Mechanistic investigation of the adrenergic induction of ventral prostate hyperplasia in mice

• Published in: The Prostate Vol. 54; no. 3; pp. 230 - 237
• Main Authors: Marinese, Dorene, Patel, Rupa, Walden, Paul D.
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 15.02.2003; Wiley-Liss
• Subjects: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists - pharmacology; Adrenergic alpha-Antagonists - pharmacology; adrenoceptor; Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; phenylephrine; Phenylephrine - pharmacology; prostate; prostatic hyperplasia; Prostatic Hyperplasia - chemically induced; Prostatic Hyperplasia - pathology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stromal Cells - pathology; sympathetic nervous system; Sympathomimetics - pharmacology; Testis - metabolism; Testosterone - biosynthesis; Tumors of the urinary system; Urinary tract. Prostate gland; Cell proliferation; Animal model; adrenoceptor; Urinary system disease; Prostate disease; Rodentia; Adenoma; Sympathetic nervous system; Vertebrata; Mammalia; Mouse; Cell death; Animal; Phenylephrine; Benign neoplasm; Adrenergic receptor; Male genital diseases; Prostate; Apoptosis; prostatic hyperplasia
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.10170

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 α1A‐adrenoceptor selective subtype antagonist RS100329 abrogated the phenylephrine‐induced hyperplasia. Using selective antibodies, the α1A−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 α1A‐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. Prostate 54: 230–237, 2003. © 2002 Wiley‐Liss, Inc.