The genetic and environmental heterogeneity of
essential hypertension is responsible for the individual variability of
antihypertensive therapy. An understanding of the molecular mechanisms underlying
hypertension and related organ complications is a key aspect for developing new, effective, and safe
antihypertensive agents able to cure the cause of the disease. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+ reabsorption observed in
essential hypertension: the polymorphism of the cytoskeletal
protein alpha-adducin and the increased circulating levels of endogenous
ouabain (EO). Both lead to increased activity and expression of the renal Na+-K+ pump, the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO.
Rostafuroxin (
PST 2238) is a new oral
antihypertensive agent able to selectively antagonize EO,
adducin pressor, and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ
hypertrophy in animal models representative of both
adducin and EO mechanisms. At molecular level, in the kidney,
Rostafuroxin antagonizes EO triggering of the Src-
epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+ pump, and ERK
tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar
ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate
Rostafuroxin as the first example of a new class of
antihypertensive agents designed to antagonize
adducin and EO-hypertensive mechanisms.