PST 2238: A new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension

A genetic alteration in the adducin genes is associated with hypertension a nd up-regulation of the expression of renal Na,K-ATPase in Milan-hypertensi ve (MHS) rats, in which increased ouabain-like factor (OLF) levels are also observed. PST 2238, a new antihypertensive compound that antagonizes the p resser effect of ouabain in vivo and normalizes ouabain-dependent up-regula tion of the renal Na-K pump, was evaluated for its ability to fewer blood p ressure and regulate renal Na,K-ATPase activity in MHS genetic hypertension . In this study, we show that PST 2238, given orally at very low doses (1 a nd 10 mu g/kg for 5-6 weeks), reduced the development of hypertension in MH S rats and normalized the increased renal Na,K-ATPase activity and mRNA lev els, whereas it did not affect either blood pressure or Na,K-ATPase in Mila n-normotensive (MNS) rats. In addition, a similar antihypertensive effect w as observed in adult NIHS rats after a short-term treatment. In cultured ra t renal cells with increased Na-K pump activity at V-max due to overexpress ion of the hypertensive variant of adducin, 5 days of incubation with PST 2 238 (10(-10-)-10(-9) M) lowered the pump rate to the level of normal wild-t ype cells, which in turn were not affected by the drug. In conclusion, PST 2238 is a very potent compound that in MHS rats reduces blood pressure and normalizes Na-K pump alterations caused by a genetic alteration of the cyto skeletal adducin. Because adducin gene mutations have been associated with human essential hypertension, it is suggested that PST 2238 may display gre ater antihypertensive activity in those patients carrying such a genetic al teration.