Abstract
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--10−9M) 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.
Footnotes
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Send reprint requests to: Patrizia Ferrari, Prassis Istituto Ricerche Sigma-Tau, via Forlanini 3, 20019 Settimo Milanese (Milano), Italy. E-mail: pstbio{at}tin.it
- Abbreviations:
- HR
- heart rate
- MHS
- Milan-hypertensive strain of rats
- MNS
- Milan-normotensive strain of rats
- OLF
- ouabain-like factor
- SBP
- systolic blood pressure
- SDS
- sodium dodecyl sulfate
- SSC
- standard saline citrate
- SHR
- spontaneously hypertensive rats, Okamoto strain
- Received May 18, 1998.
- Accepted September 23, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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