Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings

Spironolactone and its active metabolites canrenone and potassium canrenoat e are normally used as antihypertensive drugs. Although they are classified as antagonists of aldosterone, their mechanism of action cannot be ascribe d solely to the regulation of ion transport in the distal tubule of nephron s. Here we have evaluated the effects of spironolactone, canrenone, and pot assium canrenoate on contractile properties of isolated rat aorta rings. Sp ironolactone (1-300 mu M), canrenone (1-300 mu M), and potassium canrenoate (0.01-10 mM). in a concentration-dependent manner, relaxed rat aorta rings precontracted with phenylephrine (1 mu M) or KCl (40 mM). These relaxant e ffects were not affected by prior treatment with either aldosterone (100 mu M), glibenclamide (10 mu M), or tetraethylammonium (10 mM), excluding the possibility that these drugs can be involved in either the nongenomic effec t of aldosterone or on activation of potassium channels. Spironolactone and canrenone at concentrations of 30 and 100 mu M, but not at 10 mu M, and po tassium canrenoate at concentrations of 0.3 and 1 mM, but not at 0.1 mM, si gnificantly inhibited the phenylephrine (0.001-3 mu M) concentration-respon se curve. Conversely, all tested concentrations of spironolactone (10, 30, and 100 mu M), canrenone (10, 30, and 100 mu M), and potassium canrenoate ( 0.1, 0.3, and 1 mM) significantly inhibited the concentration-response curv e induced by cumulative concentrations of KCI (10-80 mM). Because both phen ylephrine- and KCl-induced contractions imply an intra cellular Ca2+ influx , Lye suggest that these drugs could act through an inhibition of voltage-d ependent Ca2+ channels.