Pre-Diabetes Augments Neuropeptide Y1- and α1-Receptor Control of Basal Hindlimb Vascular Tone in Young ZDF Rats

BACKGROUND Peripheral vascular disease in pre-diabetes may involve altered sympathetically-mediated vascular control. Thus, we investigated if pre-diabetes modifies baseline sympathetic Y(1)-receptor (Y(1)R) and α(1)-receptor (α(1)R) control of hindlimb blood flow (Q(fem)) and vascular conductance (VC). METHODS Q(fem) and VC were measured in pre-diabetic ZDF rats (PD) and lean controls (CTRL) under infusion of BIBP3226 (Y(1)R antagonist), prazosin (α(1)R antagonist) and BIBP3226+prazosin. Neuropeptide Y (NPY) concentration and Y(1)R and α(1)R expression were determined from hindlimb skeletal muscle samples. RESULTS Baseline Q(fem) and VC were similar between groups. Independent infusions of BIBP3226 and prazosin led to increases in Q(fem) and VC in CTRL and PD, where responses were greater in PD (p<0.05). The percent change in VC following both drugs was also greater in PD compared to CTRL (p<0.05). As well, Q(fem) and VC responses to combined blockade (BIBP3226+prazosin) were greater in PD compared to CTRL (p<0.05). Interestingly, an absence of synergistic effects was observed within groups, as the sum of the VC responses to independent drug infusions was similar to responses following combined blockade. Finally, white and red vastus skeletal muscle NPY concentration, Y(1)R expression and α(1)R expression were greater in PD compared to CTRL. CONCLUSIONS For the first time, we report heightened baseline Y(1)R and α(1)R sympathetic control of Q(fem) and VC in pre-diabetic ZDF rats. In support, our data suggest that augmented sympathetic ligand and receptor expression in pre-diabetes may contribute to vascular dysregulation.