Many clinical studies have shown a possible relationship between hypertension and insulin resistance, since patients with type 2 diabetes are frequently associated with hypertension. Our previous in vivo study showed that chronic hyperinsulinemia and insulin resistance induced by drinking 15% fructose elicited abnormal neuronal regulation of vascular tone, which may partly contribute to the development of hypertension. Therefore, in this study, to clarify further mechanisms of malfunctioned neuronal regulation, we investigated the neurogenic vascular responses and perivascular innervation using isolated mesenteric vascular beds in fructose-drinking rats (FDR). Male Wistar rats received 15% fructose as drinking solution for 10 weeks, which resulted in significant increases in plasma levels of insulin, glucose-insulin index and systolic blood pressure, but not of blood glucose levels. In perfused mesenteric artery of FDR, adrenergic nerve-mediated vasoconstriction was enhanced without changing vasoconstriction induced by exogenously injected noradrenaline. The density of adrenergic neuropeptide Y- like immunoreactive (LI) innervating fibers in FDR mesenteric arteries was significantly increased, compared with control. Furthermore, serum noradrenaline levels in FDR were greater than in controls. In the FDR perfused mesenteric vascular bed precontracted with methoxamine, calcitonin gene-related peptide-containing nerve (CGRPergic nerve)-mediated vasodilation and the density of CGRPergic nerve innervation were significantly decreased, and the contents of CGRP in the dorsal root ganglia of FDR were smaller than those in control. These findings suggest that abnormal innervation of perivascular nerves resulted from hyperinsulinemia contributing to development of hypertension in FDR.