Exposure of human seminal vesicle tissue to phosphodiesterase (PDE) inhibitors antagonizes the contraction induced by norepinephrine and increases production of cyclic nucleotides.
OBJECTIVE
To investigate further the role of phosphodiesterase (PDE) isoenzymes in the control of human seminal vesicle (SV) smooth muscle contractility, we examined the functional responses of isolated SV tissue to various PDE inhibitors. It has been suggested that the application of inhibitors of the PDE type 5 may facilitate SV smooth muscle relaxation and, subsequently, retard ejaculatory response.


METHODS
Using the organ bath technique, strip preparations of human SV were exposed for 5 minutes to 1 μM of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram, Ro 20-1724 (PDE4 inhibitors), and sildenafil (PDE5 inhibitor). Norepinephrine (NE, alpha agonist) was then added (0,1 μM, 1 μM, and 10 μM) and isometric responses were recorded. A contraction-response curve to NE in the absence of PDE inhibitors was also generated. Drug effects on the production of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) were measured by means of radioimmunometric assays.


RESULTS
The contraction induced by NE was effectively antagonized by 1 μM of rolipram (83.3% inhibition), Ro 20-1724 (72.3% inhibition), sildenafil (41.6% inhibition), and milrinone (37.5% inhibition). The inhibition of force generation was paralleled by a 1.6-fold to 2.8-fold increase in tissue cyclic AMP (induced by milrinone, rolipram, Ro 20-1724), and a 12-fold rise in cyclic GMP (induced by sildenafil).


CONCLUSIONS
The findings demonstrate that PDE inhibitors can counteract the contraction of human SV mediated by alpha-adrenergic receptors and enhance levels of cyclic nucleotides. This might be of importance with regard to the identification of new options for the pharmacological treatment of premature ejaculation.
Birowo
Ponco
P
University of Indonesia School of Medicine, Cipto Mangunkusumo Hospital, Department of Urology, Jakarta, Indonesia.
Uckert
Stefan
S
Kedia
George T
GT
Sonnenberg
Joachim E
JE
Sandner
Peter
P
Thon
Walter F
WF
Scheller
Friedemann
F
Rahardjo
Djoko
D
Kuczyk
Markus A
MA
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000368:Aged; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000096:biosynthesis*; D004353:Drug Evaluation, Preclinical; D004542:Ejaculation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D020889:Rolipram / Q000494:pharmacology; D012669:Seminal Vesicles / Q000187:drug effects* / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011942:Receptors, Adrenergic, alpha; D013450:Sulfones; D009599:Nitroprusside; D005576:Colforsin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D006152:Cyclic GMP; D020105:Milrinone; D020889:Rolipram; D009638:Norepinephrine