{"doi":"10.1113/jp288412","title":"Functional sympatholysis of neuropeptide Y‐mediated vasoconstriction in humans","abstract":"Abstract 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 α 1 ‐adrenergic vasoconstriction. In 12 healthy adults (seven male, age: 30 ± 7 years, body mass index: 24.9 ± 3 kg/m 2 ) 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; α 1 ‐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 α 1 ‐adrenergic vasoconstriction. image 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 α 1 ‐adrenergic mediated vasoconstriction.","journal":"The Journal of Physiology","year":2025,"id":550665,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":918183,"name":"Sarah L. Hissen","orcid":"0000-0003-3181-6961","position":1,"is_corresponding":false},{"id":421827,"name":"James P. MacNamara","orcid":"0000-0003-2795-6021","position":2,"is_corresponding":false},{"id":826996,"name":"Scott L. Davis","orcid":"0000-0002-9290-7085","position":3,"is_corresponding":false},{"id":371953,"name":"Paul J. Fadel","orcid":"0000-0002-0115-0743","position":4,"is_corresponding":false},{"id":350885,"name":"Benjamin D. Levine","orcid":"0000-0001-9064-7251","position":5,"is_corresponding":false},{"id":369483,"name":"Christopher M. Hearon","orcid":"0000-0002-6561-3532","position":6,"is_corresponding":false},{"id":1234133,"name":"Denis J. Wakeham","orcid":"0000-0002-4200-3790","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:54:20.915388Z","pmid":"40448698","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}