title: Combination therapy with losartan and L-carnitine protects against endothelial dysfunction of streptozotocin-induced diabetic rats.
abstract: Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications and angiotensin II appears to play a pivotal role in this setting. The present study aimed to investigate whether the combination therapy with losartan and the nutritional supplement, L-carnitine can provide an additional protection against diabetes-associated endothelial dysfunction and elucidate the possible mechanism(s) underlying this effect. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg) in rat. Effects of losartan (20 mg/kg, orally, 3 months) and L-carnitine (200 mg/kg, orally, 3 months) on tumor necrosis factor (TNF)-α, oxidative stress parameters, endothelial nitric oxide synthase expression (eNOS), and vascular function were evaluated. Our results showed a marked increase in aortic superoxide anion (O2(-)) production and serum malondialdehyde (MDA) level alongside attenuating antioxidant enzyme capacities in diabetic rats. This was associated with a significant increase in anigiotensin II type 1 receptor gene expression and TNF-α serum level of diabetic rats alongside reducing aortic eNOS gene expression and nitric oxide (NO) bioavailability. The single or combined administration of losartan and L-carnitine significantly inhibited these changes. Additionally, the vascular endothelium-dependent relaxation with acetylcholine (ACh) in aortic diabetic rat was significantly ameliorated by the single and combined administration of losartan or L-carnitine. Noteworthy, the combination therapy exhibited a more profound response over the monotherapy. Collectively, our results demonstrate that the combined therapy of losartan and L-carnitine affords additive beneficial effects against diabetes-associated endothelial dysfunction, possibly via normalizing the dysregulated eNOS and reducing the inflammation and oxidative stress in diabetic rats.
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, Egypt.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Sleem
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, Egypt. Electronic address: Ashraf_taye70@yahoo.com.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Taye
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: El-Moselhy
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Assiut University, Egypt.
authors.forename: Safwat A
authors.initials: SA
authors.lastname: Mangoura
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020011:Protective Agents; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D008315:Malondialdehyde; D013311:Streptozocin; D052250:Nitric Oxide Synthase Type III; D019808:Losartan; D000109:Acetylcholine; D002331:Carnitine
keywords: Diabetes; Endothelial dysfunction; Losartan; Oxidative stress; l-carnitine