Long-Term Smoking Causes Nitroglycerin Resistance in Platelets by Depletion of Intraplatelet Glutathione

Abstract

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 (PϽ0.05).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, nϭ6) to decrease intraplatelet GSH. The intraplatelet GSH level was significantly lower in BSO-treated rabbits than in saline-treated rabbits (PϽ0.001). 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.

Coexistence of Impairment of Endothelium-Derived Nitric Oxide and Platelet-Derived Nitric Oxide in Patients With Coronary Risk Factors.

“…3,18 Indeed, we have previously shown that impaired PDNO bioactivity and augmented platelet aggregability in smokers may be caused by an imbalance of the intraplatelet redox state through increased oxidative stress. 14,19 In general, EDNO and PDNO act in coordination as anti-atherothrombogenic molecules, 3,4,8,9 and in the previous clinical studies, impaired EDNO or PDNO has been associated with an increase in cardiovascular events such as acute coronary syndromes. 20,21 Accordingly, impaired EDNO and PDNO bioactivities may synergistically contribute to atherothrombogenesis in patients with coronary risk factors.…”

Reactive Oxygen Species

“…Muscat et al 2004 109 Haramaki et al 2001 110 Takajo et al 2001 111 Diabetes Enhanced platelet O 2 Ϫ production in diabetic subjects is associated with enhanced platelet activation. Reduction of platelet activation in diabetic subjects by antioxidant vitamins.…”

Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers

“…We have previously shown that long-term smoking impairs platelet-derived nitric oxide (PDNO) release (6), which acts as a negative feedback mechanism to inhibit not only platelet aggregation (11) but also recruitment after aggregation (12). Furthermore, we have recently shown that impaired PDNO bioactivity and augmented platelet aggregability in long-term smokers are related to the imbalance of the intraplatelet redox state, suggesting the smokinginduced oxidative stress for platelet activation (5,6). Thus, smoking-induced platelet-mediated thrombotic mechanisms may be involved in the pathophysiology of coronary artery disease of long-term smokers.…”