CHARACTERIZATION OF CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES INTHE HUMAN URETER AND THEIR FUNCTIONAL-ROLE IN-VITRO

An increase in cyclic nucleotide monophosphate levels is suggested to play a prominent role in mediating smooth-muscle relaxation. Cyclic nu cleotide phosphodiesterase (PDE) influences smooth-muscle tone by decr easing the level of cyclic nucleotides. At present, five different fam ilies of isoenzymes of PDE exist that show a distinct species- and org an-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 diethylamino ethyl (DEAE)-Sephacel chromatography. A PDE assay was then performed a nd the peak fractions were added to different specific PDE activators and inhibitors. In vitro, longitudinal ureteral strips were precontrac ted and different selective and nonselective PDE inhibitors were added incremently. Three different PDE isoenzymes were characterized: PDE I (calmodulin-sensitive), PDE II (cGMP-stimulated), and PDE IV (cAMP-sp ecific). All PDE inhibitors relaxed the strips dose-dependently, with the 50% effective concentrations (EC(50)) being 30 mu M for papaverine , 40 mu M for zaprinast, 25 mu M for quazinone, and 0.1 mu M for rolip ram. The ureter-relaxing effect of the PDE TV inhibitor at low concent rations, combined with its low-level effect on the systemic circulator y parameters, may open the possibility of using selective PDE IV- inhi bitors in the treatment of ureteral colics or for ureteral stone passa ge.