Since the publication of the data of the San Antonio Heart Study, the link between metabolic and cardiovascular disorders has been increasingly recognized, as well as the features these disorders have in common: insulin resistance and vascular endothelial dysfunction. Therefore, we are interested in the mechanisms underlying the impairment of endothelial function in insulin-resistant states. In particular, we have recently found that insulin stimulates the vascular activity of both ET-1 and NO in the normal human vasculature. It is therefore reasonable to speculate that the occurrence of insulin resistance and/or endothelial dysfunction may lead to an imbalance in this mechanism with a resulting increased vascular activity of ET-1.
A new class of insulin sensitizing agents, the thiazolidinediones, have been shown to possess, in addition to their numerous metabolic roles, positive effects on blood pressure and on vascular endothelial function, including decreased endothelin-1 production and reduced circulating levels of endothelial surface molecules. Based on these data, we plan to investigate the hypothesis that thiazolidinediones may improve both insulin resistance and endothelial dysfunction in essential hypertension and hypercholesterolemia. We hypothesize that treatment with rosiglitazone improves endothelium-dependent vascular relaxation in both conductance and resistance vessels, decreases vascular endothelin-1 activity and reduces plasma levels of leptin and of markers of endothelial activation.
