Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate

Purpose: Current pharmacological concepts in the treatment of benign prosta tic hyperplasia are aimed at the static and dynamic component of the diseas e. Mainly a-blocking agents are used to reduce the adrenergic tone of prost atic myocytes, thus, increasing urine flow through the prostatic urethra by reducing urethral resistance. With the introduction of the phosphodiestera se (PDE) 5 inhibitor sildenafil the concept of PDE inhibition has gained tr emendous interest in the field of urology. We characterized PDE isoenzymes from human prostatic tissue by molecular biology and protein chemistry, and investigated the effects of various PDE inhibitors compared with standard pharmacological agents on adrenergic tension in isolated human prostatic st rips. Materials and Methods: PDE isoenzymes were characterized by reverse transcr iptase-polymerase chain reaction and anion exchange chromatography. Using t he organ bath technique we determined the relaxing effects of the PDE inhib itors papaverine, vinpocetine (Biomol GmbH, Hamburg, Germany), erythro-9-[2 -hydrox-3-nonyl]adenine hydrochloride (Tocris Cookson, Ltd., Bristol, Unite d Kingdom) rolipram (Schering AG, Berlin, Germany), zaprinast (Rhone-Poulen c Rorer, Ltd., Dagenham, United Kingdom) and sildenafil (Pfizer, Ltd., Sand wich, United Kingdom), the adenylate cyclase activating agent forskolin (IC N Biomedicals, Aurora, Ohio) and the nitric oxide donor sodium nitroprussid e on adrenergic tension in prostatic strips isolated from the transition zo ne. Results: Reverse transcriptase-polymerase chain reaction revealed messenger RNA transcripts encoding for PDE 1, 2, 4, 5, 7, 8, 9 and 10 in the various anatomical regions of the human prostate, including the peripheral, centra l and transition zones. Except for complementary DNA encoding for PDE 1C, c omplementary DNA fragments encoding for PDE 1A, 1B, 2A, 4A, 4B, 4C, 4D, 5A, 7A, 8A, 9A and 10A were found at almost even ratios in the different histo logical regions of the prostate. The hydrolytic activities of PDE 4 and 5 w ere present in the cytosolic fraction of prostatic tissue, whereas in the p articulate fraction only the hydrolytic activity of PDE 4 was detected. Adr energic tension in prostatic strip preparations was reversed by forskolin, sodium nitroprusside, and inhibitors of PDE 4 and 5. Conclusions: Our results demonstrate the presence and functional relevance of PDE isoenzymes 4 and 5 in human prostatic tissue. These studies support the possible use of inhibitors of PDE 4 and 5 for treating urinary obstruct ion secondary to benign prostatic hyperplasia.