Abstract
BackgroundPeripheral vascular disease in pre-diabetes may involve altered sympathetically-mediated vascular control. Thus, we investigated if pre-diabetes modifies baseline sympathetic Y1-receptor (Y1R) and α1-receptor (α1R) control of hindlimb blood flow (Qfem) and vascular conductance (VC).MethodsQfem and VC were measured in pre-diabetic ZDF rats (PD) and lean controls (CTRL) under infusion of BIBP3226 (Y1R antagonist), prazosin (α1R antagonist) and BIBP3226+prazosin. Neuropeptide Y (NPY) concentration and Y1R and α1R expression were determined from hindlimb skeletal muscle samples.ResultsBaseline Qfem and VC were similar between groups. Independent infusions of BIBP3226 and prazosin led to increases in Qfem 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, Qfem 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, Y1R expression and α1R expression were greater in PD compared to CTRL.ConclusionsFor the first time, we report heightened baseline Y1R and α1R sympathetic control of Qfem 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.
Highlights
In the peripheral vasculature, sympathetic neurons regulate arteriolar tone through the release of norepinephrine (NE) and neuropeptide Y (NPY)
Baseline Body mass, blood glucose, insulin, lactate, mean end tidal CO2 and respiratory rate were significantly greater in pre-diabetic ZDF rats (PD) versus CTRL (p,0.001, Table 1), expired O2 and blood pH were similar between groups (Table 1)
Both groups displayed similar mean arterial pressure (MAP) (85–95 mmHg), Heart rate (HR) was greater in PD versus CTRL (p,0.025, Table 2)
Summary
Sympathetic neurons regulate arteriolar tone through the release of norepinephrine (NE) and neuropeptide Y (NPY). Recent evidence has shown that NPY contributes modestly to baseline vascular tone in skeletal muscle of male rats [5], its effects are suggested to predominate under conditions of elevated sympathetic nerve activity [6,7,8]. A large proportion of the body’s resistance vasculature lies within skeletal muscle, which is highly regulated by sympathetic nerve activity (SNA) to maintain blood pressure and blood flow distribution under healthy conditions. In type 2 diabetes, sympathetic regulation of vascular tone can become augmented, leading to alterations in normal blood flow control. NPY-mediated vascular modulation becomes more pronounced under conditions of elevated SNA [6,7,8]; to date, studies addressing NPY/Y1Rmediated vascular control in pre-diabetes are lacking. We investigated if pre-diabetes modifies baseline sympathetic Y1-receptor (Y1R) and a1-receptor (a1R) control of hindlimb blood flow (Qfem) and vascular conductance (VC)
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