Both arterial hypertension and insulin resistance have been documented in either Cladribine endothelial NO synthase null mice or mice with partial deletion of the eNOS gene when challenged with a nutritional stress such as high fat diet. In the clinical setting, polymorphic variants of the eNOS gene are associated with arterial hypertension and insulin resistance in various populations. In particular, in a recent paper from our group, we showed that the CC polymorphic variant of eNOS 2786 T/C polymorphism was associated with a significant increase in arterial blood pressure and impairment of glucose metabolism in a population of cardiomyopathic patients. These recent experimental and clinical evidences suggest that eNOS gene abnormalities, possibly interacting with HFD, may contribute to endothelial/vascular dysfunction as well as to deregulation of glucose metabolism. Whether eNOS genetic determinants and metabolic abnormalities might interact to affect coronary circulatory function has not been fully elucidated. In the present experimental study, deletion of eNOS gene, either partial or total, results in a significant impairment in coronary vasodilating capability. Genetically modified mice also show a peculiar abnormality of glucose homeostasis characterized by a normoglycemic/hyperinsulinemic state with partial preservation of peripheral insulin sensitivity. In the myocardium of these animals, the molecular pathways downstream the insulin receptor are altered leading to a shift of the ERK1-2/Akt balance towards a prevalent vasoconstrictive pattern. HFD, while causing overt diabetes and marked insulin resistance, does not independently affect coronary tone and the balance of cardiac molecular pathways downstream insulin receptor. A diagrammatic representation of proposed mechanisms of interaction between eNOS deficiency, metabolic stress and insulin- dependent signaling pathways in endothelial cells is shown in Figure 8.In the present study, HFD caused a somewhat expected overt Embelin diabetic state concomitantly with basal hyperinsulinemia, indicative of insufficient compensation of a quite relevant insulin resistance, but such metabolic alteration was neither associated per se with abnormal coronary vascular function nor induced synergistic changes at coronary level when used in eNOS-deficient animals.