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

Abstract

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.

Keywords: benign prostatic hyperplasia (BPH); endothelin-1; lower urinary tract symptoms (LUTS); prostate smooth muscle contraction; tamsulosin; α1-adrenoceptors.