Published Online
on October 27, 2003

A more recent version of this article appeared on November 1, 2003

This Article Full Text (PDF) All Versions of this Article: 42/5/991    most recent 01.HYP.0000098661.37637.89v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Widder, J. Articles by Bauersachs, J. Search for Related Content PubMed PubMed Citation Articles by Widder, J. Articles by Bauersachs, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB L-SERINE Related Collections Endothelium/vascular type/nitric oxide

Submitted on June 17, 2003
Revised on July 8, 2003

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; and 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.

^* To whom correspondence should be addressed. E-mail: bauersachs_j{at}klinik.uni-wuerzburg.de.

Abstract--Both known estrogen receptors, ER and ER, 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 17-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

This article has been cited by other articles:

				K. Athirakul, J. A. Bradbury, J. P. Graves, L. M. DeGraff, J. Ma, Y. Zhao, J. F. Couse, R. Quigley, D. R. Harder, X. Zhao, et al. Increased blood pressure in mice lacking cytochrome P450 2J5 FASEB J, December 1, 2008; 22(12): 4096 - 4108. [Abstract] [Full Text] [PDF]

				V. M. Miller and S. P. Duckles Vascular Actions of Estrogens: Functional Implications Pharmacol. Rev., June 1, 2008; 60(2): 210 - 241. [Abstract] [Full Text] [PDF]

				V. Jazbutyte, P. A. Arias-Loza, K. Hu, J. Widder, V. Govindaraj, C. von Poser-Klein, J. Bauersachs, K.-H. Fritzemeier, C. Hegele-Hartung, L. Neyses, et al. Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats Cardiovasc Res, March 1, 2008; 77(4): 774 - 781. [Abstract] [Full Text] [PDF]

				J. P. Konhilas and L. A. Leinwand The Effects of Biological Sex and Diet on the Development of Heart Failure Circulation, December 4, 2007; 116(23): 2747 - 2759. [Full Text] [PDF]

				T. Traupe, C. D. Stettler, H. Li, E. Haas, I. Bhattacharya, R. Minotti, and M. Barton Distinct Roles of Estrogen Receptors {alpha} and {beta} Mediating Acute Vasodilation of Epicardial Coronary Arteries Hypertension, June 1, 2007; 49(6): 1364 - 1370. [Abstract] [Full Text] [PDF]

				R. J. Paul, P. S. Bowman, J. Johnson, and A. F. Martin Effects of sex and estrogen on myosin COOH-terminal isoforms and contractility in rat aorta Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R751 - R757. [Abstract] [Full Text] [PDF]

				H. A. Harris Estrogen Receptor-{beta}: Recent Lessons from in Vivo Studies Mol. Endocrinol., January 1, 2007; 21(1): 1 - 13. [Abstract] [Full Text] [PDF]

				L. Luksha, L. Poston, J.-A. Gustafsson, K. Hultenby, and K. Kublickiene The oestrogen receptor {beta} contributes to sex related differences in endothelial function of murine small arteries via EDHF J. Physiol., December 15, 2006; 577(3): 945 - 955. [Abstract] [Full Text] [PDF]

				P. A. Arias-Loza, K. Hu, A. Schafer, J. Bauersachs, T. Quaschning, J. Galle, V. Jazbutyte, L. Neyses, G. Ertl, K.-H. Fritzemeier, et al. Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17{beta}-Estradiol in Aldosterone Salt-Treated Rats Hypertension, November 1, 2006; 48(5): 994 - 1001. [Abstract] [Full Text] [PDF]

				C. Bolego, E. Vegeto, C. Pinna, A. Maggi, and A. Cignarella Selective Agonists of Estrogen Receptor Isoforms: New Perspectives for Cardiovascular Disease Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2192 - 2199. [Abstract] [Full Text] [PDF]

				V. Jazbutyte, K. Hu, P. Kruchten, E. Bey, S. K.G. Maier, K.-H. Fritzemeier, K. Prelle, C. Hegele-Hartung, R. W. Hartmann, L. Neyses, et al. Aging Reduces the Efficacy of Estrogen Substitution to Attenuate Cardiac Hypertrophy in Female Spontaneously Hypertensive Rats Hypertension, October 1, 2006; 48(4): 579 - 586. [Abstract] [Full Text] [PDF]

				T. Pelzer, V. Jazbutyte, K. Hu, S. Segerer, M. Nahrendorf, P. Nordbeck, A. W. Bonz, J. Muck, K.-H. Fritzemeier, C. Hegele-Hartung, et al. The estrogen receptor-{alpha} agonist 16{alpha}-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats Cardiovasc Res, September 1, 2005; 67(4): 604 - 612. [Abstract] [Full Text] [PDF]

				R. A. Khalil Sex Hormones as Potential Modulators of Vascular Function in Hypertension Hypertension, August 1, 2005; 46(2): 249 - 254. [Abstract] [Full Text] [PDF]

				C. Bolego, A. Cignarella, P. Sanvito, V. Pelosi, F. Pellegatta, L. Puglisi, and C. Pinna The Acute Estrogenic Dilation of Rat Aorta Is Mediated Solely by Selective Estrogen Receptor-{alpha} Agonists and Is Abolished by Estrogen Deprivation J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1203 - 1208. [Abstract] [Full Text] [PDF]

				J. F. Reckelhoff Sex Steroids, Cardiovascular Disease, and Hypertension: Unanswered Questions and Some Speculations Hypertension, February 1, 2005; 45(2): 170 - 174. [Full Text] [PDF]