Presentation Authors: Qingfeng Yu, Bingsheng Li, Christian Gratzke, Alexander Tamalunas*, Yiming Wang, Frank Strittmatter, Christian G. Stief, Martin Hennenberg, Munich, Germany
Introduction: Alpha1-blockers are the major option for treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia, as they reduce urethral obstruction and symptoms by inhibition of Î±1-adrenergic prostate smooth muscle contraction. However, their efficacy is limited, as non-adrenergic mediators (thromboxane A2 (TXA2), endothelin-1) contribute to prostate smooth muscle tone in parallel to Î±1-adrenoceptors, what may keep prostate smooth muscle tone and symptoms despite application of Î±1-blockers. Novel compounds addressing non-adrenergic contractions in the prostate are required to develop future therapies with enhanced efficacy. Recently, inhibition of neurogenic and endothelin-induced prostate smooth muscle contraction by the p21-activated kinase (PAK) inhibitor FRAX486 has been reported. However, effects of PAK inhibitors on TXA2-induced contractions, and of other PAK inhibitors on endothelin-induced contractions are unknown. Here, we assessed effects of FRAX486 and IPA3 on non-adrenergic contractions of human prostate smooth muscle.
Methods: Human prostate tissues were obtained from radical prostatectomy. Contractions of prostate strips were studied in an organ bath, where they were induced by endothelin-1 or the TXA2 analog U46619. Contractions were compared between whole corresponding groups (inhibitor vs. control) by two-way ANOVA, and at each single concentration by multivariate analysis.
Results: U46619 (0.1-30 ÂµM) and endothelin-1 (0.1-3 ÂµM) induced concentration-dependent contractions of human prostate tissues. FRAX486 (30 ÂµM) inhibited U46619-induced contractions, which was significant between whole groups (p < 0.002 between FRAX486 and controls). Similarly, IPA3 (300 ÂµM) inhibited U46619-induced contractions, which was significant between whole groups (p < 0.005 between IPA3 and controls), and at 30 ÂµM (p < 0.05 between IPA3 and control). In contrast, IPA3 did not inhibit endothelin-1-induced contractions.
Conclusions: The divergent effects of both PAK inhibitors may reflect their different pharmacologic profiles, as FRAX486 is known to inhibit group I (PAK1-3) and group II PAKs (PAK4-6), while IPA3 inhibits only group II PAKs. Endothelin- and TXA2-induced contractions in the prostate are promoted by different PAK isoforms, so that FRAX486 as a pan-PAK inhibitor may be most promosing from a translational view.
Source of Funding: Deutsche Forschungsgemeinschaft (DFG)