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Phentolamine\u2010mediated vasodilation leads to faster clearance of injected drugs. Previous electrophysiological studies hypothesized that phentolamine acts as a modulator of voltage\u2010gated sodium channels, which could conflict with its indication as local anaesthetic reversal agent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We performed manual and high throughput patch\u2010clamp recordings on HEK and CHO cells expressing Na<jats:sub>V<\/jats:sub>1.7 and Na<jats:sub>V<\/jats:sub>1.5. We investigated the effects of phentolamine on sodium channel biophysics and the additive impact of phentolamine on cells preconditioned with the local anaesthetic mexiletine. We used site\u2010directed mutagenesis, homology modelling and drug docking to identify phentolamine's binding site. We compared the effect on sodium channels with other clinically established <jats:italic>\u03b1<\/jats:italic>\u2010adrenoreceptor antagonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Phentolamine inhibits Na<jats:sub>V<\/jats:sub>1.7 in HEK and CHO cells with an IC<jats:sub>50<\/jats:sub> value of 72 and 57\u2009\u03bcM and Na<jats:sub>V<\/jats:sub>1.5 in CHO cells with an IC<jats:sub>50<\/jats:sub> of 27\u2009\u03bcM. Phentolamine enhances the tonic block induced by the local anaesthetic mexiletine. Phentolamine binds to sodium channels at the local anaesthetic receptor site. The <jats:italic>\u03b1<\/jats:italic>\u2010adrenoreceptor antagonists alfuzosin, urapidil and phenoxybenzamine show lower potency on Na<jats:sub>V<\/jats:sub>1.5 and Na<jats:sub>V<\/jats:sub>1.7 in patch\u2010clamp recordings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Phentolamine blocks voltage\u2010gated sodium channels via the local anaesthetic receptor site. This may conflict with its current indication as an antidote for local anaesthetics. We propose alternative <jats:italic>\u03b1<\/jats:italic>\u2010adrenoreceptor antagonists as possible candidates for local anaesthetic reversal because these are less potent inhibitors of both cardiac and neuronal voltage\u2010gated sodium channels.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17450","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T04:20:07Z","timestamp":1738297207000},"page":"1879-1896","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>\u03b1<\/i>\u2010Adrenoreceptor blocker phentolamine inhibits voltage\u2010gated sodium channels via the local anaesthetic binding site"],"prefix":"10.1111","volume":"182","author":[{"given":"Idil","family":"Toklucu","sequence":"first","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Department of Neurology Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Sudha Bhagavath Eswaran","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Scientific Center for Neuropathic pain Aachen SCN<sup>AACHEN<\/sup> Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raya Atlanta","family":"Bott","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylin Bilge","family":"Kesdo\u011fan","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnim Johannes","family":"Gaebler","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Department of Psychiatry, Psychotherapy and Psychosomatics Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Stingl","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Hausmann","sequence":"additional","affiliation":[{"name":"Scientific Center for Neuropathic pain Aachen SCN<sup>AACHEN<\/sup> Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Institute of Clinical Pharmacology Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannis","family":"K\u00f6rner","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Scientific Center for Neuropathic pain Aachen SCN<sup>AACHEN<\/sup> Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Clinic of Anaesthesiology, Medical Faculty Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Department of Intensive and Intermediate Care Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Lampert","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiology Uniklinik RWTH Aachen University  Aachen Germany"},{"name":"Scientific Center for Neuropathic pain Aachen SCN<sup>AACHEN<\/sup> Uniklinik RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab294"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511492"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_13_6_1","first-page":"33","article-title":"A clinician guide to patients afraid of dental injections and numbness","volume":"27","author":"Armfield J. 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