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. Functional sympatholysis occurs primarily through post-junctional attenuation of norepinephrine and α-adrenergic-mediated vasoconstriction, though other non-adrenergic neurotransmitters are co-released with norepinephrine. Neuropeptide Y (NPY) is a neurotransmitter that elicits robust vasoconstriction and is co-released with norepinephrine during exercise in an intensity dependent manner. Evidence from animal models indicate that NPY is sensitive to metabolic inhibition, however metabolic inhibition of NPY-mediated vasoconstriction has not been tested in humans. We tested the hypothesis that NPY-mediated vasoconstriction would be attenuated during handgrip exercise in humans. In 10 healthy adults (7M:3F, age: 30±7 years, BMI: 24±5) we measured forearm blood flow (Doppler ultrasound), blood pressure (brachial artery catheter), 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) to serve as a non-metabolic vasodilatory control or 2) dynamic rhythmic handgrip exercise (EX; 15% maximal voluntary contraction). The vasoconstrictor responses to PE and NPY were quantified as a percent ΔFVC during each condition (SNP vs. EX) and were compared by two-way RM-ANOVA. The magnitude of sympatholysis (ΔFVC during exercise expressed as a percent of control) for PE and NPY was compared by a paired t-test. As expected, the vasoconstrictor response to PE was attenuated during handgrip exercise compared to SNP (ΔFVC: SNP: -50±24 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, NPY: 52±34 %; p=0.28). These data indicate that NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans, and the magnitude of sympatholysis is not different from α1-adrenergic vasoconstriction. Funding: NIH R00HL153777. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.