Targeting Ouabain- and Adducin-dependent mechanisms of hypertension and cardiovascular remodeling as a novel pharmacological approach.
Essential hypertension is a heterogeneous multifactorial syndrome associated with a high cardiovascular risk. A multiple choice of antihypertensive drugs is available; however, a high individual variability to the antihypertensive therapy is still responsible for a modest reduction of the CV risk and not satisfactory control of blood pressure levels. The success of future hypertension treatment will depend upon the understanding of the genetic molecular mechanisms operating in subsets of patients, and the ability of new drugs to specifically correct such alterations. 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 cardiovascular alterations have also been associated with adducin and EO. Rostafuroxin is a new oral antihypertensive agent able to selectively antagonize adducin and EO hypertensive 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 normalizes the enhanced activity of the Na-K pump induced by adducin mutation and antagonizes the EO triggering of the Src-EGFr-dependent signaling pathway leading to renal Na-K pump, and ERK Tyrosin phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by 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. Currently, a phase II multicenter European clinical trial is ongoing for providing the proof of concept that such a compound is effective in the subset of patients where these two mechanisms are at work.
Ferrari
Patrizia
P
Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese, Milano, Italy. patrizia.ferrari@prassis.it
Ferrandi
Mara
M
Valentini
Giovanni
G
Manunta
Paolo
P
Bianchi
Giuseppe
G
D000732:Androstanols / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D008955:Models, Cardiovascular; D010042:Ouabain / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D000099291:Adducins
D000732:Androstanols; D000959:Antihypertensive Agents; D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins; C106263:rostafuroxin