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Vol. 288, Issue 3, 1074-1083, March 1999
Prassis Research Institute Sigma-Tau (P.F., L.T., M.F.,
G.T., G.P., E.M., P.M.), Milan, Italy; and
Chair of Nephrology,
Division of Nephrology and Hypertension, University of Milan and S. Raffaele Hospital (G.B.), Milan, Italy
A genetic alteration in the adducin genes is associated with
hypertension and up-regulation of the expression of renal Na,K-ATPase in Milan-hypertensive (MHS) rats, in which increased ouabain-like factor (OLF) levels are also observed. PST 2238, a new antihypertensive compound that antagonizes the pressor effect of ouabain in vivo and
normalizes ouabain-dependent up-regulation of the renal Na-K pump, was
evaluated for its ability to lower blood pressure 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 and 10 µg/kg
for 5-6 weeks), reduced the development of hypertension in MHS rats
and normalized the increased renal Na,K-ATPase activity and mRNA
levels, whereas it did not affect either blood pressure or Na,K-ATPase
in Milan-normotensive (MNS) rats. In addition, a similar
antihypertensive effect was observed in adult MHS rats after a
short-term treatment. In cultured rat renal cells with increased Na-K
pump activity at Vmax due to overexpression of the hypertensive variant of adducin, 5 days of incubation with PST
2238 (10
10--109 M) lowered the
pump rate to the level of normal wild-type 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 cytoskeletal
adducin. Because adducin gene mutations have been associated with human
essential hypertension, it is suggested that PST 2238 may display
greater antihypertensive activity in those patients carrying such a
genetic alteration.
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