Decreased perivascular CGRP-containing nerves in Otsuka Long-Evans Tokushima Fatty rats with insulin resistance and hypertension.

We previously reported that chronic hyperinsulinemia induced by drinking fructose elicited an abnormal neuronal regulation of vascular tone, which contributed to the development of hypertension. This study was designed to elucidate the possible mechanisms underlying the dysfunctional neuronal regulation of vascular tone induced by chronic hyperinsulinemia by comparing isolated mesenteric vascular beds from Otsuka Long-Evans Tokushima Fatty (OLETF) rats with those of control Long-Evans Tokushima Otsuka rat (LETO) rats. Insulin, triglyceride and total cholesterol levels in plasma, blood glucose concentrations, a glucose-insulin index, systolic blood pressure and perivascular innervations were assessed using biochemical and immunohistochemical methods. Mesenteric vascular beds isolated from OLETF and LETO rats were perfused with a Krebs solution containing methoxamine, and changes in perfusion pressure in response to periarterial nerve stimulation (PNS) and the perfusion of vasoactive agents were measured. OLETF rats (8-25 weeks old) showed age-related increases in insulin, triglycerides, total cholesterol, blood glucose, the glucose-insulin index (homeostasis model assessment ratio (HOMA-IR)) and systolic blood pressure compared with LETO rats. In perfused mesenteric vascular beds, the PNS-induced adrenergic nerve-mediated vasoconstrictor responses in OLETF rats were significantly greater than those in LETO rats, whereas the PNS-induced calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator responses in OLETF rats were significantly smaller than those in LETO rats. In immunohistochemical experiments, the density of CGRP-immunopositive nerves in the mesenteric arteries of OLETF rats decreased significantly with age. The present findings suggest that the abnormal innervation of perivascular nerves in mesenteric resistance arteries induced by chronic hyperinsulinemia disturbs the neuronal regulation of vascular tone and may cause hypertension in OLETF rats.