Ouabain-dependent signaling in caveolae as a novel therapeutic target for hypertension.

Experimental and clinical evidence indicates that Endogenous Ouabain (EO) and Adducin polymorphism play a pathogenetic role in hypertension and related organ complications. These effects occur through a complex interaction of genetic molecular mechanisms regulating renal sodium reabsorption and vascular function. The activation of a Na-K ATPase-Src-EGFr-ERK signaling pathway within the restricted membrane subdomains of caveolae by Ouabain has been associated to hypertension and cardiac remodeling. Rostafuroxin (PST 2238) is a novel anti-hypertensive compound able to selectively antagonize EO/Ouabain and Adducin hypertensive effect and Ouabain-induced cardiac hypertrophy in rats. Studies have been conducted in vivo and in a cell-free system to prove that Rostafuroxin exerts its antihypertensive and antihypertrophic effects by antagonizing the Src-dependent signaling triggered by Ouabain. At the vascular level, Rostafuroxin antagonizes the Ouabain-mediated increase of myogenic vascular tone. This peculiar and novel mechanism of action, together with a good tolerability and efficacy both in animal models and hypertensive patients, make Rostafuroxin the prototype of a new class of antihypertensive compounds able to antagonize EO/ Ouabain and Adducin molecular effects.