Antihypertensive compounds that modulate the Na-K pump.
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 micro g/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 micro g/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.
Ferrari
P
P
Prassis Research Institute, Sigma Tau, Milan, Italy. patrizia.ferrari@prassis.it
Ferrandi
M
M
Torielli
L
L
Barassi
P
P
Tripodi
G
G
Minotti
E
E
Molinari
I
I
Melloni
P
P
Bianchi
G
G
D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D000732:Androstanols; D000959:Antihypertensive Agents; D011994:Recombinant Proteins; D000254:Sodium-Potassium-Exchanging ATPase; C106263:rostafuroxin