Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na⁺-K⁺- ATPase alterations in ouabain and adducin-dependent hypertension

Abstract

The genetic and environmental heterogeneity of essential hypertension is responsible for the individual variability of antihypertensive therapy. An understanding of the molecular mechanisms underlying hypertension and related organ complications is a key aspect for developing new, effective, and safe antihypertensive agents able to cure the cause of the disease. 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 vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a new oral antihypertensive agent able to selectively antagonize EO, adducin pressor, 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 antagonizes EO triggering of the Src-epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+ pump, and ERK tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar 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.

Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

“…Furthermore, a lack of MBG production following NaCl loading could result in a relatively high renotubular sodium pump activity. Indeed, activation of renal Na ϩ -K ϩ -ATPase was shown to contribute to hypertension in Milan hypertensive rats, and was attributed to mutation of the ␣-adducin gene (15). A polymorphism of the adducin gene has been detected in 20% of human hypertensive population (23).…”

Cardiovascular Problems on Hemodialysis

“…In dialysis patients, a relationship was reported between left ventricular mass and another cardiotonic steroid: Ouabain (28). It is of interest that an inhibitor of ouabainrostafuroxin-is currently in clinical evaluation (29).…”

“…• An additional option may be the administration of antagonists of the cardiotonic steroid ouabain (e.g., rostafuroxin [29]). It reverses the ouabain-dependent increase of vascular resistance.…”

How does salt retention raise blood pressure?

“…Indeed, many linkage studies have been unrewarding (5). Some recent studies, however, suggest that polymorphisms in G protein-coupled receptor kinase (GRK) and ␣-adducin genes may be associated with hypertension in subsets of the population (7,25,62,119). GRKs regulate dopamine receptors that are involved in modulating renal proximal tubule Na ϩ transport, especially during Na ϩ excess (119).…”

“…GRKs regulate dopamine receptors that are involved in modulating renal proximal tubule Na ϩ transport, especially during Na ϩ excess (119). Adducins are cytoskeletal proteins, and some ␣-adducin variants augment the activity of Na ϩ pumps (Na ϩ -K ϩ -ATPase) with ␣ 1 -subunits and enhance Na ϩ reabsorption in renal epithelia (25,111).…”