A primary renal alteration due to a genetic polymorphism of the cytoskeletal
protein adducin associated with an up-regulation of the renal Na-K pump and increased levels of ouabainlike factor (OLF) has been identified as a possible causes of
hypertension in Milan rats (MHS). This
adducin polymorphism has also been found to be associated with
hypertension and the blood pressure changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased activity and expression of the Na-K pump has also been observed under the following 'in vitro' and 'in vivo' conditions: rat renal cells transfected with the 'hypertensive' variant of
adducin, as compared with normal cells; normal 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 rats). An up-regulation of the Na-K pump seems therefore to be a common biochemical alteration induced both by an
adducin polymorphism and/or chronic exposure to low concentrations of
ouabain (or OLF). A new
antihypertensive compound,
PST 2238, that selectively antagonizes the pressor effect and the alteration of the renal Na-K pump induced both by an
adducin polymorphism and OLF, is described. The ability of
PST 2238 to lower blood pressure and normalize the Na-K pump both in MHS and OS rats suggests that this compound could be useful in the treatment of those forms of
essential hypertension in which renal Na-handling alterations are associated with either
adducin polymorphisms and/or increased OLF levels.