Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways

Phosphodiesterases (PDE) are key enzymes regulating intracellular cyclic nu cleotide turnover and, thus. smooth muscle tension. Recent reports have ind icated the presence of PDE isoenzymes 1, 2, 4, and 5 in cytosolic supernata nts prepared from human ureteral smooth muscle homogenates and the ability of second-generation inhibitors of PDE 3, 4, and 5 to relax KCl-induced ten sion of human ureteral muscle in vitro. The aim of the present study was to evaluate the functional effects of recently developed, third-generation is oenzyme-selective PDE inhibitors, the nitric oxide (NO)donating agents sodi um nitroprusside (SNP) and dihydropyridine (DHP), which is also described a s an antagonist of L-type calcium channels, and the adenylyl cyclase-stimul ating drug forskolin on tissue tension and cyclic nucleotide levels of huma n ureteral smooth muscle segments in vitro. Relaxant responses of human ure teral smooth muscle were investigated in vitro using the organ bath techniq ue. Cyclic nucleotides cAMP and cGMP were determined by specific radioimmun oassay following time and dose-dependent incubation of the ureteral tissue with the drugs. The most pronounced relaxing effects on KCl-induced tension of ureteral smooth muscle were exerted by nitrovasodilator SNP, PDE4 inhib itor rolipram, and PDES inhibitors E 4021 and morpholinosulfonyl-pyrazolopy rimidine (MSPP). Relaxing potency of the drugs was paralleled by their abil ity to elevate intracellular levels of cGMP and cAMP, respectively. Our dat a suggest the possibility of using selective inhibitors of PDE isoenzymes 4 and 5 in the treatment of ureteral stones and ureteral colic.