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.