Both
bleeding and
thrombosis are complications of
uremia in patients on regular
hemodialysis. An excessive endogenous formation of the
vasodilator and
platelet inhibitor nitric oxide (NO) has been proposed to contribute to the
bleeding defect. Since exposure to pharmacological donors of NO, nitrovasodilators, can cause tolerance to NO, we investigated whether platelets from uremic patients on regular
hemodialysis are influenced differently by NO donors than platelets from healthy subjects. A frequently used
S-nitrosothiol,
S-nitroso-N-acetylpenicillamine (SNAP), was compared to a recently synthezised mesoionic oxatriazole derivate,
GEA 3175, regarding its capacity to inhibit
adenosine 5'-diphosphate (
ADP)-induced platelet aggregation in vitro. The final products of NO production,
nitrite +
nitrate, were found to be significantly increased in uremic patients. The capacity to inhibit platelet aggregation by SNAP was only slightly different between the groups. However,
GEA 3175 showed a significantly marked and reduced capacity to inhibit aggregation of uremic platelets compared to controls. Interactions of
erythropoietin (EPO) with NO have earlier been reported. Addition of EPO to platelets from healthy donors in vitro did not significantly influence the NO donor capacity to inhibit platelet aggregation, but showed a tendency to enhance the effect of SNAP while the effect of
GEA 3175 was inhibited. These results suggest compound-specific resistance to NO donors in uremic platelet activation.