We investigated molecular changes that occurred during chronic administration of
doxazosin, an alpha1-adrenoceptor (AR) antagonist, using Affymetrix GeneChip analysis of gene expression. Rats were treated with
doxazosin (4 mg/kg/day subcutaneously, supplemented with 4 mg/kg/day orally) for 12 weeks. Labeled
cRNA was prepared and the subsequent hybridization to rat 230A arrays was performed. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential
biological relevance were verified by real-time reverse transcription polymerase chain reaction (RT-PCR) using
SYBR Green I.
Doxazosin treated rats had significantly heavier prostates compared to control rats. Microarray analysis revealed that chronic
doxazosin treatment caused changes in the expression levels of 625 genes, of which 39 were related to cell death,
necrosis, growth, proliferation and
G-protein signalling pathways in the rat prostate. Furthermore, RT-PCR experiments, in accord with the microarray analysis, indicated that chronic
doxazosin treatment caused an up-regulation in the
mRNA expression level of
clusterin, an antiapoptotic mediator, and
epiregulin, a
mitogen, in the ventral and dorsolateral prostate, respectively. These findings, that demonstrate chronic
doxazosin administration causes significant changes in the expression of several hundred genes in the rat prostate, may provide insight into the long-term efficacy of alpha1-AR antagonists in the treatment of
benign prostatic hyperplasia.