Abstract 14148: Combination Therapy of an Angiotensin Receptor Blocker and a Calcium Channel Blocker Ameliorated Vascular Insulin Resistance in Metabolic Syndrome Rats Synergistically via a Reduction in Adipocyte Size and an Anti-Inflammatory Effect
[Aim] The significance of combination therapy of angiotensin receptor blocker (ARB)- and calcium channel blocker (CCB) for metabolic syndrome remains to be elucidated. We examined the efficacy of ARB plus CCB combination in a metabolic syndrome model rat.
[Methods] We used SHR/NDmcr-cp(SHRcp) which is regarded as a useful model of metabolic syndrome. We divided SHRcp into 4 groups and orally administered (1) Vehicle; (2) Candesartan (ARB) 0.3mg/kg/day; (3) Amlodipine(CCB) 3mg/kg/day and (4)Candesartan 0.3mg/kg/day plus Amlodipine 3mg/kg/day (ARB plus CCB), for 4 weeks. Vascular insulin resistance was estimated by examining a vascular endothelium-dependent relaxation with insulin.
[Results] ARB, CCB, and ARB plus CCB equally normalized the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. On the other hand, ARB only partially ameliorated the impairmant of insulin-induced endothelium-dependent relaxation whereas CCB did not. Interestingly, ARB plus CCB combination synergistically ameliorated the impairment of insulin-induced endothelium-dependent relaxation, compared with either monotherapy. This synergistic improvement of vascular insulin resistance, by ARB plus CCB, was partially attributable to greater attenuation of p22phox-related oxidative stress. To examine the potential contribution of metabolic disorder to vascular insulin resistance, we compared each group's effects on obesity and inflammation. ARB plus CCB significantly decreased the enlarged size of visceral adipocytes in SHRcp, while neither monotherapy succeeded to decrease it. ARB plus CCB synergistically reduced the increased serum free fatty acid levels and the increased tumor necrosis factor-α levels in SHRcp, compared with either monotherapy. Thus, the ARB plus CCB combination synergistically improved obesity and subsequently exerted an anti-inflammatory effect in SHRcp.
[Conclusions] ARB plus CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome and the underlying mechanism of this synergistic effect was attributable to greater attenuation of p22phox-related oxidative stress and to a greater anti-inflammatory effect through the reduction of visceral adipocyte size.
- © 2011 by American Heart Association, Inc.