Rosiglitazone increases extravasation of macromolecules and endothelial nitric oxide synthase in skeletal muscles of the fructose-fed rat model

Abstract

Reduced extravasation of macromolecules in skeletal muscle has recently been documented in the fructose-fed rat model, corroborating a hypothesis that a functional obliteration of muscle regional microcirculation might lead to hypertension and restrict access of nutrients and hormones to their target cells. The goal of this study was to assess the impact of a treatment with rosiglitazone on the reduced muscle vasopermeability observed previously in the fructose-fed rat model. Fructose-fed Sprague–Dawley rats were gavaged with rosiglitazone (10 μmol kg −1 per day; n=21) or the vehicle only ( n=19) for 3 consecutive weeks before assessing the extravasation of Evans Blue (EB) dye in vivo in distinct muscle groups. Relative to control group, rosiglitazone reduced mean arterial blood pressure ( Δ=−16.7%, P<0.001), plasma insulin ( Δ=−39.1%, P<0.05) and plasma triglyceride ( Δ=−32.8%, P<0.01) concentrations in a significant manner. Plasma VEGF concentrations were significantly lower in the rosiglitazone-treated animals compared to the control animals (32.7±0.8 pg ml −1 versus 46.1±1.2 pg ml −1, P<0.001). While no changes were observed in the lungs or the kidneys, fructose-fed rats treated with rosiglitazone had a 30–50% increase ( P<0.005) in the extravasation of EB regardless of the skeletal muscle group studied (rectus femoris, soleus, gastrocnemius lateralis, vastus lateralis and tibialis cranalis). In homogenates of skeletal muscles (vastus lateralis) of fructose-fed rats, rosiglitazone resulted in a significant increase in NO synthase (NOS) activity ( Δ=+41.9%, P<0.003) as well as endothelial NOS immunoreactive mass ( Δ=+37.8%, P<0.01) compared to the control animals. There was no change in the immunoreactive level of the nNOS isoform, the most abundant muscle isoform, or in the immunoreactive levels of VEGF. In conclusion, rosiglitazone appears to restore a vascular dysfunction previously documented in the skeletal muscle microcirculation, as evidenced by improved skeletal muscle vasopermeability and upregulation of the muscle endothelium-NO system in the fructose-fed rat model. These effects on muscle per se might also result in a partial improvement of the insulin resistance phenomenon by improving the distribution of nutrients and insulin to skeletal muscle. This effect appears to be independent of circulating levels of VEGF since changes in plasma concentrations of this permeability factor were lower in the rosiglitazone-treated group.