Hydrogen sulfide replenishment ameliorates impaired platelet response to clopidogrel in mice with experimental diabetes mellitus.

This study aimed to reveal whether blood hydrogen sulfide (H2S) reduction could result in attenuated platelet inhibition of clopidogrel and whether replenishing blood H2S would reverse such attenuation in mice with diabetes mellitus (DM).Control (non-diabetic) versus DM mice were treated with vehicle control or GYY4137 (a synthetic H2S donor) alone or in combination with clopidogrel. Body weight gain, blood glucose, glucose tolerance, insulin tolerance, blood H2S, adenosine diphosphate (ADP)-induced whole-blood platelet aggregation, main clopidogrel metabolites (active thiol metabolite H4 and inactive clopidogrel carboxylate) in plasma, and the expression of main clopidogrel-metabolizing enzymes and interleukin-1β as well as their genes in the liver were measured, respectively.Compared with control mice, DM mice exhibited significant decreases in plasma H2S and H4 levels, glucose tolerance, insulin sensitivity, and clopidogrel-metabolizing enzyme expression, but significant increases in blood glucose, ADP-induced whole-blood platelet aggregation, and hepatic interleukin-1β expression, respectively. After use of GYY4137, boosting blood H2S levels ameliorated or reversed all other changes observed in DM mice, except for blood glucose elevation.Blood H2S reduction may contribute to impaired platelet inhibition of clopidogrel in DM mice, suggesting that replenishing blood H2S may benefit DM patients more when taking clopidogrel concomitantly.