Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats.
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. Treatments 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 malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature.
El Midaoui
Adil
A
Department of Medicine, Mount Sinai Hospital and University Health Network, Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada.
Ismael
Mahmoud Ali
MA
Lu
Huogen
H
Fantus
I George
IG
de Champlain
Jacques
J
Couture
Réjean
R
D000111:Acetylcysteine / Q000494:pharmacology*; D000447:Aldehydes / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects*; D004032:Diet; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D000806:Angiotensin-Converting Enzyme Inhibitors; D016166:Free Radical Scavengers; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D008315:Malondialdehyde; D019255:NADPH Oxidases; D005947:Glucose; C027576:4-hydroxy-2-nonenal; D017257:Ramipril; D000111:Acetylcysteine