In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach

Abstract

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes are key proteins regulating intracellular cyclic nucleotide turnover and thus smooth muscle tension. Several in vitro studies have indicated that the cyclic GMP and cyclic AMP-mediated signaling may play a role in the control of human ureteral muscle. The aim of the present study was to evaluate the functional effects of PDE5 inhibitors sildenafil (Sil), vardenafil (Var) and tadalafil (Tad), as well as nitric oxide (NO)-donating agent sodium nitroprusside (SNP) and non-selective muscarinic antagonist butylscopolamine (BSC) on the tension induced by KCl and the turnover of cyclic nucleotides in isolated human ureteral smooth muscle. In vitro relaxant responses of human ureteral smooth muscle to the PDE5 inhibitors mentioned above were investigated using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by means of specific radioimmunoassay following incubation of the tissue with Sil, Var, Tad and SNP. The tension induced by KCl of the ureteral tissue was dose dependently reversed by the drugs with the following rank order of efficacy: SNP > Var >or= Sil > Tad > BSC. R(max) values ranged from 25 +/- 9% (SNP) to 5 +/- 3% (BSC). Relaxant responses were paralleled by threefold to fourfold increase in tissue levels of cGMP. Our results indicate that PDE5 inhibitors can reverse the tension of isolated human ureteral smooth muscle via cGMP-mediated pathways. Nevertheless, further studies are indicated in order to evaluate as to whether there might be a use for PDE5 inhibitors in the treatment of ureteral stone disease.

Safety and efficacy of silodosin and tadalafil in ease of negotiation of large ureteroscope in the management of ureteral stone: A prosective randomized trial

“…[11,12] Gratzke et al [13] demonstrated the effectiveness of PDE 5 inhibitors vardenafil, sildenafil, and tadalafil in relaxation of ureteral smooth muscle in order of decreasing potency. [14,15] As tadalafil is more selective PDE-5i receptor as compared to sildenafil, visual problems are less likely. To minimize adverse effects we use tadalafil at a lower dose.…”

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

“…Symptoms of overactive bladder syndrome and urge urinary incontinence occur in both male and female patients and are related to those that occur in LUTS; inhibitors that block PDE5 and/or PDE1 activity have shown some promise in relieving symptoms and are considered potential therapies for these problems (Gacci et al, 2007). In addition, use of PDE inhibitors is being tested for treatment of premature ejaculation, Peyronie's disease, and ureteral relaxation for eased passage of kidney stones (Gratzke et al, 2007;Sandner et al, 2009). There is some evidence that elevation of cGMP by use of PDE5 inhibitors is atheroprotective in the vasculature (KempHarper and Schmidt, 2009) and may improve endothelial health (Rosano et al, 2005;Aversa et al, 2007).…”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…Other possibilities for use of PDE5 inhibitors include treatment of Raynaud's disease (54,86,118), suppression of other autoimmune diseases (48, 343), and relief of symptoms associated with cystic fibrosis (67,222,223). Potential treatment of genitourinary tract dysfunctions (benign prostate syndrome, overactive bladder, and urge incontinence) has garnered a lot of attention (324,325,362,397,425), as has treatment of Peyronie's disease (128), premature ejaculation, and ureteral relaxation for passage of kidney stones (132,325). Some PDE5 inhibitors reportedly slow tumor cell growth (1,268,380).…”