Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetesReport as inadecuate




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Cardiovascular Diabetology

, 10:43

First Online: 21 May 2011Received: 24 March 2011Accepted: 21 May 2011

Abstract

BackgroundPlatelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione GSH. Clinical delivery of N-acetylcysteine NAC, a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes.

MethodsBlood samples n = 13 were incubated 2 h, 37°C with NAC 10-100 micromolar in vitro. Platelet aggregation in response to thrombin and ADP whole blood aggregometry was assessed, together with platelet GSH concentration reduced and oxidized, antioxidant status, reactive oxygen species ROS generation, and plasma NOx a surrogate measure of platelet-derived nitric oxide; NO.

ResultsAt therapeutically relevant concentrations 10-100 micromolar, NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC.

ConclusionsOur results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes.

Keywordstype 2 diabetes platelets thrombosis antioxidants glutathione N-acetylcysteine AbbreviationsADPadenosine diphosphate

ANOVAanalysis of variance

BMIbody mass index

CPH1-hydroxy-3-carboxy-pyrrolidine

DTNB5,5-dithio-bis 2 nitrobenzoic acid

EPRelectron paramagnetic resonance

GSHglutathione

GSSGoxidsied glutathione

HPLChigh performance liquid chromatography

LDLlow density lipoprotein

L-NAMEN-nitro-L-arginine methyl ester

NACN-acetylcysteine

NOnitric oxide

NOSNO synthase

NOxnitrite + S-nitrosothiols

PRPplatelet rich plasma

PGI2prostacyclin prostaglandin I2

TNB5-thio nitrobenzoic acid.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2840-10-43 contains supplementary material, which is available to authorized users.

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Author: Kyle R Gibson - Tim J Winterburn - Fiona Barrett - Sushma Sharma - Sandra M MacRury - Ian L Megson

Source: https://link.springer.com/article/10.1186/1475-2840-10-43







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