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

Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence. However, muscarinergic receptor blockers with adequa te selectivity for detrusor smooth muscle are not available. Also, in contr ast to the normal detrusor, the unstable detrusor neurotransmission seems t o be at least partially regulated by non-cholinergic (NANC) pathways. These factors may explain the common side effects and the limited clinical effic acy of these compounds. Specific modulation of intracellular second messeng er pathways offers the possibility of organ selective manipulation of tissu e function, specifically contraction and relaxation of smooth musculature. Because of their central role in the intracellular regulation of smooth mus cle tone phosphodiesterases (PDEs) are an attractive pharmacological target s. The PDE 5 specific inhibitor sildenafil (Viagra) has revolutionized the treatment of patients with erectile dysfunction. Numerous other PDE inhibit ors are currently under investigation for the treatment of various disorder s. We investigated the role of PDEs in human detrusor smooth muscle. Our da ta demonstrate the presence of five PDE isoenzymes in human detrusor and su ggest, for the first time, that the cAMP pathway and the calcium/calmodulin -stimulated PDE (PDE 1) are of functional importance in the intracellular r egulation in this tissue in vitro. In addition, initial clinical data with the PDE 1 inhibitor vinpocetine in patients not responding to standard anti cholinergic therapy indicate a possible role for vinpocetine in the treatme nt of urgency, urge incontinence and, possibly, low compliance bladder and interstitial cystitis. The results of a larger randomized, double-blind, pl acebo-controlled, multicenter trial with vinpocetine show a tendency in fav or 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 patien t population. Modulation of intracellular key enzymes effecting second mess enger metabolism, i.e. isoenzyme-selective PDE inhibition is a novel approa ch which possibly avoids the limitations of anticholinergic therapy in pati ents with lower urinary tract dysfunction.