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Antihypertensive Compounds That Modulate the Na‐K Pump
Author(s) -
FERRARI P.,
FERRANDI M.,
TORIELLI L.,
BARASSI P.,
TRIPODI G.,
MINOTTI E.,
MOLINARI I.,
MELLONI P.,
BIANCHI G.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb07284.x
Subject(s) - endocrinology , medicine , ventricle , ouabain , chemistry , kidney , blood pressure , renal function , excretion , left ventricular hypertrophy , in vivo , renal hypertrophy , sodium , biology , microbiology and biotechnology , organic chemistry , diabetic nephropathy
A bstract : A primary impairment of the kidney sodium excretion has been documented both in hypertensive patients (EH) and genetic animal models (Milan hypertensive rat [MHS]) carrying mutations of the cytoskeletal protein adducin and/or increased plasma levels of endogenous ouabain (EO). Ouabain (OU) itself induces hypertension in rats and both OU and mutated adducin activate the renal Na/K‐ATPase function both in vivo and in cultured renal cells (NRK). A new antihypertensive agent, PST 2238, able to selectively interact with these alterations has been developed. PST lowers blood pressure (BP) by normalizing the expression and activity of the renal Na‐K pump selectively in those rat models carrying the adducin mutation (MHS) and/or increased EO levels (OS) at oral doses of 0.1‐10 μg/kg. In NRK cells either transfected with mutated adducin or incubated with 10 −9 M OU, PST normalizes the Na‐K pump activity. Recently, an association between EO and cardiac complications has been observed in both EH and rat models consistent with a prohypertrophic activity of OU. OS rats showed a 10% increase of left ventricle and kidney weights as compared with controls, and PST 2238 (1 μg/kg OS) prevented both ventricle and renal hypertrophy. This effect was associated with the ability of PST to antagonize the OU‐dependent activation of growth‐related genes, in the membrane subdomains of caveolae. In conclusion, PST is a new antihypertensive agent that may prevent cardiovascular complications associated with hypertension through the selective modulation of the Na‐K pump function.