title: Mechanistic investigation of the adrenergic induction of ventral prostate hyperplasia in mice.
abstract: BACKGROUND
  The norepinephrine (NE) analog phenylephrine has previously been shown to induce atypical prostate hyperplasia in rats. The objective of the present study was to provide further insight into the mechanism of phenylephrine-induced prostate growth.
  
  
  METHODS
  Adult male C57/BL6 mice were given daily subcutaneous injection of phenylephrine, isoproterenol, or phenylephrine in combination with BMY7378, cyclazosin, RS100329, or yohimbine, and the effects on ventral prostate histology, and proliferative and apoptotic indices determined. Phenylephrine was also administered in combination with testosterone in castrated mice.
  
  
  RESULTS
  Atypical prostatic hyperplasia characterized by piling up and/or papillary infolding of epithelial cells with concomitant stromal smooth muscle hyperplasia was seen in adult mice given subcutaneous injection of phenylephrine daily for 26 days. Phenylephrine induced hyperplasia was more severe proximally and was associated with significantly reduced rates of apoptosis (but no change in cell proliferation) in both stromal and epithelial compartments. Only the alpha(1A)-adrenoceptor selective subtype antagonist RS100329 abrogated the phenylephrine-induced hyperplasia. Using selective antibodies, the alpha(1A-1)-adrenoceptor subtype was predominantly localized to the stromal compartments of the mouse and rat ventral prostates. The effects of phenylephrine were mediated independent of testicular androgens.
  
  
  CONCLUSIONS
  Prostatic hyperplasia in mice occurs as a consequence of subchronic administration of the sympathomimetic phenylephrine. Response to phenylephrine is mediated by the alpha(1A)-adrenoceptor, which predominates in the stroma of the rodent ventral prostate. Conceivably, therefore, phenylephrine could directly modulate prostate stromal growth, and indirectly modulate epithelial growth in a paracrine fashion. We cannot, however, rule out the contribution of other indirect effects such as hypoxia/reperfusion or effects on intermediary metabolism.
authors.affiliation: Department of Urology, NYU Medical Center, New York, New York, USA.
authors.forename: Dorene
authors.initials: D
authors.lastname: Marinese
authors.forename: Rupa
authors.initials: R
authors.lastname: Patel
authors.forename: Paul D
authors.initials: PD
authors.lastname: Walden
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010656:Phenylephrine / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000139:chemically induced* / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017154:Stromal Cells / Q000473:pathology; D013566:Sympathomimetics / Q000494:pharmacology; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D013566:Sympathomimetics; D010656:Phenylephrine; D013739:Testosterone