Influence of the alpha(1)-adrenergic antagonist, doxazosin, on noradrenaline-induced modulation of cytoskeletal proteins in cultured hyperplastic prostatic stromal cells

BACKGROUND. Doxazosin, an alpha(1)-adrenergic antagonist inhibits sympathet ic contraction of prostatic stromal smooth muscle cells and is used in the relief of obstructive benign prostatic hyperplasia (BPH). In vitro applicat ion of noradrenaline stimulates expression of cytoskeletal filaments, parti cularly actin and myosin, by prostatic stromal cells, thus enhancing their differentiation towards smooth muscle cells. This study examined the possib le role of doxazosin in reversing this phenotypic modulation as well as in inhibiting smooth muscle cell contraction. METHODS. Stromal cell tissue cultures derived from 10 human hyperplastic pr ostates were rendered quiescent by reduction of stripped fetal calf serum ( FCS) to 1% (v/v) in the medium followed by treatment with 20 mu M noradrena line and/or 1 mu M doxazosin for 10 days. Doxazosin, in 10-fold increments of concentration, was also added, separately, to two of these cell cultures , which were either quiescent or growing in 10% normal (unstripped) FCS. Ha rvested cells were labelled with fluorescein-labelled antisera to smooth mu scle cytoskeletal filaments, and their individual fluorescence levels were analyzed flow-cytometrically. RESULTS. Noradrenaline increased expression of all cytoskeletal filaments s tudied. This effect was greatest for actin and myosin in proliferating cell cultures. Doxazosin largely reversed the increase in filament expression. This effect was most significant for actin and myosin and greatest in quies cent cultures. However, inhibition of the agonist effect of nor-adrenaline by doxazosin showed no clear dose-related response, in that expression of c ytoskeletal filaments was differentially inhibited. CONCLUSIONS. The data suggest that doxazosin may inhibit not only stromal c ontraction of differentiated smooth muscle cells in BPH but also the phenot ypic modulation of stromal smooth muscle cell differentiation induced by no radrenaline. These actions, together, may render prostatic stroma less cont ractile, and hence less able to respond to sympathetic stimulation, in pati ents with BPH. While effects on isolated stromal cells are of undoubted imp ortance, failure to demonstrate a consistent dose-response relationship bet ween expression of smooth muscle cell phenotype and inhibition by doxazosin suggests that additional influences, including humoral factors as well as the proximity of differentiated epithelium, are also likely to be involved in this interaction in the intact tissue. (C) 1999 Wiley-Liss, Inc.