*4.4. Endogenous Ouabain as Therapeutic Target*

As already said in this review, several studies during the last decays individuated a central core in the increased EO levels that could connect the pathogenesis of several cardiac and renal diseases, including hypertension, cardiac hypertrophy, heart failure, renal failure and ADPKD. This fundamental evidence stimulated the birth of a new research branch aiming to individuate a selective competitor of EO, paving the way for the formulation of new antihypertensive agents that could selectively correct the molecular mechanisms behind. On this basis, authors' research groups developed a new digitoxigening-derived compound, called Rostafuroxin. Its mechanism of action expects to display EO from its specific binding sites on the Na+/K+-ATPase, modulating its abnormal expression in the cell surface without inhibiting other renal sodium transporters and without influencing other hormonal pathways [19,43,63]. As already mentioned, the interaction between EO and its receptor triggers a complex cascade of intracellular second-messengers that ends with the generation of hypertrophic stimuli. It was seen that nanomolar concentrations of Rostafuroxin could antagonize the interaction between EO and the Na+/K+ pump, normalizing this signal response and blocking the excessive activation of EGFR [19]. In both normotensive and MHS rat models, low oral doses of Rostafuroxin could normalize the up-regulation of renal Na+-pump, leading to a reduction of blood pressure levels [19,63]. A similar effect was obtained with the use of Rostafuroxin in other rat models, such as the deoxycorticosterone acetate–salt rat and the reduced-renal-mass hypertensive rat. Both models were characterized by a condition of low plasmatic renin, volume expansion and increased levels of EO [64]. In contrast, it was interesting to evaluate that Rostafuroxin does not act as an antihypertensive agent in these models, in which EO and α-adducin polymorphism are not implicated in the pathogenesis of hypertension, such as the normotensive control rats and spontaneous hypertensive rats. Moreover, preliminary results suggest that this molecule, used at oral doses of 7–10 μg/kg/day, might revert the ouabain-induced hypertrophic activity [35,37]. In a trial of unselected patients, it was shown that

Rostafuroxin does not influence blood pressure in these patients with no elevated EO levels, assuming that its effect on blood pressure is strictly related to the genetic background that regulates the synthesis and the clearance of EO. It was assessed that in Rostafuroxin-sensitive patients, there is a decline of systolic blood pressure of 14 mmHg after 4 weeks of treatment [65]. Nowadays, we do not have data about the effect of Rostafuroxin on the treatment of renal failure and the effects of hypertension on patients with end-stage renal disease, but this compound might have the effect of amelioration of the grade of hypertrophy and heart failure [46]. The pharmacological profile and the selective mechanism of action of Rostafuroxin make it the prototype of a compound devoid of the cardiovascular and hormonal side effects associated with digitalis and diuretic. Indeed, there was no evidence of intrinsic cardiac inotropic effects or arrhythmogenic activity.
