1. ¹Department of Basic Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
2. ²Department of Pharmacology, School of Medicine University of California Irvine, Irvine, California, USA

Correspondence: Dr RJ Gonzales, Department of Basic Medical Sciences, University of Arizona College of Medicine, in partnership with Arizona State University, Phoenix, Arizona 85004, USA. E-mail: rjgonzal@arizona.edu

Received 9 May 2008; Revised 20 August 2008; Accepted 8 September 2008; Published online 22 October 2008.

Abstract

Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-B (NFB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFB activation in cerebral arteries and increased levels of the proinflammatory products of NFB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.