Long-Term N-Acetylcysteine and L-Arginine Administration Reduces Endothelial Activation and Systolic Blood Pressure in Hypertensive Patients With Type 2 Diabetes

Department of Internal Medicine, University of Torino, Corso Dogliotti 14, I-10121 Torino, Italy.
Diabetes care (Impact Factor: 8.42). 05/2008; 31(5):940-4. DOI: 10.2337/dc07-2251
Source: PubMed


Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation.
A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months.
The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed.
NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.

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    • "Previous clinical studies have examined the potential of NAC as a therapeutic agent in Type 2 diabetes patients for improving various clinical outcomes. Oral NAC supplementation was reported to enhance platelet-monocyte conjugation in diabetic patients [24], and reduce endothelial activation and systolic blood pressure in hypertensive patients with Type 2 diabetes [25], but to have no effect on contrast inducednephropathy in diabetes mellitus patients [26]. However, none of the reported studies have explored the effect of oral NAC supplementation on the immune response to infection in diabetic patients. "
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    ABSTRACT: Type 2 diabetic patients have increased susceptibility to melioidosis, an infectious disease caused by Burkholderia pseudomallei. We had previously shown that peripheral blood mononuclear cells (PBMCs) from diabetic patients with poor glycemic control had a defective IL-12 and IFNγ response to B. pseudomallei infection, resulting in poor intracellular bacterial control. The impaired IL-12 response was due to glutathione (GSH) deficiency characterized by a low reduced to oxidized glutathione ratio (GSH ratio) and could be restored by the addition of reduced GSH to the infected cells. Our goal is to determine whether N-acetyl cysteine (NAC, a GSH pro-drug) supplementation in diabetic patients could improve their immune control of B. pseudomallei. Type 2 diabetic patients with poor glycemic control were given oral supplementation of NAC for six weeks at 1200mg daily. Their PBMCs and subsets of immune cells showed a significant increase in free GSH concentration. However, the GSH ratio, IL-12 and IFNγ production, and intracellular bacterial killing upon ex-vivo infection did not improve. Thus, oral NAC supplementation in diabetic patients is sufficient to increase intracellular GSH content in blood cells. However, modulating the free GSH content is not sufficient to improve infection outcome as it is the GSH ratio that regulates the IL-12 response in monocytes.
    Microbes and Infection 07/2014; 16(8). DOI:10.1016/j.micinf.2014.07.007 · 2.86 Impact Factor
    • "This is a particularly important target group on account of the increased risk of cardiovascular disease in diabetes, coupled with the lack of efficacy of aspirin in primary prevention of cardiovascular complications amongst these patients. First, it has been shown that 6 month treatment with a combination of L-arginine (to prime synthesis of the endothelium-derived vasodilator, nitric oxide; NO) with NAC reduced blood pressure by ~5 mmHg in patients with type 2 diabetes and hypertension (Martina et al., 2008). Meanwhile, several other studies focused on the impact of NAC in platelet function: Gibson et al. demonstrated that NAC increased intraplatelet levels of GSH, decreased ROS detection and reduced platelet activation in vitro (Gibson et al., 2011). "
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    ABSTRACT: N-acetyl-L-cysteine (NAC) has long been used therapeutically for treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (L-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.
    Pharmacology [?] Therapeutics 09/2013; 141(2). DOI:10.1016/j.pharmthera.2013.09.006 · 9.72 Impact Factor
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    • "Recombinant enzyme uptake following intravenous injection may be primarily regulated at the level of the cation-independent mannose-6-phosphate receptor (CI-MPR) [8] [21], and tissue perfusion characteristics may be of secondary importance. Alternatively, chaperone therapy with imino sugars [54] or venous infusion of L-arginine and N-acetylcysteine [55] [56] may improve nitric oxide bioavailability and rhGAA delivery with potential antioxidant benefits. Lastly, we did not observe a significant difference in GAA activity between exercised and non-exercised wild-type mice following 14 weeks of endurance training (Fig. 1B), suggesting that chronic exercise does not affect basal lysosomal enzyme activities. "
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    ABSTRACT: BACKGROUND: Aerobic exercise may be used in conjunction with enzyme replacement therapy (ERT) to attenuate cardiovascular deconditioning, skeletal muscle wasting, and loss of motor function in Pompe disease (glycogen storage disease type II; GSDII), but the effects on lysosomal glycogen content and macroautophagy have not been defined to date. PURPOSE: The main objectives of this study were to determine if acute aerobic exercise enhances 24-h uptake of recombinant human enzyme (rhGAA; Myozyme® [aim 1]) and if endurance training improves disease pathology when combined with ERT [aim 2] in Pompe mice. METHODS: For the first aim in our study, Pompe mutant mice (6(neo)/6(neo)) were grouped into ERT (Myozyme® injection only [40mg/kg]) and ERT+EX (Myozyme® injection followed by 90min treadmill exercise) cohorts, and enzyme uptake was assessed in the heart and quadriceps 24h post injection. For the second aim of our study, mutant mice were randomized into control, endurance-trained, enzyme-treated, or combination therapy groups. Exercised animals underwent 14weeks of progressive treadmill training with or without biweekly Myozyme® injections (40mg/kg) and tissues were harvested 1week post last treatment. RESULTS: Myozyme® uptake (GAA activity) was not improved in ERT+EX over ERT alone at 24-h post injection. Endurance exercise training, with or without ERT, improved aerobic capacity and normalized grip strength, motor function, and lean mass (P<0.05), but did not reduce glycogen content or normalize macroautophagy beyond traditional enzyme replacement therapy. CONCLUSIONS: Endurance training is beneficial as an adjunctive therapy to ERT in Pompe disease, although it works by mechanisms independent of a reduction in glycogen content.
    Molecular Genetics and Metabolism 09/2012; 107(3). DOI:10.1016/j.ymgme.2012.09.010 · 2.63 Impact Factor
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