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CARDIOVASCULAR

The Acute Estrogenic Dilation of Rat Aorta Is Mediated Solely by Selective Estrogen Receptor- Agonists and Is Abolished by Estrogen Deprivation

Department of Pharmacological Sciences, University of Milan, Milan, Italy (C.B., A.C., P.S., V.P., F.P., L.P., C.P.); and Department of Pharmacology and Anesthesiology, University of Padua, Padua, Italy (A.C.)

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 ER 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 17-estradiol. By contrast, the selective ER 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-nitro-L-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17-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 (7,17-[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 ER and ER. These data show that selective ER but not ER agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17-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.

Address correspondence to: Dr. Andrea Cignarella, Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, I-20133 Milan, Italy. E-mail: andrea.cignarella{at}unimi.it

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