THE PHOSPHODIESTERASE-ISOENZYMES OF THE H UMAN URETER - CHARACTERIZATION AND FUNCTIONAL-SIGNIFICANCE

The existence of phosphodiesterase (PDE) isoenzymes in human ureter ti ssue and the relaxant effect of different selective phosphodiesterase inhibitors on human ureteral strips in vitro was evaluated. Isoenzyme characterization was carried out after homogenizing and centrifuging u reteral tissue. The supernatant fraction was applied to anion-exchange DEAE-Sephacel chromatography and eluted using sodium acetate gradient . Assay for PDE activity was then performed and peak fractions were ad ded to different specific PDE activators and inhibitors. Three differe nt PDE isoenzymes were characterized: PDE I (calmodulin-sensitive), PD E II (cGMP-stimulated) and PDE IV (cAMP-specific). Relaxing potency of PDE-inhibitors was measured on isolated ureteral muscle strips. Diffe rent selective phosphodiesterase inhibitors as well as the non-selecti ve inhibitor papaverine were added incremently. There was no spontaneo us ureteral activity in any ureteral strip examined. Papaverine as wel l as the selective phosphodiesterase inhibitors relaxed KCI preconract ed strips dose-dependently with an IC50 of 30 mu M for papaverine, 40 mu M for zaprinast, 25 mu M for quazinone and 0.1 mu M for rolipram. T hese data show that at low concentrations the phosphodiesterase IV inh ibitor rolipram was the most potent drug examined. Our findings suppor t the involvement of cyclic nucleotide metabolism in the regulation of ureteral smooth muscle tone. The existence of three different isoenzy mes and their involvement in cyclic nucleotide metabolism in the regul ation of ureteral smooth muscle tone has been shown. The ureter relaxi ng effect of specific PDE-IV-inhibitor at low concentrations, combined with its low effect on the systemic circulatory parameters, may be of use in treating ureteral colics.