{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:17:26Z","timestamp":1792811846135,"version":"4.5.0"},"reference-count":27,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Na<jats:sub>V<\/jats:sub>1.7 plays a crucial role in inducing and conducting action potentials in pain\u2010transducing sensory nociceptor fibres, suggesting that Na<jats:sub>V<\/jats:sub>1.7 blockers could be effective non\u2010opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt\u2010PCR analysis revealed that 82% of sympathetic neurons isolated from guinea\u2010pig stellate ganglia expressed Na<jats:sub>V<\/jats:sub>1.7 mRNA, with Na<jats:sub>V<\/jats:sub>1.3 being the only other tetrodotoxin\u2010sensitive channel expressed in approximately 50% of neurons. We investigated the role of Na<jats:sub>V<\/jats:sub>1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective Na<jats:sub>V<\/jats:sub>1.7 inhibitors. Two highly selective Na<jats:sub>V<\/jats:sub>1.7 blockers, GNE8493 and PF\u00a005089771, significantly inhibited postganglionic compound action potentials by approximately 70% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), with residual activity being blocked by the Na<jats:sub>V<\/jats:sub>1.3 inhibitor, ICA\u00a0121431. Electrical field stimulation (EFS) induced rapid contractions in guinea\u2010pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the Na<jats:sub>V<\/jats:sub>1 blocker tetrodotoxin. Our results demonstrated that blocking Na<jats:sub>V<\/jats:sub>1.7 with GNE8493, PF\u00a005089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea\u2010pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting Na<jats:sub>V<\/jats:sub>1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16088-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>82% of sympathetic neurons isolated from the stellate ganglion predominantly express Na<jats:sub>V<\/jats:sub>1.7 mRNA.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Na<jats:sub>V<\/jats:sub>1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Na<jats:sub>V<\/jats:sub>1.7 blockade substantially inhibits sympathetic nerve\u2010mediated adrenergic contractions in human and guinea\u2010pig blood vessels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Pharmacologically blocking Na<jats:sub>V<\/jats:sub>1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of Na<jats:sub>V<\/jats:sub>1.7 mutations on autonomic nerve activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286538","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T15:56:00Z","timestamp":1715702160000},"page":"3505-3518","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of Na<sub>V<\/sub>1.7 in postganglionic sympathetic nerve function in human and guinea\u2010pig arteries"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8505-7887","authenticated-orcid":false,"given":"Joyce S.","family":"Kim","sequence":"first","affiliation":[{"name":"Johns Hopkins School of Medicine Division of Clinical Immunology  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Meeker","sequence":"additional","affiliation":[{"name":"Johns Hopkins School of Medicine Division of Clinical Immunology  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Ru","sequence":"additional","affiliation":[{"name":"Johns Hopkins School of Medicine Division of Clinical Immunology  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh","family":"Tran","sequence":"additional","affiliation":[{"name":"Johns Hopkins School of Medicine Division of Clinical Immunology  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1225-6844","authenticated-orcid":false,"given":"Tanja S.","family":"Zabka","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hackos","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-9029","authenticated-orcid":false,"given":"Bradley J.","family":"Undem","sequence":"additional","affiliation":[{"name":"Johns Hopkins School of Medicine Division of Clinical Immunology  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16178"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152405"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.224204"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05413"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2695-04.2004"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-060909-153234"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-070918-050144"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3404"},{"issue":"2","key":"e_1_2_5_10_1","first-page":"646","article-title":"Antigen\u2010induced enhancement of noncholinergic contractile responses to vagus nerve and electrical field stimulation in guinea pig isolated trachea","volume":"262","author":"Ellis J. 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