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Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

¹Department of Physiology, Chinese University of Hong Kong, Hong Kong; and ²Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai, China

Submitted 16 September 2004 ; accepted in final form 27 January 2005

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 17-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17-estradiol. Endothelial denudation did not affect raloxifene- or 17-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 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.

17-estradiol; relaxation; rat renal artery

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