Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx.

Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of the endothelium and Ca(2+) channels in rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U-46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl(2) were studied. Changes in intracellular Ca(2+) concentration levels ([Ca(2+)](i)) of vascular smooth muscle (VSM) were measured by fura 2 fluorescence. Raloxifene or 17beta-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17beta-estradiol. Endothelial denudation did not affect raloxifene- or 17beta-estradiol-induced relaxation. N(G)-nitro-l-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI-182, 780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U-46619 and high K(+). Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl(2)-induced contractions. K(+) (80 mM) stimulated an increase in VSM [Ca(2+)](i), and raloxifene attenuated this effect. Raloxifene-induced reduction of contraction and increase in VSM [Ca(2+)](i) were insensitive to ICI-182, 780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182, 780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca(2+)](i) in response to CaCl(2), indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca(2+) influx via Ca(2+) channels. There is little sex difference in raloxifene-induced relaxation.