Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx

Abstract

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 Ca2+ 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 CaCl2 were studied. Changes in intracellular Ca2+ concentration levels ([Ca2+]i) of vascular smooth muscle (VSM) were measured by fura 2 fluorescence. Raloxifene or 17β-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17β-estradiol. Endothelial denudation did not affect raloxifene- or 17β-estradiol-induced relaxation. NG-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 CaCl2-induced contractions. K+ (80 mM) stimulated an increase in VSM [Ca2+]i, and raloxifene attenuated this effect. Raloxifene-induced reduction of contraction and increase in VSM [Ca2+]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 [Ca2+]i in response to CaCl2, indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca2+ influx via Ca2+ channels. There is little sex difference in raloxifene-induced relaxation.