Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels.
OBJECTIVE
Because of their mixed estrogen-agonist and estrogen-antagonist properties, selective estrogen receptor modulators (SERMs) are considered promising substitutes for hormone replacement therapy. Raloxifene and other SERMs confer estrogen-like cardiovascular protective effects but lack the carcinogenic activity of exogenous estrogen. However, little is known about the cerebrovascular action of raloxifene. Therefore, we studied the effects of raloxifene on the mechanisms regulating rat cerebral artery tone.


METHODS
Ring segments of the isolated rat posterior communicating cerebral arteries were mounted in a microvessel myograph for measurement of isometric tension. Whole-cell L-type voltage-sensitive Ca2+ currents were recorded using the perforated patch-clamp technique. Raloxifene (0.1 to 10 micromol/L) reduced the contractile responses to U46619, phenylephrine, and endothelin-1 in normal Krebs solution or to CaCl2 in Ca2+-free, high K+-containing solution. Raloxifene-induced relaxation was identical in endothelium-intact and endothelium-denuded rings. ICI 182780 had no effect on raloxifene-induced relaxation. Raloxifene reduced L-type Ca2+ currents with a pD2 of 5.98+/-0.06, close to that (6.44+/-0.09) for raloxifene-induced relaxation of 60 mmol/L K+-contracted rings.


CONCLUSIONS
This study demonstrates that raloxifene acutely relaxes rat cerebral arteries largely via an endothelium-independent mechanism, involving inhibition of Ca2+ influx through L-type Ca2+ channels.
Tsang
Suk-Ying
SY
Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Yao
Xiaoqiang
X
Essin
Kirill
K
Wong
Chi-Ming
CM
Chan
Franky L
FL
Gollasch
Maik
M
Huang
Yu
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002536:Cerebral Arteries / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004730:Endothelium, Vascular; D066298:In Vitro Techniques; D008297:Male; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D020845:Selective Estrogen Receptor Modulators; D014662:Vasoconstrictor Agents; D020849:Raloxifene Hydrochloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid