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 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 μg 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 n m diprotin A) and aminopeptidase P (via 180 n m 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.