We recently reported that male, but not female, rats exhibit basal endogenous neuropeptide Y Y(1)-receptor modulation of hindlimb vasculature. The lack of baseline endo-genous Y(1)-receptor control in females was evident despite the expression of Y(1)-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 Y(2)-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 Y(2)-receptor expression in skeletal muscle compared to males (P < 0.05). To address the prevalence/impact of baseline endogenous Y(2)-receptor activation on neuropeptide Y release in hindlimb vasculature, an arterial infusion of BIIE0246 (specific non-peptide Y(2)-receptor antagonist; 170 microg kg(-1)) was carried out on female and male rats. Y(2)-receptor blockade resulted in a decrease in hindlimb vascular conductance in females and males (P < 0.05). However, the BIIE0246-induced decrease in vascular conductance was Y(1)-receptor dependent in females, but not males (P < 0.05). In addition, compared to baseline, BIIE0246 infusion resulted in increased plasma neuropeptide Y concentration in females (P < 0.05), while there was no observable change in males. In a final experiment, systemic inhibition of proteolytic enzymes dipeptidylpeptidase IV (via 500 nM diprotin A) and aminopeptidase P (via 180 nM 2-mercaptoethanol) elicited a Y(1)-receptor-dependent decrease in hindlimb vascular conductance in females (P < 0.05). It was concluded that our previously reported lack of basal endogenous Y(1)-receptor activation in female hindlimb vasculature was (at least partially) due to prejunctional Y(2)-receptor autoinhibition and proteolytic processing of neuropeptide Y.