Functional sympatholysis of neuropeptide Y-mediated vasoconstriction in humans

Metabolic inhibition of sympathetic vasoconstriction (functional sympatholysis) is essential for adequate perfusion of skeletal muscle during exercise. Neuropeptide Y (NPY) is a neurotransmitter that elicits potent vasoconstriction and is co-released with noradrenaline during sympathoexcitation. NPY is released from sympathetic nerves during exercise; however, no study has assessed whether NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans. We tested the hypothesis that post-junctional NPY-mediated vasoconstriction would be sensitive to metabolic inhibition during handgrip exercise to a similar degree as α₁-adrenergic vasoconstriction. In 12 healthy adults (seven male, age: 30 ± 7 years, body mass index: 24.9 ± 3 kg/m²) we measured forearm blood flow (Doppler ultrasound), blood pressure (brachial artery catheter) and heart rate, and calculated changes in forearm vascular conductance (FVC) to local intra-arterial infusions of phenylephrine (PE; α₁-agonist) or NPY (Y1R-agonist) during: (1) intra-arterial infusion of sodium nitroprusside (SNP; nitric oxide donor), a non-metabolic vasodilatory control, and (2) dynamic rhythmic handgrip exercise (EX; 15% maximal voluntary contraction). As expected, the vasoconstrictor response to PE was attenuated during handgrip exercise compared to SNP (ΔFVC: SNP: -44 ± 25% vs. EX: -17 ± 9%; P = 0.002). Similarly, NPY-mediated vasoconstriction was blunted during handgrip exercise compared to SNP (ΔFVC: SNP: -32 ± 22% vs. EX: -11 ± 7%; P = 0.029). There was no difference in the magnitude of sympatholysis between PE and NPY (PE: 68 ± 18 vs. NPY: 52 ± 34%; P = 0.28). NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans, and the magnitude of sympatholysis is not different from α₁-adrenergic vasoconstriction. KEY POINTS: Neuropeptide Y (NPY) is a neurotransmitter that is co-released from sympathetic nerve terminals and elicits potent vasoconstriction, particularly during periods of sympathoexcitation. NPY is released from sympathetic nerves during exercise, but it is currently unclear whether NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans (i.e. functional sympatholysis). For the first time we have shown that NPY-mediated vasoconstriction is sensitive to metabolic inhibition during exercise in healthy adults, and that the magnitude of inhibition is similar to the inhibition observed for α₁-adrenergic mediated vasoconstriction.