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(Hypertension. 2003;42:991.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Improvement of Endothelial Dysfunction by Selective Estrogen Receptor- Stimulation in Ovariectomized SHR

Julian Widder^*; Theo Pelzer^*; Christine von Poser-Klein; Kai Hu; Virginija Jazbutyte; Karl-Heinrich Fritzemeier; Christa Hegele-Hartung; Ludwig Neyses; Johann Bauersachs

From Medizinische Klinik der Julius-Maximilians-Universität (J.W., T.P., C.V.P.-K., K.H., V.J., J.B.), Würzburg, Germany; Schering AG (K.-H.F., C.H.-H.), Berlin, Germany; and the University of Manchester, Manchester Royal Infirmary (L.N.), Manchester, UK.

Correspondence to Priv Doz Dr Johann Bauersachs, Medizinische Universitätsklinik, Josef-Schneider-Str 2, D-97080 Würzburg, Germany. E-mail bauersachs_j{at}klinik.uni-wuerzburg.de

Both known estrogen receptors, ER and ERß, are expressed in blood vessels. To gain further insight into the role of ER in a functional setting, we investigated the effect of the novel highly selective ER agonist Cpd1471 on vascular reactivity in ovariectomized spontaneously hypertensive rats (SHR). After ovariectomy or sham operation, 12-week-old female SHR received either 17ß-estradiol (E2, 2 µg/kg body wt per day), the selective ER agonist Cpd1471 (30 µg/kg body wt per day), or placebo. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from ovariectomized rats (R_max, 53%±3% versus sham, 79%±2%; P<0.001). Treatment with E2 or Cpd1471 significantly augmented acetylcholine-induced relaxation in ovariectomized rats (R_max, 70%±2%; resp, 73%±2%). Endothelium-independent relaxation induced by sodium nitroprusside was not different among the four groups. The contractile response induced by the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine, an index of basal NO formation, was significantly lower in ovariectomized rats compared with sham-operated animals (53±2% versus 77%±5%; P<0.01) and was normalized by both E2 (70%±2%) and Cpd1471 (70%±3%). Aortic endothelial NO synthase (eNOS) expression and phosphorylation of the vasodilator-stimulated phosphoprotein, an index of NO/cGMP-signaling, was reduced in ovariectomized SHR and normalized by E2 and Cpd1471. In SHR after ovariectomy, endothelium-dependent NO-mediated vasorelaxation and eNOS expression are attenuated. The novel selective ER agonist Cpd1471 prevented these pathophysiological changes to a similar extent as E2. Thus, the pharmacological principle of selective ER activation mediates positive vascular effects.

Key Words: estrogen • endothelium • nitric oxide • nitric oxide synthase • rats, spontaneously hypertensive

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