The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation.
Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ERalpha agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17beta-estradiol. By contrast, the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ERalpha and ERbeta. These data show that selective ERalpha but not ERbeta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.
Bolego
Chiara
C
Department of Pharmacological Sciences, University of Milan, Italy.
Cignarella
Andrea
A
Sanvito
Paola
P
Pelosi
Valeria
V
Pellegatta
Fabio
F
Puglisi
Lina
L
Pinna
Christian
C
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D010052:Ovariectomy; D010636:Phenols; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D047628:Estrogen Receptor alpha; D010636:Phenols; D011720:Pyrazoles; D020845:Selective Estrogen Receptor Modulators; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol