This double-blind, randomized cross-over study showed no improvement in FMD after four weeks of NAC therapy compared with placebo. This could be explained by the lack of glutathione induction, which has been shown to have favorable effects on endothelial function. However, NAC did have a modest effect in decreasing CRP, suggesting that this compound may have some efficacy in reducing systemic inflammation.
A few reports have studied the effect of NAC on vascular endothelial function. In a recent study by Andrews et al.
, NAC was administered into the coronary and femoral arteries of patients with and without atherosclerosis.14
NAC potentiated acteylcholine-mediated vascular dilation, indicating its usefulness in improving endothelial function. In another study, intravenous infusion of NAC showed significant vasodilation in small epicardial arteries and augmented coronary blood flow.15
In an animal model of diabetes mellitus, the oral administration of NAC completely prevented the development of endothelial dysfunction independent of the degree of glycemic control.16
The present study failed to show any beneficial effects of NAC on endothelial function in this high-risk diabetic patient population, despite striking endothelial dysfunction at baseline in the majority of patients. The most likely explanation for the lack of effect is that NAC did not increase glutathione levels sufficiently. Glutathione acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of oxidative tissue injury.10
Oxygen-free radicals, responsible for inactivating NO, are scavenged from plasma or endothelial cells by both NAC and glutathione, thereby increasing the bioavailability of NO. In particular, intracellular reduced glutathione has a vital role in protecting endothelial cells from oxygen-free radicals17
and improves endothelial vasomotor response to acetylcholine when directly infused into the coronary artery.18
Recently, a low level of red blood cell glutathione peroxidase-1 activity has been associated with an increased risk of cardiovascular events in a patient population with established coronary artery disease, suggesting the importance of glutathione in cardiovascular disease prevention.19
Glutathione is synthesized intracellularly from the amino acids glycine, glutamate, and cysteine. Since the former two are abundantly available in the intracellular space, an adequate supply of cysteine into the cell becomes the rate-limiting step in the synthesis of glutathione.
In a preliminary animal study, we demonstrated that oral NAC administration substantially increased both glutathione and cysteine levels.20
It is unclear why NAC supplementation failed to increase plasma and red blood cell glutathione levels in this study but one explanation could be that glutathione cannot be increased to supra-normal levels. Previously published studies have demonstrated that NAC increases glutathione in patients with decreased levels but no data exists on increasing glutathione above normal levels. For example, in one study in patients with the human immune-deficiency virus, a condition associated with substantially decreased glutathione levels, the oral administration of NAC replenished glutathione to normal levels.21
Another potential explanation for the lack of increase in glutathione levels could be the reduced bioavailability of NAC during supplementation.
There are a number of reports indicating that therapy with NAC may have beneficial effects in suppressing systemic inflammation, a condition that is closely linked to the development of atherosclerosis.22
For instance, VCAM-1 enables the attachment of circulating cells to the endothelium and thus promotes intravascular accumulation of various inflammatory cells.23
NAC effectively decreased VCAM-1 expression in a diabetic population that is prone to elevated plasma soluble VCAM-1 concentrations.24
Similarly, in patients undergoing liver transplantation, high-dose NAC administration significantly inhibited the increase in both ICAM-1 and VCAM-1 after reperfusion.25
In cell cultures, Faruqi et al.
showed that NAC inhibited IL-1-induced mRNA as well as cell surface expression of both Eselectin and VCAM-1, suggesting potent antiinflammatory effects of NAC.26
This study demonstrated no significant effect of NAC on ICAM-1, VCAM-1, and IL-6 but showed a modest decrease in CRP levels after four weeks of therapy. However, after the exclusion of one patient with severely elevated CRP secondary to an infection, there was only a trend toward CRP reduction with NAC (p=
0.053). Given that relatively few therapies have been shown to reduce CRP to date,27
NAC may represent an addition to the armamentarium of agents that can lower systemic inflammation. Whether the extent of CRP reduction observed in this study translates into clinically measurable benefits is unknown, but a recent study of 134 patients with end-stage renal disease suggests that NAC may be a clinically useful agent.28
In that study, patients were randomized to either NAC or placebo and found to have a 40% lower incidence of cardiac events, ischemic strokes, and peripheral vascular disease in the NAC treated group after a median follow-up of 14 months. A larger study linking the reduction in CRP with clinical outcomes may provide useful information in the future.
In conclusion, a four-week course of oral NAC therapy did not improve endothelial dysfunction in patients with diabetes mellitus and clinically absent cardiovascular disease. However, NAC therapy significantly decreased CRP levels in this challenging patient population. Further study is warranted to confirm this finding.