Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace [alpha]1-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 [alpha]1-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 [alpha]1-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 (300nM), 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 [alpha]1-adrenergic tone under therapy with [alpha]1-blockers, explaining the limited efficacy of [alpha]1-blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed [alpha]1-adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.