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Androgen receptor independent cardiovascular action of the antiandrogen flutamide

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Abstract

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor (tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 µM: 51.3±5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.

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Abbreviations

L-NAME :

N G-Nitro-l-arginine methylester

MAPK :

Mitogen activated protein kinase

NOS :

Nitric oxide synthase

SD :

Sprague-Dawley

tfm :

Testicular feminization mutation

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Acknowledgements

This work was supported in part by the German Bundesministerium für Bildung und Forschung (grant 0310681B). We thank Irene Strauss and Gabriele Born for the measurement of plasma hormone levels and Lieselotte Winkler for excellent technical assistance.

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Authors and Affiliations

  1. Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin-Buch, Germany

    Radu Iliescu, Luciana A. Campos, Wolfgang-Peter Schlegel, Ingo Morano, Ovidiu Baltatu & Michael Bader

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  1. Radu Iliescu
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  2. Luciana A. Campos
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  3. Wolfgang-Peter Schlegel
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  4. Ingo Morano
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  5. Ovidiu Baltatu
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Correspondence to Ovidiu Baltatu.

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Iliescu, R., Campos, L.A., Schlegel, WP. et al. Androgen receptor independent cardiovascular action of the antiandrogen flutamide. J Mol Med 81, 420–427 (2003). https://doi.org/10.1007/s00109-003-0449-4

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  • DOI: https://doi.org/10.1007/s00109-003-0449-4

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