Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate.
OBJECTIVE
Current pharmacological concepts in the treatment of benign prostatic hyperplasia are aimed at the static and dynamic component of the disease. Mainly alpha-blocking agents are used to reduce the adrenergic tone of prostatic myocytes, thus, increasing urine flow through the prostatic urethra by reducing urethral resistance. With the introduction of the phosphodiesterase (PDE) 5 inhibitor sildenafil the concept of PDE inhibition has gained tremendous 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 strips.


METHODS
PDE isoenzymes were characterized by reverse transcriptase-polymerase chain reaction and anion exchange chromatography. Using the organ bath technique we determined the relaxing effects of the PDE inhibitors papaverine, vinpocetine (Biomol GmbH, Hamburg, Germany), erythro-9-[2-hydrox-3-nonyl]adenine hydrochloride (Tocris Cookson, Ltd., Bristol, United Kingdom) rolipram (Schering AG, Berlin, Germany), zaprinast (Rhône-Poulenc Rorer, Ltd., Dagenham, United Kingdom) and sildenafil (Pfizer, Ltd., Sandwich, United Kingdom), the adenylate cyclase activating agent forskolin (ICN Biomedicals, Aurora, Ohio) and the nitric oxide donor sodium nitroprusside on adrenergic tension in prostatic strips isolated from the transition zone.


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, central and transition zones. Except for complementary DNA encoding for PDE 1C, complementary 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 histological regions of the prostate. The hydrolytic activities of PDE 4 and 5 were present in the cytosolic fraction of prostatic tissue, whereas in the particulate fraction only the hydrolytic activity of PDE 4 was detected. Adrenergic 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 obstruction secondary to benign prostatic hyperplasia.
Uckert
S
S
Department of Urology, Hannover Medical School, Hannover, Germany.
Küthe
A
A
Jonas
U
U
Stief
C G
CG
D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000032:analysis / Q000378:metabolism*; D011467:Prostate / Q000737:chemistry / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007527:Isoenzymes; D010727:Phosphoric Diester Hydrolases