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No effects of atorvastatin (10 mg/d or 80 mg/d) on nitric oxide, prostacyclin, thromboxane and oxidative stress in type 2 diabetes mellitus patients of the DALI study

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Author: Tsikas, D. · Pham, V.V. · Suchy, M.T. · Ree, M.A. van de · Huisman, M.V. · Frölich, J.C. · Princen, H.M.G.
Type:article
Date:2015
Source:Pharmacological Research, 94, 1-8
Identifier: 524120
doi: DOI:10.1016/j.phrs.2015.01.004
Keywords: Biology · 8-iso-Prostaglandin F2α · Carbonic anhydrase · Cardiovascular disease · Diabetes mellitus type 2 · Nitric oxide · Oxidative stress · Prostacyclin · Statins · Thromboxane · 2,3 dinor 6 oxoprostaglandin F1 alpha · 2,3 dinorthromboxane B2 · 8 isoprostaglandin F2 alpha · Atorvastatin · Carbonate dehydratase · Cholesterol · Nitrate · Nitric oxide · Nitrite · Placebo · Prostacyclin · Prostaglandin synthase · Thromboxane · Thromboxane A2 · Adult · Aged · Antioxidant activity · Biosynthesis · Cholesterol metabolism · Controlled study · Dose response · Double blind procedure · Drug effect · Drug treatment failure · Dyslipidemia · Female · Heart protection · Lipid peroxidation · Lipolysis · Major clinical study · Male · Mass fragmentography · Middle aged · Non insulin dependent diabetes mellitus · Oxidative stress · Randomized controlled trial · Tandem mass spectrometry · Treatment duration · Urine level · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

Abstract

The present study describes the effects of atorvastatin on whole body synthesis of nitric oxide (NO), prostacyclin (PGI2), and thromboxane A2 (TxA2), on oxidative stress and nitrite/nitrate-related renal carbonic anhydrase (CA) activity in patients with type 2 diabetes mellitus (T2DM). A double-blind, randomized, placebo-controlled parallel-group trial (the DALI study group) on 217 patients with T2DM and dyslipidemia was performed. Urinary samples were collected before and after administration of a standard dose (10 mg/d, n = 73), a maximal dose atorvastatin (80 mg/d, n = 72) or placebo (n = 72) for 30 weeks. Urinary nitrite and nitrate were measured to assess whole body NO synthesis. The urinary molar ratio of nitrate to nitrite (UNOxR) served as a measure of renal CA activity. Free radical- and cyclooxygenase (COX)-catalyzed lipid peroxidation was estimated by measuring urinary 8-iso-prostaglandin F2α (8-iso-PGF2α). In subgroups, systemic PGI2 and TxA2 synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-6-keto-prostaglandin F1α and 2,3-dinor-thromboxane B2, respectively. All biochemical parameters were measured by GC-MS and GC-MS/MS methods. T2DM patients had elevated levels of nitrate, nitrite, UNOxR, and 8-iso-PGF2α compared to healthy non-diabetic and normolipidemic subjects. Thirty-week treatment with atorvastatin (10 or 80 mg/d) did not significantly alter NO, PGI2, TxA2 and 8-iso-PGF2α synthesis and did not improve the renal reabsorption of nitrite which is considered an important reservoir of NO. Our study suggests that atorvastatin (10 or 80 mg/d) does not provide cardiovascular benefit beyond its cholesterol lowering effect in patients with T2DM. © 2015 Elsevier Ltd. All rights reserved.