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Description:

IC50: 2 μM for Na+-K+-ATPase

Two mechanisms are involved in determining the abnormalities of tubular Na+ reabsorption observed in hypertension: the polymorphism of the cytoskeletal protein α-adducin and the increased circulating endogenous ouabain (EO) levels. Both lead to increased activity and expression of the renal Na+-K+ pump, which is the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a novel oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects.

In vitro: At molecular level, in the kidney, Rostafuroxin antagonizes EO by 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 [1].

In vivo: Rostafuroxin reduces blood pressure without affecting heart rate, and restores the normal activity of the renal Na+-K+-ATPase in MHS rats when orally treated at doses from 1 to 100 μg/kg/day. Similarly, NUA rats have their blood pressure normalized by rostafuroxin [1].

Clinical trial: Rostafuroxin has already satisfied safety requirements in phase I studies showing complete tolerability either after single or repeated administrations up to a dose of 10 mg/day, without showing differences in side effect patterns compared with placebo. In two small exploratory studies in patients with mild uncomplicated hypertension, rostafuroxin has been demonstrated to be effective in lowering blood pressure at oral doses from 0.1 to 1 mg/day [1].

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