Ferrari P.,Prassis Research Institute sigma tau
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010
An innovative approach to the therapy of essential hypertension (EH) and the related complications has been pursued by our group with the aim of defining specific genetic-molecular mechanisms underlying the disease in sub-sets of patients. This approach is anticipated to have a major effect on the clinical practice, diagnostics and development of new drugs able to selectively target such mechanisms. The final achievement is the definition of biomarkers for identifying patients who more likely should benefit for a given therapy both in terms of efficacy and reduction of the adverse reactions. Among many, two mechanisms have been defined and addressed: 1)polymorphisms in the gene coding for the cytoskeletal protein, adducin; 2)increased levels of the salt and blood pressure-regulating hormone, endogenous ouabain (EO).Both alterations lead to hypertension, organ hypertrophy, negative vascular remodeling and increased cardiovascular risk by affecting the renal Na+ handling, through the up-regulation of the Na+-K+ pump and the activation of the Src-dependent signal transduction pathway. A novel antihypertensive agent, rostafuroxin (PST2238), has been selected and developed for its ability to correct the renal Na+-K+ pump abnormalities sustained by the mutant adducin and EO-dependent mechanisms. It is endowed with high potency and efficacy in reducing blood pressure (BP) and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, rostafuroxin normalizes the enhanced activity of the Na+-K+ pump induced by mutant adducin and antagonizes the EO triggering of the Src-EGFr-dependent signaling pathway leading to renal Na+-K+ pump and ERK phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by ouabain. A very high safety ratio and the absence of interaction with other mechanisms involved in BP regulation, together with 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. A recently concluded Phase II clinical trial (OASIS) has provided the proof of concept that such a compound is effective in the subset of patients where these two mechanisms are at work. © 2010 Elsevier B.V.