Phosphodiesterase (PDE) enzymes are considered key proteins in the control of the function of smooth musculature in the human upper and lower urinary tract (ureter, urinary bladder, prostate, urethra). Consequently, the use of PDE inhibitors has been identified as a promising approach to treat urological dysfunctions including the overactive bladder syndrome (OAB) and the so-called lower urinary tract symptomatology (LUTS, secondary to benign prostatic hyperplasia) [1,2]. In order to evaluate further the significance of cyclic GMP-PDE isoenzymes in detrusor smooth muscle relaxation, we have investigated by means of molecular biology techniques the expression of mRNA specifically encoding for PDE isoenzymes in the human urinary bladder and also assessed the functional effects of a new class of PDE inhibitors on the contraction induced by carbachol in isolated human detrusor tissue.

Non-diseased human detrusor tissue, excised from the dome and lateral walls, was obtained from three male and two female subjects who had undergone cystectomy surgery. The expression of PDE1(A, B and C), PDE2(A), PDE3(A and B), PDE4(B1, B2 and D) and PDE5(A) was evaluated by means of quantitative real time polymerase chain reaction (qRT-PCR). Using the tissue bath technique, the effects of a new class of inhibitors of the PDE isoenzymes PDE1, PDE2, PDE3 and PDE5 were evaluated on the tension induced by the mucarinergic compound carbachol (1 µM) of isolated detrusor smooth muscle.

RT-PCR analysis revealed a predominant relative expression (rE, in arbitrary units = AU) of mRNA transcripts specifically encoding for PDE1A and PDE5A (rE = 967/958), PDE4B2 and 4D (rE = 687/643), PDE3A and 3B (rE = 269/425), only little amounts of mRNA encoding for PDE1C and 1B were registered. The tension induced by carbachol was dose-dependently (10 nM - 100 µM) reversed by the drugs with the following rank order of efficacy (mean maximum relaxation): DHP (nitric oxide donor drug) (62%) > MSPP (PDE5 inhibitor)/vincamine (PDE1 inhibitor)/trequinsin (PDE3 inhibitor)/BAY 12-7717 (PDE2 inhibitor) (58%/55%/52%, respectively) > BAY 13-1197 (activator of soluble guanylyl cyclase) (47%) > DASPP (PDE5 inhibitor) (40%) > E 4021 (PDE5 inhibitor) (32%) > BAY 12-9266 (PDE1 inhibitor) (23%).

The findings from the RT-PCR and tissue bath experiments are in favor of the hypothesis that the cyclic GMP pathway is involved in the control of detrusor smooth muscle. The exact mechanism by which PDE inhibitors modulate urinary voiding and storage function remains to be elucidated in detail.

Future studies to delineate as to whether selective PDE5 or PDE1 inhibitors, such as MSPP or vincamine, may have clinical significance in the treatment of OAB are indicated.

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