Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Alpha-1-Adrenergic Receptor Blockade Modifies Insulin-Regulated Aminopeptidase (IRAP) Activity in Rat Prostate and Modulates Oxytocin Functions

Author(s): Marcela Arrazola Saniger, Maria Jesus Ramirez-Exposito, Susana de la Chica, Maria Pilar Carrera-Gonzalez, Maria Dolores Mayas, Jose Manuel Martinez-Martos.

Abstract:

Background: Oxytocin (OT) is one of the important paracrine factors that prostate synthesizes. OT maintains its resting tone and stimulates its contractile activity. However, the involvement of OT in modulating cell proliferation of the prostate is being investigated. In fact, alterations in OT concentrations accompany both benign prostatic hyperplasia/ hypertrophy and carcinoma of the prostate. The enzyme Insulin-regulated aminopeptidase (IRAP) is the main responsible of OT levels regulation through its catabolism. To date, the long-acting selective α1-adrenergic receptor antagonist doxazosin is widely used to the treatment of BPH. Thus, our aim was to analyze the effects of doxazosin on IRAP specific activity and its putative effects on prostate OT regulation and functions.

Methods: Fifteen male Wistar rats were treated subcutaneously with 10 mg/Kg doxazosin during 15 days and fifteen controls were treated with the vehicle only. After the treatment period, prostate was removed to obtain soluble and membrane-bound fractions. Soluble and membrane-bound IRAP specific activities were assayed fluorometrically using leucyl-β-naphthylamide as substrate. Prostate OT content was assayed by enzyme immunoassay.

Results: Doxazosin treatment significantly increased membrane-bound IRAP specific activity in rat prostate by 59.4%, whereas no changes were observed in the soluble fraction. Treatment with doxazosin also significantly increased OT concentration by 26.3%.

Conclusions: In vivo administration of doxazosin to male rats modify both prostatic IRAP activity and OT levels. Because there is now evidence that OT plays a physiological role in the regulation of growth and muscular contractility within the gland, more attention should be paid to IRAP activity, which could represent a new target for the regulation of the functions of OT under physiological or pathological conditions such as BPH and prostate cancer.

Keywords: Oxytocin, Prostate, Insulin-regulated aminopeptidase, Adrenergic receptors, Doxazosin, Wistar rat, alpha1-adrenergic receptor antagonist, hyperplasia

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Article Details

VOLUME: 5
ISSUE: 3
Year: 2011
Page: [192 - 196]
Pages: 5
DOI: 10.2174/187231211796905035
Price: $58