We recently reported that male, but not female, rats exhibit basal endogenous neuropeptide Y Y1-receptor modulation of hindlimb vasculature. The lack of baseline endo-genous Y1-receptor control in females was evident despite the expression of Y1-receptors and neuropeptide Y in hindlimb skeletal muscle tissue. The following study addressed the hypothesis that neuropeptide Y bioavailability is blunted in female rats under baseline conditions. It was further hypothesized that enhanced prejunctional autoinhibitory neuropeptide Y Y2-receptor expression and/or proteolytic processing of released neuropeptide Y may persist in female rats. Using western blot analysis, it was observed that females had greater overall neuropeptide Y Y2-receptor expression in skeletal muscle compared to males ( P 2-receptor activation on neuropeptide Y release in hindlimb vasculature, an arterial infusion of BIIE0246 (specific non-peptide Y2-receptor antagonist; 170 μg kg−1) was carried out on female and male rats. Y2-receptor blockade resulted in a decrease in hindlimb vascular conductance in females and males ( P 1-receptor dependent in females, but not males ( P 1-receptor-dependent decrease in hindlimb vascular conductance in females ( P 1-receptor activation in female hindlimb vasculature was (at least partially) due to prejunctional Y2-receptor autoinhibition and proteolytic processing of neuropeptide Y.