title: High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin-induced inhibition of thromboxane synthesis in human platelets.
abstract: Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5-25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1-300 μmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA-induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA-induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.
authors: Internal Medicine and Metabolic Disease Unit, San Luigi Gonzaga Hospital, Department of Clinical and Biological Sciences, San Luigi Gonzaga School of Medicine, University of Turin, Turin, Italy.
authors: Isabella
authors: I
authors: Russo
authors: Michela
authors: M
authors: Viretto
authors: Cristina
authors: C
authors: Barale
authors: Luigi
authors: L
authors: Mattiello
authors: Gabriella
authors: G
authors: Doronzo
authors: Andrea
authors: A
authors: Pagliarino
authors: Franco
authors: F
authors: Cavalot
authors: Mariella
authors: M
authors: Trovati
authors: Giovanni
authors: G
authors: Anfossi
mesh_terms: D000328:Adult; D004999:Amifostine / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000201:enzymology* / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects*; D013931:Thromboxanes / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D008239:Lysine; D004999:Amifostine; D001241:Aspirin; C010395:acetylsalicylic acid lysinate