Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro.

Abstract

An increase in cyclic nucleotide monophosphate levels is suggested to play a prominent role in mediating smooth-muscle relaxation. Cyclic nucleotide phosphodiesterase (PDE) influences smooth-muscle tone by decreasing the level of cyclic nucleotides. At present, five different families of isoenzymes of PDE exist that show a distinct species- and organ-specific distribution. Our study was done to evaluate the existence of specific PDE isoenzymes and its functional role in human ureteral tissue. Normal ureteral tissue was homogenized and centrifuged and the supernatant fraction was separated using anioin-exchange diethylaminoethyl (DEAE)-Sephacel chromatography. A PDE assay was then performed and the peak fractions were added to different specific PDE activators and inhibitors. In vitro, longitudinal ureteral strips were precontracted and different selective and non-selective PDE inhibitors were added incremently. Three different PDE isoenzymes were characterized: PDE I (calmodulin-sensitive), PDE II (cGMP-stimulated), and PDE IV (cAMP-specific). All PDE inhibitors relaxed the strips dose-dependently, with the 50% effective concentrations (EC50) being 30 microM for papaverine, 40 microM for zaprinast, 25 microM for quazinone, and 0.1 microM for rolipram. The ureter-relaxing effect of the PDE IV inhibitor at low concentrations, combined with its low-level effect on the systemic circulatory parameters, may open the possibility of using selective PDE IV-inhibitors in the treatment of ureteral colics or for ureteral stone passage.