1. Amlodipine enhances amelioration of vascular insulin resistance, oxidative stress, and metabolic disorders by candesartan in metabolic syndrome rats.
- Author
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Sueta D, Nakamura T, Dong YF, Kataoka K, Koibuchi N, Yamamoto E, Toyama K, Yasuda O, Ogawa H, and Kim-Mitsuyama S
- Subjects
- Amlodipine pharmacology, Angiotensin II Type 1 Receptor Blockers pharmacology, Angiotensin II Type 1 Receptor Blockers therapeutic use, Animals, Benzimidazoles pharmacology, Biphenyl Compounds, Blood Pressure drug effects, Blood Pressure physiology, Body Weight drug effects, Body Weight physiology, Calcium Channel Blockers pharmacology, Calcium Channel Blockers therapeutic use, Disease Models, Animal, Drug Synergism, Drug Therapy, Combination, Heart Rate drug effects, Heart Rate physiology, Male, Metabolic Syndrome metabolism, NADPH Oxidases metabolism, Oxidative Stress drug effects, Rats, Rats, Inbred WKY, Superoxides metabolism, Tetrazoles pharmacology, Vasodilation drug effects, Vasodilation physiology, Amlodipine therapeutic use, Benzimidazoles therapeutic use, Insulin Resistance physiology, Metabolic Syndrome drug therapy, Metabolic Syndrome physiopathology, Oxidative Stress physiology, Tetrazoles therapeutic use
- Abstract
Background: The pharmacological advantage of combination of an angiotensin receptor blocker (ARB) and a calcium-channel blocker (CCB) is not fully defined. This study was undertaken to elucidate the potential benefit of their combination in metabolic syndrome., Methods: SHR/NDmcr-cp (SHRcp), a rat model of human metabolic syndrome, were divided into four groups, and were administered (i) vehicle, (ii) candesartan (an ARB) 0.3 mg/kg/day, (iii) amlodipine (a CCB) 3 mg/kg/day, and (iv) candesartan 0.3 mg/kg/day plus amlodipine 3 mg/kg/day, for 4 weeks., Results: Candesartan, amlodipine, or their combination significantly ameliorated the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. However, the impairment of insulin-induced vasodilation in SHRcp was partially improved by candesartan alone, but not by amlodipine alone. Interestingly, amlodipine added to candesartan synergistically enhanced the improvement of impaired insulin-induced vasodilation by candesartan, indicating the synergistic improvement of vascular insulin resistance by the combination of these drugs. Candesartan alone, but not amlodipine alone, significantly attenuated vascular superoxide and NADPH oxidase subunit p22phox in SHRcp. Amlodipine added to candesartan synergistically enhanced the reduction of vascular p22phox levels and superoxide by candesartan in SHRcp, suggesting the association of vascular insulin resistance with oxidative stress. Furthermore, the combination of candesartan with amlodipine synergistically decreased the increase in visceral adipocyte size, serum free-fatty acid, and tumor necrosis factor-α in SHRcp., Conclusions: ARB and CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome, being associated with the synergistic attenuation of vascular oxidative stress and metabolic disorders.
- Published
- 2012
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