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MP11-10 INHIBITION OF CHOLINERGIC, NEUROGENIC, AND NON-CHOLINERGIC/NON-NEUROGENIC DETRUSOR CONTRACTIONS BY THE RAC INHIBITOR EHT1864

INTRODUCTION AND OBJECTIVES: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by involuntary, exaggerated detrusor contractions. Medical therapy aims to inhibit detrusor contractions, but overall results from available medications are unsatisfactory. The introduction of &bgr;3-agonists reflects the high demand for novel medications. However, their efficacy is not higher than that of anticholinergics, raising the need for ongoing research to identify new compounds to inhibit detrusor contractions. A role of the monomeric GTPase Rac1 for smooth muscle contraction has been reported from the prostate and trigone, but is still unknown in the detrusor. Here, we examined effects of the Rac inhibitor EHT1864 on smooth muscle contraction of human detrusor tissues. METHODS: Female and male human detrusor tissues were obtained from radical cystectomy. Detrusor contractions were studied in an organ bath. Contractions were compared between whole corresponding groups (inhibitor vs. control without inhibitor) by two-way ANOVA, and at each single concentration by multivariate analysis. RESULTS: Electric field stimulation (EFS) induced frequence-dependent contractions of female and male detrusor tissues. EFS-induced contractions were inhibited in both genders by EHT1864 (100 µM), amounting up to 31% inhibition in female detrusor (p<0.001 for EHT1864 vs. control for whole groups; p<0.009 at 2-32 Hz) and 55% inhibition in male detrusor (p<0.002 for whole groups; p<0.03 at 16 Hz). Carbachol induced concentration-dependent contractions in female and male detrusor tissues. Carbachol-induced contractions were inhibited in both genders by EHT1864 (100 µM), amounting up to 73% inhibition in female detrusor (p<0.001 for whole groups; p<0.02 at 0.1-1 µM and at 10-1000 µM) and 72% inhibition in male detrusor (p<0.001 for whole groups; p<0.02 at 0.3-1000 µM). Effects of EHT1864 on contractions by the thromboxane A2 analog U46619 were only examined in male tissues, due to limited availability of female tissues. U46619 induced concentration-dependent contractions, which were inhibited by EHT1864 (100 µM). Inhibition amounted up to 84% (p<0.001 for whole groups; p<0.002 at 0.1-30 µM). CONCLUSIONS: EHT1864 inhibits detrusor contractions in the female and male bladder with high efficacy. At least in male patients, inhibition also applies to non-cholinergic, non-neurogenic contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is non-cholinergic. In vivo, EHT1864 may improve LUTS attributed to OAB. Source of Funding: Deutsche Forschungsgemeinschaft (DFG)