prostaglandin-a1 and zaprinast

In the presence of 3-isobutyl-methylxanthine (IBMX), induction of cyclic 3',5'-guanosine monophosphate (GMP) production in human washed platelets (HWP) by nitric oxide donors (NOD) is followed by its accumulation in the surrounding medium in a time- and concentration-dependent manner. Thirty minutes incubation of HWP with 3-morpholino-sydonimine (SIN-1, 10 microM) at 37 degrees C resulted in a 4.6-fold increase of cyclic GMP in platelets, whereas in the extracellular medium the increase was 17.6-fold. Similar results were obtained when other NOD such as S-nitroso-N-acetylpenicyllamine (SNAP) and 3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine (GEA 3184) and the selective phosphodiesterase inhibitor, zaprinast (M&B 22948, 10 microM), were used. Probenecid (1-300 microM), an inhibitor of organic anion transport, or ouabain (1-300 microM), an inhibitor of Na+/K+ adenine triphosphate (ATP)-ase had no effect on cyclic GMP production or extrusion after stimulation with SIN-1. Significantly prostaglandin A1 (PGA1) and prostaglandin D2 (PGD2) inhibited the efflux of cyclic GMP from platelets induced by SNAP (10 microM) in a concentration-dependent fashion, with an IC50 of 63 +/- 16 and 143 +/- 17 microM, respectively. These studies suggest that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cyclic GMP levels in platelets with potential physiological and therapeutic consequences.

Topics: 1-Methyl-3-isobutylxanthine; Blood Platelets; Cells, Cultured; Culture Media; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Space; Guanylate Cyclase; Humans; Ion Transport; Molsidomine; Nitric Oxide; Ouabain; Penicillamine; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Probenecid; Prostaglandin D2; Prostaglandins; Prostaglandins A; Purinones; S-Nitroso-N-Acetylpenicillamine; Sodium-Potassium-Exchanging ATPase; Time Factors; Triazoles