Effects of phosphodiesterase inhibitors on contraction induced by endothelin-1 of isolated human prostatic tissue.

OBJECTIVES: To study the effects of selective phosphodiesterase (PDE) inhibitors on the contraction induced by endothelin-1 (ET-1) of isolated human prostatic tissue. METHODS: Using the organ bath technique, the effects of the cumulative addition of the PDE1 inhibitor vinpocetine, PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA), PDE4 inhibitor rolipram, and PDE5 inhibitors sildenafil, vardenafil, and tadalafil (1 nM to 10 microM) were investigated on the contraction brought about by the peptide ET-1 (1 microM) on normal human prostatic tissue isolated from the transition zone. In the present study, the nitric oxide donor drug sodium nitroprusside and adenylyl cyclase activator forskolin were used as reference compounds. RESULTS: ET-1 induced stable and long-lasting contraction of the isolated prostatic tissue. The tension induced by ET-1 was dose-dependently reversed by the drugs with the following rank order of efficacy: rolipram, forskolin, tadalafil, sodium nitroprusside, sildenafil, vinpocetine, vardenafil, EHNA. The maximal reversion of tension ranged from 67% (rolipram) to 20% (EHNA). CONCLUSIONS: Our results have provide additional evidence that the function of prostatic smooth muscle is under the control of peptidergic and cyclic nucleotide (cyclic guanosine monophosphate, cyclic adenosine monophosphate)-mediated pathways. This might give a rationale for the use of drugs interacting with cyclic guanosine monophosphate or cyclic adenosine monophosphate signaling, such as PDE inhibitors or nitric oxide donors, in the pharmacotherapy of the benign prostatic syndrome.

Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours.

OBJECTIVE: To evaluate CpG island methylation patterns of cancer-associated genes for their applicability as molecular biomarkers for the detection of superficial bladder cancer and for the discrimination of invasive from noninvasive tumours. PATIENTS AND METHODS: We analysed the methylation status of CpG islands in the promoter region of the cancer-associated genes GSTP1, DAPK, MDR1, TPEF, PAX6, and TSLC1 in primary papillary bladder cancer specimens from 39 patients (pT1 10, pTis one, pTa 20, pT2 five). Tumour-adjacent normal mucosa served as the control. The DNAs were bisulphite-treated and submitted to methylation-specific real-time polymerase chain reactions. RESULTS: Only TPEF and PAX6 had substantial CpG island methylation percentages. The TPEF- and PAX6-promoters also had significantly higher methylation rates in tumour tissue compared with the normal tumour-adjacent tissue. Interestingly, the methylation rates of the TPEF- and the PAX6-promoter were higher in adjacent normal tissues from bladders with pTa then in those with pT1 tumours. CONCLUSION: Our results shed a critical light on the hypothesis that CpG island hypermethylation of the GSTP1-, DAPK-, MDR1- and TSLC1-promoter could represent molecular biomarkers for bladder cancer diagnosis and detection. However, methylated PAX6- or TPEF-promoters could represent biomarkers for this disease. Additional studies are needed to evaluate whether methylation rates of these genes in normal bladder tissues are applicable as accessory markers for the tumour state or its invasive behaviour.