Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: From bench to bedside

Abstract

Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence. However, muscarinergic receptor blockers with adequate selectivity for detrusor smooth muscle are not available. Also, in contrast to the normal detrusor, the unstable detrusor neurotransmission seems to be at least partially regulated by non-cholinergic (NANC) pathways. These factors may explain the common side effects and the limited clinical efficacy of these compounds. Specific modulation of intracellular second messenger pathways offers the possibility of organ selective manipulation of tissue function, specifically contraction and relaxation of smooth musculature. Because of their central role in the intracellular regulation of smooth muscle tone phosphodiesterases (PDEs) are an attractive pharmacological targets. The PDE 5 specific inhibitor sildenafil (Viagra) has revolutionized the treatment of patients with erectile dysfunction. Numerous other PDE inhibitors are currently under investigation for the treatment of various disorders. We investigated the role of PDEs in human detrusor smooth muscle. Our data demonstrate the presence of five PDE isoenzymes in human detrusor and suggest, for the first time, that the cAMP pathway and the calcium/calmodulin-stimulated PDE (PDE 1) are of functional importance in the intracellular regulation in this tissue in vitro. In addition. initial clinical data with the PDE 1 inhibitor vinpocetine in patients not responding to standard anticholinergic therapy indicate a possible role for vinpocetine in the treatment of urgency, urge incontinence and, possibly, low compliance bladder and interstitial cystitis. The results of a larger randomized, double-blind, placebo-controlled, multicenter trial with vinpocetine show a tendency in favor of vinpocetine over placebo; however, statistically significant results were documented for one parameter only. This might be due to the rather low dosage chosen and the small sample size. Further studies are necessary and currently underway to delineate the optimal dosage, indications and patient population. Modulation of intracellular key enzymes effecting second messenger metabolism, i.e. isoenzyme-selective PDE inhibition is a novel approach which possibly avoids the limitations of anticholinergic therapy in patients with lower urinary tract dysfunction.

Detrusor myocyte activity and afferent signaling

“…90 Studies with the PDE 1 inhibitor vinpocetin, which reduces the breakdown of cAMP, showed relaxant effects in vitro but poor clinical efficacy in OAB/DO patients. 132 PDE 4, which also preferably hydrolyses cAMP, has been implicated in the control of bladder smooth muscle tone. PDE 4 inhibitors reduced the in vitro contractile responses of guinea pig, 133 suppressed rhythmic bladder contractions of the isolated guinea pig bladder, 5 and also suppressed non-voiding contractions in rats with bladder outlet obstruction.…”

Effect of sildenafil citrate in testosterone induced benign prostate hyperplasia rat model

“…Five isoforms of PDEs (1)(2)(3)(4)(5) were isolated and demonstrated in human and porcine detrusor in functional studies. [16,17] The effect of vardenafil on cyclic nucleotide levels and bladder contraction was investigated in rat detrusor by Werkstrom et al [18] Relexation was accompanied with increased levels of both cAMP and cGMP, and it was proposed that vardenafil-induced relaxation of rat detrusor was mediated by cAMP through inhibition of cGMP dependent cAMP-PDE. Relaxation of bladder neck was achieved with high levels of sildenafil in contracted human bladder neck by phenylephrine which suggests that PDE inhibitors may have potential effect to relax the bladder outlet.…”

Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5)

“…The central role of cyclic AMP and cyclic GMP and PDE isoenzymes in the control of various tissue functions has been established and the pharmacological concept of increasing tissue levels of cyclic nucleotides, for example, by the use of selective PDE inhibitors, to treat diseases of the urogenital tract, such as urinary stone disease (ureterolithiasis), urinary Cyclic GMP binding proteins in the human clitoris S Ückert et al incontinence, symptoms of the so-called benign prostatic syndrome including lower urinary tract symptoms and bladder outlet obstruction, has been evaluated in clinical studies. [18][19][20] Based on the hypothesis that the response to sexual stimulation in women is, in part, mediated by the same biological pathways than in the male, it has been speculated as to whether the application of PDE inhibitors may also facilitate female genital smooth muscle relaxation, thus resulting in an improvement of subnormal arousal. 21 A few efforts were made in order to characterize PDE isoenzymes of the human clitoris; however, these studies were mainly limited to the cyclic GMP-specific PDE5, whereas other cyclic GMP- Cyclic GMP binding proteins in the human clitoris S Ückert et al binding PDE isoenzymes, such as PDE2, PDE3, PDE9, PDE10 or PDE11, or other key proteins of the NO/cyclic GMP pathway, such as cGK, have either not or only randomly been investigated.…”