Short-Term Therapy with Rosiglitazone, a PPAR-γAgonist, Improves Metabolic Profile and Vascular Function in Nonobese Lean Wistar Rats

Mohammad M Naderali,Abdul-Razak Abubakari,Imose Itua,Ebrahim K Naderali

doi:10.5402/2012/130347

Mohammad M Naderali, Abdul-Razak Abubakari + Show 2 more

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https://doi.org/10.5402/2012/130347

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Abstract

A number of preclinical and clinical studies have reported blood-pressure-lowering benefits of thiazolidinediones in diabetic subjects and animal models of diabetes. This study was designed to further elucidate vascular effects of rosiglitazone, on healthy nonobese, lean animals. Adult male Wistar rats were randomized and assigned to control and rosiglitazone-treated groups and were dosed daily with either vehicle or rosiglitazone (10 mg kg−1 day−1) by oral gavage for 5 days. Compared with control group, rosiglitazone treatment significantly reduced plasma levels of triglycerides (>240%) and nonesterified free fatty acids (>268%) (both, P < 0.001). There were no changes in vascular contractility to KCl or noradrenaline between two groups. However, rosiglitazone therapy improved carbamylcholine-induced vasorelaxation (93 ± 3 % versus control 78 ± 2, P < 0.01) an effect which was abolished by L-NAME. There was no difference in sodium nitroprusside-induced vasorelaxation between the control and rosiglitazone-treated animals. These results indicate that short-term rosiglitazone therapy improves both metabolic profile and vascular function in lean rats. The vascular effect of rosiglitazone appears to be mediated by alteration in NO production possibly by activation of endothelial PPARγ. This increased NO production together with improved lipid profile may explain mechanism(s) of blood-pressure-lowering effects of thiazolidinediones on both human and experimental animals.

Highlights

Metabolic syndrome, known as a cluster of insulin resistance, abnormal glucose tolerance, abdominal obesity, dyslipidaemia, and arterial disease [1], is associated with substantially increased risk of cardiovascular disease resulting in increased morbidity and premature mortality
Rosiglitazone, a thiazolidinedione insulin-sensitizing agent which acts by stimulating peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to improve endothelial function in both human and animals [20, 24, 25]
It is reported that rosiglitazone had no effect on contractile responses to NA, but markedly increased sensitivity to Acetylcholine- (Ach-) induced vasorelaxation [28]

Summary

Introduction

Metabolic syndrome (syndrome X), known as a cluster of insulin resistance, abnormal glucose tolerance, abdominal obesity, dyslipidaemia, and arterial disease [1], is associated with substantially increased risk of cardiovascular disease resulting in increased morbidity and premature mortality. Thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, are effective in the management of type 2 diabetes mellitus They bind to the nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ), and consequential improvements in insulin resistance and glucose metabolism are principally attributed to decreased free fatty acid concentrations [8, 9]. They improve metabolic abnormalities in animal models of insulin resistance and type 2 diabetes [5, 10] and in human subjects with type. Similar studies in human subjects with type 2 diabetes mellitus have reported endothelial function improvement [20, 21] It appears that TZDs have a significantly positive effects on vascular function. Resistance arteries were deployed to measure vascular function, as these vessels represent endothelial function throughout the vasculature and are believed to be involved in determining the increase in peripheral resistance that leads to the development of hypertension [22]

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