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

Abstract

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 α -adrenergic tone under therapy with α -blockers, explaining the limited efficacy of α -blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed α -adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.

Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate

“…We used tamsulosin in a concentration of 300 nM. This concentration inhibits norepinephrine-induced contractions of human prostate tissues completely, while EFS-induced contractions in our present study were inhibited by 50% (24). A very similar phenomenon has been described recently for another ␣ 1 -blocker, silodosin (8).…”

“…1H-1,2,4-triazol-1-yl]phenyl}-2-(phenylthio)acetamide (secinH3) is a cytohesin family-specific inhibitor, showing IC 50 values of 2.4, 5.4, 5.4, 5.6, 5.6, 65, and Ͼ100 M for human cytohesin-2, human cytohesin-1, mouse cytohesin-3, human cytohesin-3, Drosophila steppke, yGea2-S7, and hEFA6-S7, respectively. Tamsulosin is an ␣1adrenoceptor antagonist, which completely inhibits norepinephrineinduced contractions of human prostate tissues if applied at a concentration of 300 nM(24). Stock solutions (10 mM) were prepared with DMSO and kept at Ϫ20°C until use.Phenylephrine {(R)-3-[-1hydroxy-2-(methylamino)ethyl]phenol} is a selective agonist for ␣1-adrenoceptors.…”

Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

“…In 30–35% of patients, decreases in IPSS will be restricted to 25% or less, so that α 1 ‐blockers are inadequately effective in up to 69% of patients (Chapple et al ., ; Fullhase et al ., ; Matsukawa et al ., ; Lee et al ., ). These restrictions may be attributed to non‐adrenergic mediators, which contribute to prostate smooth muscle tone in parallel with α 1 ‐adrenoceptors, but which are not affected by α 1 ‐blockers (Strittmatter et al ., ; Hennenberg et al ., ; ). Therefore, it would make sense that future therapies address adrenergic and non‐adrenergic contractions simultaneously, to obtain higher efficacy in medical LUTS treatment.…”

Inhibition of Prostate Smooth Muscle Contraction by Inhibitors of Polo-Like Kinases

“…The most important option are α 1 -adrenoceptor antagonists, as they may reduce symptoms by inhibition of α 1 -adrenergic prostate smooth muscle contraction and subsequent improvement of urethral obstruction and bladder emptying ( Caine et al, 1976 ; Oelke et al, 2013 ; Hennenberg et al, 2014 ). However, their efficacy is limited, so that novel options and better understanding of the regulation of prostate smooth muscle contraction are required ( Oelke et al, 2013 ; Hennenberg et al, 2014 , 2017 ).…”