Doxazosin reduces cell proliferation and increases collagen fibers in rat prostatic lobes

Abstract

We investigated the effects of doxazosin (Dox), an alpha-adrenoceptor antagonist used clinically for the treatment of benign prostatic hyperplasia (BPH), on the rat prostatic complex by assessing structural parameters, collagen fiber content, cell proliferation, and apoptosis. Adult Wistar rats were treated with Dox (25 mg/kg per day), and the ventral (VP), dorsolateral, and anterior prostate (AP) regions of the prostate complex were excised at 3, 7, and 30 days after treatment. At 24 h before being killed, the rats were injected once with 5-bromodeoxyuridine (BrdU; thymidine analog) to label mitotically active cells. The prostates were weighed and processed for histochemistry, morphometry-stereology, immunohistochemistry for BrdU, Western blotting for proliferating cell nuclear antigen (PCNA), and the TUNEL reaction for apoptosis. Dox-treated prostate lobes at day 3 presented increased weight, an enlarged ductal lumen, low cubical epithelial cells, reduced epithelial folds, and stretched smooth muscle cells. However, at day 30, the prostates exhibited a weight reduction of approximately 20% and an increased area of collagen and reticular fibers in the stromal space. Dox also reduced epithelial cell proliferation and increased apoptosis in the three prostatic lobes. Western blotting for PCNA confirmed the reduction of cell proliferation by Dox, with the AP and VP being more affected than the dorsal prostate. Thus, Dox treatment alters epithelial cell behavior and prostatic tissue mechanical demand, inducing tissue remodeling in which collagen fibers assume a major role.

Structural changes in α1-adrenoceptor antagonist-treated human prostatic stroma

“…Their finding suggests that a1-blockers induce dedifferentiation of smooth muscle into fibroblasts and myofibroblasts, and may thus induce alteration of tissue architecture. More recently, Justulin et al [9] reported that when rats were given repeated doses of doxazosin, they exhibited collagen fiber accumulation in prostatic stroma and reduction in smooth muscle. On the basis of this finding, they suggested the possibility that continued oral treatment with doxazosin would alter prostatic tissue architecture and reduce the efficacy of a1-blockers [9].…”

“…More recently, Justulin et al [9] reported that when rats were given repeated doses of doxazosin, they exhibited collagen fiber accumulation in prostatic stroma and reduction in smooth muscle. On the basis of this finding, they suggested the possibility that continued oral treatment with doxazosin would alter prostatic tissue architecture and reduce the efficacy of a1-blockers [9]. These views were endorsed by the findings of our study, in which treatment with a1-blockers resulted in alteration of prostatic tissue architecture.…”

“…In comparison with age (a-c), prostate volume (d-f), and serum PSA (g-i), the distribution of collagen fiber share in individual cases is graphically represented for each of the three groups: the untreated group (17 patients receiving no oral a1-blocker after prostate biopsy; a, d, and g), the oral a1-blocker-treated group (23 patients orally treated with a1-blockers following biopsy; b, e, and h), and the surgically treated group (21 patients who underwent surgery after exhibiting resistance to oral a1-blocker treatment; c, f, and i) been elucidated. Justulin et al [9] referred to transforming growth factor-b (TGF-b) as an intracellular transmitter possibly involved in such changes. TGF-b is a cytokine with diverse functions.…”

“…Shapiro et al [8] found that the percentage of prostatic stroma occupied by smooth muscle differed between responders and non-responders to drugs. More recently, Justulin et al [9] reported reduction in smooth muscle and accumulation of collagen in rat prostate glands following the treatment with doxazosin suggesting that structural changes can also occur in a1-blocker-treated human prostate gland. Structural changes in prostatic tissue architecture thus also appear to be associated with the development of resistance of BPH to drug therapy.…”

Animal Models for Benign Prostatic Hyperplasia

“…Thirty-day treatment of normal rats with a high dose of doxazosin produced a 20% reduction in prostatic weight and an increase in the density of stromal collagen fibers (Justulin et al 2008). Using the model described above, where BPH was induced in the rat by implantation of fetal urogenital sinus, 21-day treatment with naftopidil, a preferential a 1D -adrenoceptor antagonist, inhibited cellular proliferation in both epithelia and stroma.…”