title: 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.
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hennenberg
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Acevedo
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wiemer
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Aysenur
authors.initials: A
authors.lastname: Kan
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tamalunas
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Rutz
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Ciotkowska
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Herlemann
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Strittmatter
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Stief
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gratzke
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D002478:Cells, Cultured; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013223:Statistics as Topic; D013449:Sulfonamides / Q000494:pharmacology*; D000077409:Tamsulosin; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D016232:Endothelins; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000077409:Tamsulosin; D009638:Norepinephrine
keywords: benign prostatic hyperplasia (BPH); endothelin-1; lower urinary tract symptoms (LUTS); prostate smooth muscle contraction; tamsulosin; α1-adrenoceptors