Inhibition of prostate smooth muscle contraction by α1-adrenoceptor antagonists (α1-blockers) is the first option for medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). In fact, increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, the efficacy of α1-blockers is limited to improvements of 50%, because non-adrenergic mediators of prostate smooth muscle contraction including endothelin-1 and thromboxane A2 (TXA2) increase smooth tension in parallel to α1-adrenoceptors and may therefore keep urethral obstruction despite therapy with α1-blockers. Consequently, finding new approaches to target non-adrenergic contraction simultaneously with α1-adrenoceptors will be required to develop innovative therapies with improved efficacy. Recently, several compounds have been reported to inhibit adrenergic prostate contraction, but their effects on non-adrenergic contraction are still unknown. Here, we examined effects of Rac-GTPase inhibitors and of a Src family kinase (SFK) inhibitor on non-adrenergic prostate contractions.
Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, where they were induced by the α1-adrenoceptor agonist methoxamine, by the TXA2 analog U46619, or by endothelin-1.
Methoxamine, U46619, and endothelin-1 induced concentration-dependent contractions of prostate strips. Inhibitory effects of the Rac inhibitors EHT1864 (100 µM) and NSC23766 (100 µM) and of the SFK inhibitor AZM475721 (10 µM) on α1-adrenergic contraction were confirmed by inhibition of methoxamine-induced contractions by all three inhibitors. EHT1864 caused significant inhibition of endothelin-1- and U46619-induced contractions, which was observed at 0.1-3 µM of endothelin-1 (p<0.001 between EHT1864 and control group), and at 1-30 µM of U46619 (p<0.001 between EHT1864 and control group). NSC23766 caused significant inhibition of U46619-induced contractions, which was observed at 3-10 µM of U46619 (p<0.001 between NSC23766 and control group). NSC23766 did not change endothelin-1-induced contractions. AZM475721 did not change U46619- or endothelin-1-induced contractions.
From the three examined inhibitors, EHT1864 is the most promising from a translational view, as it inhibited TXA2- and endothelin-1-induced besides α1-adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. Applied in vivo, urodynamic effects of EHT1864, but not of AZM475721 may theoretically exceed those of α1-blockers.