PST 2238: A new antihypertensive compound that modulates the Na-K pump 'invivo' and 'in vitro'

A primary renal alteration due to a genetic polymorphism of the cytoskeleta l protein adducin associated with an up-regulation of the renal Na-K pump a nd increased levels of ouabainlike factor(OLF) has been identified as a pos sible causes of hypertension in Milan rats(MHS), This adducin polymorphism has also been found to be associated with hypertension and the blood pressu re changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased a ctivity and expression of the Na-K pump has also been observed under the fo llowing 'in vitro' and 'in vivo' conditions: rat renal cells transfected wi th the 'hypertensive' variant of adducin, as compared with normal cells; no rmal rat renal cells incubated for 5 days with 10(-9) M ouabain and normal rats made hypertensive by a chronic infusion of low doses of ouabain (OS ra ts). An up-regulation of the Na-K pump seems therefore to be a common bioch emical alteration induced both by an adducin polymorphism and/or chronic ex posure to low concentrations of ouabain (or OLF), A new antihypertensive co mpound, PST 2238, that selectively antagonizes the presser effect and the a lteration of the renal Na-K pump induced both by an adducin polymorphism an d OLF, is described. The ability of PST 2238 to lower blood pressure and no rmalize the Na-K pump both in MHS and OS rats suggests that this compound c ould be useful in the treatment of those forms of essential hypertension in which renal Na-handling alterations are associated with either adducin pol ymorphisms and/or increased OLF levels.