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

Abstract

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.

Potential Protective Properties of a Stable, Slow‐releasing Nitric Oxide Donor, GEA 3175, in the Lung

“…The compounds were equally potent and more potent than either 3-morpholinosydnonimine or S-nitroso-N-acetyl-D,Lpenicillamine (24). This effect could also be seen in platelets from uremic patients, although the response was significantly impaired (55). However, it has also been demonstrated that GEA 3175 alone does not prevent human platelet aggregation (15).…”