Haramaki N, Ikeda H, Takajo Y, Katoh A, Kanaya S, Shintani S, Haramaki R, Murohara T, Imaizumi T
Department of Internal Medicine III, the Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1852-6. doi: 10.1161/hq1001.097021.
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.
我们研究了长期吸烟者血小板对硝酸甘油（NTG）的反应性是否得以维持，若未维持，其机制是什么。在有或无NTG的情况下，对10名长期吸烟者和10名年龄匹配的非吸烟者测量了血小板内还原型谷胱甘肽（GSH）水平、ADP诱导的血小板聚集以及血小板内cGMP水平。吸烟者的血小板内GSH水平显著低于非吸烟者（P<0.05）。两组中NTG均能剂量依赖性地抑制血小板聚集；然而，吸烟者中的抑制作用明显较弱。N-乙酰半胱氨酸（1 mmol/L），一种外源性硫醇试剂，能显著增强NTG对非吸烟者血小板的抑制作用，但对吸烟者无效。在非吸烟者中，NTG存在时ADP诱导的血小板内cGMP水平显著升高，但吸烟者并非如此。由于长期吸烟的影响是多因素的，通过慢性给予丁硫氨酸亚砜胺（BSO，n=6）以降低血小板内GSH来建立兔模型。BSO处理的兔血小板内GSH水平显著低于盐水处理的兔（P<0.001）。BSO处理的兔中NTG诱导的血小板聚集抑制作用明显较弱。在BSO处理的兔中未观察到N-乙酰半胱氨酸诱导的增强作用，而在盐水处理的兔中则发现有显著增强。这些发现与长期吸烟者的情况相似。相反，代表谷胱甘肽氧化还原状态的血小板内GSH与氧化型谷胱甘肽的比值，吸烟者显著低于非吸烟者，而盐水处理的兔和BSO处理的兔之间未发现差异。总之，长期吸烟可能通过消耗血小板内GSH导致血小板对NTG诱导的聚集产生抵抗。
