Relaxant Effects of the Selective Estrogen Receptor Modulator, Bazedoxifene, and Estrogen Receptor Agonists in Isolated Rabbit Basilar Artery

Autores de IIS La Fe

• María Castelló Ruiz

  Autor

• Juan Bautista Salom Sanvalero

  Autor

• Ricardo Fernandez Musoles

  Autor

• María Consuelo Burguete López

  Autor

• Mikahela Andrea López Morales

  Autor

• Teresa Jover Mengual

  Autor

• David Hervás Marín

  Autor

• Germán Torregrosa Bernabé

  Autor

• Enrique Alborch Domínguez

  Autor

Participantes ajenos a IIS La Fe

• Arduini A

Grupos

• Unidad Mixta de Investigación Cerebrovascular

Abstract

We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-beta-estradiol, 4,4',4 ''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) alpha agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4 ''-(4-propyl-[ 1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-beta-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ER beta agonist) had no effect. Expression profile of genes encoding for ER alpha (ESR1), ER beta (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-G-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K+ channels, both a high-K+ medium and the K-v blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K+ channel blocker), glibenclamide (selective K-ATP blocker) or iberiotoxin (selective K-Ca blocker) were without effect. Bazedoxifene also inhibited both Ca2+- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ER alpha receptors; (2) increase of K+ conductance through K-v channels; and (3) inhibition of Ca2+ entry through L-type Ca2+ channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).

Keywords

• bazedoxifene; calcium channels; cerebral arteries; estrogen receptors; potassium channels; selective estrogen receptor modulators