title: PST 2238: a new antihypertensive compound that modulates renal Na-K pump function without diuretic activity in Milan hypertensive rats.
abstract: PST 2238 is a new antihypertensive compound that is able to correct the molecular and functional alterations of the renal Na-K pump and the pressor effect associated with either alpha-adducin mutations or high circulating levels of endogenous ouabain (EO) in genetic and experimental rat models. Due to the close relationship between renal Na-K pump function and tubular Na reabsorption, PST 2238 was investigated to determine whether it is endowed with diuretic activity and consequently might trigger alterations of the renin-aldosterone system and the carbohydrate and lipid metabolism often associated with chronic diuretic therapy. In Milan hypertensive (MHS) rats, in which hypertension is genetically associated with alpha-adducin mutation, increased tubular Na reabsorption, and hyperactivation of the renal Na-K pump. PST 2238 reduced blood pressure and normalized the renal Na-K pump activity at oral doses of micro g/kg, but did not induce, either acutely or chronically, any diuretic activity or hormonal or metabolic alterations. In contrast, HCTZ, given to MHS rats orally at 40 mg/kg, although it displayed diuretic activity and reduced the renal Na-K pump activity, did not lower blood pressure and caused hyperactivation of the renin-aldosterone system, hypokaliemia, and hyperglycemia. The findings lead to the conclusion that PST 2238 is a new antihypertensive compound that normalizes the altered function of the renal Na-K pump associated with hypertension in rat models, but that it is devoid of diuretic activity and does not induce the diuretic-associated side effects.
authors.affiliation: Prassis Research Institute sigma tau, Settimo M se, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Ferrandi
authors.forename: Paolo
authors.initials: P
authors.lastname: Barassi
authors.forename: Elena
authors.initials: E
authors.lastname: Minotti
authors.forename: Liliana
authors.initials: L
authors.lastname: Duzzi
authors.forename: Isabella
authors.initials: I
authors.lastname: Molinari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D000732:Androstanols / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects*; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*
chemical_list: D000732:Androstanols; D006852:Hydrochlorothiazide; D000254:Sodium-Potassium-Exchanging ATPase; C106263:rostafuroxin