Abstract
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 ERα agonist 4,4′,4″-(4-propyl-[1H]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 17β-estradiol. By contrast, the selective ERβ 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 Nω-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17β-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 (7α,17β-[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 ERα and ERβ. These data show that selective ERα but not ERβ agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17β-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.
Footnotes
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doi:10.1124/jpet.104.082867.
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ABBREVIATIONS: ER, estrogen receptor; E2, 17β-estradiol; PPT, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) tris-phenol; DPN, 2,3-bis(4-hydroxyphenyl)-propionitrile; OVX, ovariectomized; NA, noradrenaline; l-NAME, Nω-nitro-l-arginine methyl ester; ICI 182,780, 7α,17β-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol; RAEC, rat aortic endothelial cell; ANOVA, analysis of variance.
- Received December 24, 2004.
- Accepted February 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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