Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace α1 -Adrenergic Tension in the Human Prostate.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α1 -adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate. METHODS: Prostate tissues were obtained from radical prostatectomy (n = 127 patients). Contractile responses were studied in an organ bath. RESULTS: Endothelin-1 and noradrenaline induced contractions of similar magnitude (116 ± 23 and 117 ± 18% of KCl-induced contractions). Endothelin-2- and -3-induced maximum contractions of 63 ± 8.6 and 71 ± 19% of KCl, while contractions by the thromboxane analog U46619 amounted up to 63 ± 9.4%. Dopamine-induced contractions averaged to 22 ± 4.5% of KCl, while maximum contractions by serotonin, histamine, and carbachol stayed below 10% of KCl-induced. While noradrenaline-induced contractions were inhibited by tamsulosin (300 nM), endothelin-1-, -2-, or -3-induced contraction were not. No additive effects were observed if endothelins and noradrenaline were applied consecutively to the same samples. If endothelin-1 was applied after U46619, resulting tension (172 ± 43% of KCl) significantly exceeded noradrenaline-induced contraction. Tensions following combined application of endothelin-2 or -3 with U46619 stayed below noradrenaline-induced contractions. Tension following combined application of all three endothelins with U46619 resembled maximum noradrenaline-induced tone. CONCLUSIONS: Contractions following concomitant confrontation of human prostate tissue with noradrenaline and endothelin-1 are not additive. Endothelin-1 is sufficient to induce a smooth muscle tone resembling that of noradrenaline. This may replace lacking α1 -adrenergic tone under therapy with α1 -blockers, explaining the limited efficacy of α1 -blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed α1 -adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.

Explosive Strength of the Knee Extensors: The Influence of Criterion Trial Detection Methodology on Measurement Reproducibility.

The present study was conducted to assess test-retest reproducibility of explosive strength measurements during single-joint isometric knee extension using the IsoMed 2000 dynamometer. Thirty-one physically active male subjects (mean age: 23.7 years) were measured on two occasions separated by 48-72 h. The intraclass correlation coefficient (ICC 2,1) and the coefficient of variation (CV) were calculated for (i) maximum torque (MVC), (ii) the peak rate of torque development (RTDpeak) as well as for (iii) the average rate of torque development (RTD) and the impulse taken at several predefined time intervals (0-30 to 0-300 ms); thereby explosive strength variables were derived in two conceptually different versions: on the one hand from the MVC-trial (version I), on the other hand from the trial showing the RTDpeak (version II). High ICC-values (0.80-0.99) and acceptable CV-values (1.9-8.7%) could be found for MVC as well as for the RTD and the impulse taken at time intervals of ≥100 ms, regardless of whether version I or II was used. In contrast, measurements of the RTDpeak as well as the RTD and the impulse taken during the very early contraction phase (i.e. RTD/impulse0-30ms and RTD/impulse0-50ms) showed clearly weaker reproducibility results (ICC: 0.53-0.84; CV: 7.3-16.4%) and gave rise to considerable doubts as to clinical usefulness, especially when derived using version I. However, if there is a need to measure explosive strength for earlier time intervals in practice, it is, in view of stronger reproducibility results, recommended to concentrate on measures derived from version II, which is based on the RTDpeak-trial.

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate.

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients' adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 µM) or IPA3 (300 µM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 µM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1-10 µM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 µM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.