In previous studies performed in partially eNOS-deficient mice subjected to HFD, the two conditions were additive in causing an increase in systemic vascular Cyproheptadine HCl resistance and hypertension. It is conceivable that different vascular districts may have different behaviors. Moreover, while systemic resistance is measured in vivo, coronary resistance can be only measured exvivo, in the absence of the in vivo circulating milieu, which in turn may differently affect vascular function. In genetic or chemically-induced animal Bromhexine HCl models of diabetes with marked hypoinsulinemia, we have previously shown the occurrence of increased coronary resistance ex-vivo, associated with decreased cardiac expression of eNOS,,. In the same models, pharmacological treatments able to restore the eNOS expression were also able to reduce coronary resistance, leading to improvement of cardiac function,. Differences in the animal models employed may account for the apparent difference between previous and present results. In particular, in the genetic model of db/db mice, diabetes and obesity are the result of a deficit in the leptin receptor, while the beta-cytotoxic agent streptozotocin causes a severe hyperglycemic/hypoinsulinemic state. In the present experiments, diabetes associated with insulin resistance and partially compensatory hyperinsulinemia was induced by HFD; however, HFD per se was unable to interfere with coronary resistance. The exact mechanism by which eNOS gene deficiencies lead to increased circulating insulin awaits further investigations, although several authors suggest that the increased peripheral vascular resistance and the consequent reduction of blood flow might reduce glucose uptake by skeletal muscle, thereby favouring a trend to increased blood glucose levels which on turn stimulate insulin secretion,,. This is also interpreted as a compensatory mechanism that in physiological/healthy conditions aids to maintain vascular homeostasis, by means of the vasodilating effects of insulin, during temporary stresses.Insulin binding to its receptor triggers a phosphorylation cascade that on the one hand activates eNOS through PI3K/ Akt pathway and on the other hand activates the pro-atherogenic MAPK/ERK1-2 pathway which is associated with mitogenesis, cell growth and the production of ET-1.