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

Abstract

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.