title: Long-term smoking causes nitroglycerin resistance in platelets by depletion of intraplatelet glutathione.
abstract: We investigated whether platelet responsiveness to nitroglycerin (NTG) is maintained in long-term smokers and if not, the mechanism. In the absence or presence of NTG, intraplatelet reduced glutathione (GSH) levels and ADP-induced platelet aggregation and intraplatelet cGMP levels were measured in 10 long-term smokers and 10 age-matched nonsmokers. The intraplatelet GSH level was significantly lower in smokers than in nonsmokers (P<0.05). Platelet aggregation was dose-dependently inhibited by NTG in both groups; however, inhibition was significantly weaker in smokers. N-acetylcysteine (1 mmol/L), an exogenous thiol agent, significantly potentiated NTG-induced platelet inhibition in nonsmokers but not in smokers. The ADP-induced intraplatelet cGMP level was significantly greater in the presence of NTG in nonsmokers but not so in smokers. Because the effects of long-term smoking are multifactorial, a rabbit model was made by chronic administration of buthionine sulfoximine (BSO, n=6) to decrease intraplatelet GSH. The intraplatelet GSH level was significantly lower in BSO-treated rabbits than in saline-treated rabbits (P<0.001). The NTG-induced inhibition of platelet aggregation was significantly weaker in BSO rabbits. N-acetylcysteine-induced potentiation was not observed in BSO rabbits, whereas significant potentiation was found in saline rabbits. These findings were similar to those of long-term smokers. In contrast, the intraplatelet GSH-to-oxidized glutathione ratio, which represents the redox state of glutathione, was significantly lower in smokers than in nonsmokers, whereas no difference was found between saline rabbits and BSO rabbits. In conclusion, long-term smoking causes NTG resistance to aggregation in platelets, possibly through the depletion of intraplatelet GSH.
authors.affiliation: Department of Internal Medicine III, the Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Haramaki
authors.forename: H
authors.initials: H
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Takajo
authors.forename: A
authors.initials: A
authors.lastname: Katoh
authors.forename: S
authors.initials: S
authors.lastname: Kanaya
authors.forename: S
authors.initials: S
authors.lastname: Shintani
authors.forename: R
authors.initials: R
authors.lastname: Haramaki
authors.forename: T
authors.initials: T
authors.lastname: Murohara
authors.forename: T
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003328:Coronary Thrombosis / Q000209:etiology; D006152:Cyclic GMP / Q000096:biosynthesis; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D012907:Smoking / Q000009:adverse effects*
chemical_list: D020030:Nitric Oxide Donors; D019328:Buthionine Sulfoximine; D005996:Nitroglycerin; D005978:Glutathione; D006152:Cyclic GMP