Adenosine 5 '-diphosphate-induced platelet aggregation in uremia shows resistance to inhibition by the novel nitric oxide donor GEA 3175 but not by S-nitroso-N-acetylpenicillamine

Both bleeding and thrombosis are complications of uremia in patients on reg ular hemodialysis. An excessive endogenous formation of the vasodilator and platelet inhibitor nitric oxide (NO) has been proposed to contribute to th e bleeding defect. Since exposure to pharmacological donors of NO, nitrovas odilators, can cause tolerance to NO, we investigated whether platelets fro m uremic patients on regular hemodialysis are influenced differently by NO donors than platelets from healthy subjects. A frequently used S-nitrosothi ol, S-nitroso-N-acetylpenicillamine (SNAP), was compared to a recently synt hezised mesoionic oxatriazole derivate, GEA 3175, regarding its capacity to inhibit adenosine 5'-diphosphate (ADP)-induced platelet aggregation in vit ro. The final products of NO production, nitrite + nitrate, were found to b e significantly increased in uremic patients. The capacity to inhibit plate let aggregation by SNAP was only slightly different between the groups. How ever, GEA 3175 showed a significantly marked and reduced capacity to inhibi t aggregation of uremic platelets compared to controls. Interactions of ery thropoietin (EPO) with NO have earlier been reported. Addition of EPO to pl atelets from healthy donors in vitro did not significantly influence the NO donor capacity to inhibit platelet aggregation, but showed a tendency to e nhance the effect of SNAP while the effect of GEA 3175 was inhibited. These results suggest compound-specific resistance to NO donors in uremic platel et activation.