MP44-15 SPONTANEOUS MYOGENIC CONTRACTILITY IN THE HUMAN PROSTATE GLAND: IMPLICATIONS FOR THE TREATMENT OF LUTS ASSOCIATED WITH BPH.

Abstract

INTRODUCTION AND OBJECTIVES: The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms, while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE7-selective inhibitor BRL 50481, and the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in the hyperplastic human prostate. METHODS: Prostate samples were obtained from patients (n1⁄495) undergoing radical prostatectomy. Expression of PDE isoforms was addressed by RT-PCR, Western blot, and immunofluorescence. Effects of TC-E 5005, BRL 50481, and tadalafil on contractility of prostate strips were studied in an organ bath. RESULTS: PDE7A1/2 and PDE10A were detectable by RTPCR, Western blot, and fluorescence staining. Colocalization with calponin and tyrosine hydroxylase suggested expression of PDE7A1/2 and PDE10A in smooth muscle cells and catecholaminergic nerves. Noradrenaline, the a1-adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of noradrenaline-, phenylephrine-, and endothelin-3-induced contractions. Similarly, TC-E 5005 caused significant inhibiton of EFS-induced contractions. Inhibition of EFS-induced contraction by TC-E 5005 amounted to approximately 50 %, resembling inhibition of EFS-induced contraction by tadalafil (10 mM) (also around 50 %) (see figure). EFSand norepinephrine-induced tension were similar after application of tadalafil, and after combined application of tadalafil and TC-E 5005. BRL 50481 was without effect on noradrenaline-induced contraction. CONCLUSIONS: The PDE10-selective inhibitor TC-E 5005 inhibits neurogenic, adrenergic, and endothelin-3-induced smooth muscle contractions in the hyperplastic human prostate. TC-E 5005 inhibits neurogenic contractions with an efficacy similar to tadalafil. Urodynamic effects in vivo appear possible.