Assistant Professor of Urology University Hospital Munich, LMU Munich, Munich, Germany
Introduction: Prostate smooth muscle contraction is one of the main targets for medical treatment in lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Due to an unfavorable balance between side effects and limited efficacy, current medications cause high discontinuation rates. Agonist-induced smooth muscle contractions are mediated by activation of a1-adrenoceptors, endothelin and thromboxane, and their intracellular signaling pathways including monomeric GTPases. In general, monomeric GTPases are activated by GEFs, and deactivated by GAPs. Recently, we could show, that the small monomeric GTPase ARF6 is involved in prostate smooth muscle contraction. Here, we examined the effect of the ARF1 GEF inhibitor golgicide A on agonist-induced human prostate smooth muscle contraction. Methods: Prostate tissues were obtained from patients undergoing radical prostatectomy for prostate cancer (n=30 patients). Contractility of prostate strips was then assessed in an organ bath. Data are presented as mean ±standard deviation, with Emax and EC50 values, while group p-value is given in the diagrams. Results: Noradrenaline-induced adrenergic contractions were decreased by 47±12.1% with golgicide A (10µM) for concentrations of 1-100 µM (fig. A), by 30±6.6% for 1-100µM of phenylephrine-induced contractions (fig. B), and by 61±10.1% for 1-100µM of methoxamine-induced contractions (fig. C). Additionally, golgicide A inhibited non-adrenergic contraction by thromboxane A2 analogue U46619 by 82±19.6% for 1-300µM of U46619-induced contractions (fig. D), endothelin-1 induced contraction by 53±7.0% for 1-30µM of endothelin-1-induced contractions (fig. E), and EFS-induced neurogenic contractions by 76±16.6% for 2-32 Hz (fig. F). Conclusions: Golgicide A-sensitive GEFs are involved in regulation of human prostate smooth muscle contraction, by control of ARF1 GEF activity. Knowledge about GEFs and GAPs involved in smooth muscle contraction is still limited. However, increased understanding of prostate smooth muscle contraction may assist in developing new pharmaceutical targets for LUTS medication in the future. SOURCE OF Funding: None.
