PHOSPHODIESTERASE ISOENZYMES IN HUMAN URETERAL SMOOTH-MUSCLE - IDENTIFICATION, CHARACTERIZATION, AND FUNCTIONAL-EFFECTS OF VARIOUS PHOSPHODIESTERASE INHIBITORS IN-VITRO

Phosphodiesterases (PDE) are key enzymes regulating intracellular cycl ic nucleotide metabolism and, thus, contraction and relaxation of the muscle. At present, five different families of isoenzymes of PDE exist that show a distinct species-specific and organ-specific distribution . The aim of the present study was to analyze the PDE isoenzymes prese nt in the human ureter and to evaluate the functional effects of isoen zyme-specific inhibitors in this tissue. Normal ureteral tissue was ob tained during radical nephrectomies, homogenized, centrifuged, and the supernatant fraction was separated using DEAE-Sephacel anion-exchange chromatography. PDE assay was then performed and the isoenzymes chara cterized on the basis of their kinetic characteristics and their sensi tivity to allosteric modulators and inhibitors. In vitro, longitudinal ureteral strips as well as ureteral rings were precontracted, and dif ferent selective and nonselective PDE inhibitors were added incrementa lly. Three different PDE isoenzymes were identified: PDE I (Ca/calmodu lin-stimulated), PDE II (cyclic guanosine monophosphate-stimulated), a nd PDE IV (cyclic adenosine monophosphate-specific). All PDE inhibitor s relaxed the strips dose-dependently with an EC(50) of 30 mu M for pa paverine, 40 mu M for zaprinast, 25 mu M for quazinone, and 0.1 mu M f or rolipram. The existence of three different PDE isoenzymes was shown in this study. The ureter-relaxing effect of the PDE IV inhibitor at low concentrations, combined with its low effect on the systemic circu latory parameters, may open a possibility of using selective PDE IV in hibitors in the treatment of ureteral colics or ureteral stones.