title: Phosphodiesterase isoenzymes in the human urethra: a molecular biology and functional study.
abstract: Experimental and clinical studies have suggested a role for phosphodiesterase (PDE) isoenzymes in the control of the human lower urinary tract. This study aimed to investigate the expression of PDE isoenzymes and the effects of PDE inhibitors (PDE-Is) in isolated human urethral smooth muscle (USM). The expression of messenger ribonucleic acid (mRNA) specifically encoding for PDE isoenzymes and isoforms (1A, 1B, 1C, 2A, 4A, 4B, 4C, 4D, 5A and 11A) was analyzed by means of reverse transcriptase polymerase chain reaction (RT-PCR). Using a tissue bath technique, the effects of vinpocetine (PDE1-I), erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA-HCl=MEP1) (PDE2-I), rolipram (PDE4-I), sildenafil, vardenafil and tadalafil (PDE5-Is) (0.01-10µM) on the tension of USM induced by norepinephrine were investigated. The production of cyclic guanosine monophosphate (cyclic GMP) and cyclic adenosine monophosphate (cyclic AMP) was measured by means of radioimmunoassays. RT-PCR analysis revealed the expression of PDE1B, PDE1C, PDE4A, PDE4C, PDE4D, PDE5A and PDE11A. The tension induced by norepinephrine (NE) was reversed by the PDE inhibitors with the following rank order of efficacy: rolipram (mean: -39%)≥sildenafil (-35%)>vardenafil (-26%)>tadalafil (-20%)>vinpocetine (-16%)>MEP1 (-2%). The relaxing effects of the drugs were paralleled by an elevation in tissue levels of cyclic AMP and cyclic GMP. Selective inhibitors of PDE4 and PDE5 can antagonize the tension induced by alpha-adrenergic stimulation of USM. PDE inhibition might represent an interesting option to facilitate the relaxation of the human outflow region.
authors.affiliation: Hannover Medical School, Division of Surgery, Department of Urology & Urological Oncology, Carl-Neuberg-Str. 1, Hannover 30625, Germany. Electronic address: kedia.george@mh-hannover.de.
authors.forename: George T
authors.initials: GT
authors.lastname: Kedia
authors.affiliation: Hannover Medical School, Division of Surgery, Department of Urology & Urological Oncology, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelke
authors.affiliation: Institute for Biochemical Research & Analysis, Urological Research Unit, Barsinghausen am Deister, Germany.
authors.forename: Joachim E
authors.initials: JE
authors.lastname: Sonnenberg
authors.affiliation: AGAPLESION Markus Hospital, Department of Urology, Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Sohn
authors.affiliation: Osnabrück Municipal Hospital, Department of Urology, Osnabrück, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bannowsky
authors.affiliation: Hannover Medical School, Division of Surgery, Department of Urology & Urological Oncology, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Kuczyk
authors.affiliation: Hannover Medical School, Division of Surgery, Department of Urology & Urological Oncology, Carl-Neuberg-Str. 1, Hannover 30625, Germany; Institute for Biochemical Research & Analysis, Urological Research Unit, Barsinghausen am Deister, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ückert
mesh_terms: D000328:Adult; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D009924:Organ Culture Techniques; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D014521:Urethra / Q000187:drug effects / Q000201:enzymology*
chemical_list: D007527:Isoenzymes; D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010727:Phosphoric Diester Hydrolases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: Cyclic AMP; Cyclic GMP; Forskolin (PubChem CID: 47936); Human male urethra; MEP 1=EHNA-HCl (erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride) (PubChem CID: 11957547); Norepinephrine (PubChem CID: 439260); Phosphodiesterase enzymes; Rolipram (PubChem CID: 5092); Sildenafil citrate (PubChem CID: 62853); Sodium nitroprusside (PubChem CID: 11963622); Tadalafil (PubChem CID: 110635); Vardenafil (PubChem CID: 110634); Vinpocetine (PubChem CID: 443955)