated levels of circulating EO and the genetic polymorphism of the cytoskeletal
protein adducin associate with
hypertension and high renal Na-K pump activity.
Ouabain itself induces
hypertension and up-regulates renal Na-K pump when chronically infused at low doses into rats (OS). In renal cultured cells, either incubated for several days with nanomolar concentrations of
ouabain or transfected with the hypertensive
adducin genetic variant, the Na-K pump results enhanced. Moreover, both EO and
adducin polymorphism affect cardiac complications associated to
hypertension, the former through the activation of a signalling transduction pathway. As a consequence, a compound able to interact with the cellular and molecular alterations, sustained by EO or mutated
adducin, may represent the suitable treatment for those patients in whom these mechanisms are at work. A new
antihypertensive compound,
PST 2238, that selectively antagonises the pressor effect and the alteration of renal Na-K pump, sustained both by
ouabain and
adducin polymorphism, is described. A selective ability of
PST 2238 to antagonise the
ouabain-induced organ
hypertrophy is also documented. The specificity of
PST 2238 mechanism of action is supported by the absence of interactions with receptors or
hormones involved in blood pressure regulation and by the lack of
diuretic activity and
diuretic-associated side effects. It is concluded that this compound could be useful for the treatment of those forms of
essential hypertension in which renal Na handling alterations and cardiac complications are associated with either increased EO levels and/or
adducin polymorphism.