Published Online
on September 25, 2006

A more recent version of this article appeared on November 1, 2006

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Submitted on March 28, 2006
Revised on April 23, 2006

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17-Estradiol in Aldosterone Salt-Treated Rats

Paula Anahi Arias-Loza; Kai Hu; Andreas Schäfer; Johann Bauersachs; Thomas Quaschning; Jan Galle; Virginija Jazbutyte; Ludwig Neyses; Georg Ertl; Karl-Heinrich Fritzemeier; Christa Hegele-Hartung; and Theo Pelzer^*

From the Medizinische Klinik I (P.A.A.-L., K.H., A.S., J.B., T.Q., J.G., V.J., G.E., T.P.), University of Würzburg, Würzburg, Germany; Schering AG Berlin (K.-H.F., C.H.-H.), Berlin, Germany; and the Division of Cardiology (L.N.), University of Manchester, Manchester, United Kingdom.

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

Abstract--Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.

Key words: aldosterone • estrogen • medroxyprogesterone-acetate • cardiac hypertrophy

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