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.
Ferrandi
M
M
Prassis sigma tau Research Institute, Milan, Italy. mara.ferrandi@prassis.it
Molinari
I
I
Bianchi
G
G
Ferrari
P
P
D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D010042:Ouabain / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D000099291:Adducins
D000732:Androstanols; D000959:Antihypertensive Agents; D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D000099291:Adducins; C106263:rostafuroxin