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
Pa. Whiss et R. Larsson, 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, HAEMOSTASIS, 28(5), 1998, pp. 260-267
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.