Neuropeptide Y bioavailability is suppressed in the hindlimb of female Sprague-Dawley rats

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 endogenous 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 Y2-receptor activation on neuropeptide Y release in hindlimb vasculature, an arterial infusion of BIIE0246 (specific non-peptide Y-2-receptor antagonist; 170 mu g 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.