Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats Adil El Midaoui, Mahmoud Ali Ismael, Huogen Lu, I. George Fantus, Jacques de Champlain, and Re ´ jean Couture Abstract: Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treat- ments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and ma- londialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contrib- utes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature. Key words: ACE inhibitor, hypertension, insulin resistance, N-acetyl-L-cysteine, oxidative stress, ramipril. Re ´sume ´: On a e ´value ´ les effets be ´ne ´fiques d’un antioxydant (N-ace ´tyl-L-cyste ´ine, NAC) et d’un inhibiteur de l’enzyme de conversion de l’angiotensine-I (ECA) (ramipril) dans un mode `le de rats pre ´sentant une re ´sistance a ` l’insuline induite par l’ingestion de 10 % de glucose pendant 20 semaines. On a incorpore ´ la NAC (2 g/kg par jour) et le ramipril (1 mg/kg par jour) durant la 16 e semaine dans le liquide de consommation. La pression arte ´rielle systolique, les taux plasmatiques d’insuline et de glucose et la re ´sistance a ` l’insuline ont e ´te ´ significativement plus e ´leve ´s chez les rats traite ´s avec le glu- cose pendant 20 semaines. Ce re ´sultat a e ´te ´ associe ´a ` une augmentation de la production d’anions superoxyde et de l’ac- tivite ´ de la NADPH oxydase dans l’aorte et le foie, et a ` une re ´duction marque ´e de l’expression de la prote ´ine substrat du re ´cepteur de l’insuline (IRS-1) musculaire squelettique dans le muscle gastrocne ´mien. La NAC a pre ´venu toutes ces modi- fications. Bien que le ramipril ait aussi renverse ´ l’hypertension, il a eu un plus faible effet sur la re ´sistance a ` l’insuline (y compris l’IRS-1) et a bloque ´ la production d’anions superoxyde dans l’aorte seulement. Le ramipril n’a pas diminue ´ l’ac- tivite ´ de la NADPH oxydase dans l’aorte et le foie ou les taux plasmatiques de 4-hydroxynone ´nal et de malondialde ´hyde, contrairement a ` la NAC. Les re ´sultats donnent a ` penser que l’inhibition du stress oxydatif durant l’hypertension et la re ´sis- tance a ` l’insuline contribue aux effets the ´rapeutiques de la NAC et du ramipril. La NAC exerce une activite ´ antioxydante efficace dans de multiples tissus, alors que le ramipril semble davantage cibler le syste `me vasculaire. Mots-cle ´s : inhibiteur de l’ECA, hypertension, re ´sistance a ` l’insuline, N-ace ´tyl-L-cyste ´ine, stress oxydatif, ramipril. [Traduit par la Re ´daction] Introduction The ‘metabolic syndrome’ is an emerging epidemic worldwide that consists of an association of multiple cardio- vascular risk factors (Giugliano et al. 1995). These factors, including hypertension, insulin resistance, and obesity, di- rectly contribute to a higher incidence of cardiovascular dis- ease as well as to the development of type 2 diabetes. An increase in oxidative stress is one of the main hypotheses suggested to explain the enhanced risks associated with met- abolic syndrome (Giugliano et al. 1995; Inoguchi and Na- wata 2005; Kashiwagi et al. 1999). Oxidative stress may Received 7 April 2008. Accepted 1 October 2008. Published on the NRC Research Press Web site at cjpp.nrc.ca on 14 November 2008. A. El Midaoui, H. Lu, and I.G. Fantus. Department of Medicine, Mount Sinai Hospital and University Health Network, Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada. M.A. Ismael, J. de Champlain, and R. Couture. 1 Department of Physiology, Faculty of Medicine, Universite ´ de Montre ´al, CP 6128, Succursale Centre-ville, Montre ´al, QC H3C 3J7, Canada. 1 Corresponding author (e-mail: rejean.couture@umontreal.ca). 752 Can. J. Physiol. Pharmacol. 86: 752–760 (2008) doi:10.1139/Y08-090 # 2008 NRC Canada