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However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) acts as EDHF and exerts neuroprotective effect via large\u2010conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (BK<jats:sub>Ca<\/jats:sub>\/K<jats:sub>Ca<\/jats:sub>1.1) channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The whole\u2010cell patch\u2010clamp technology was used to record the changes of BK<jats:sub>Ca<\/jats:sub> currents in rat neurons induced by EDHF. The cerebral ischaemia\/reperfusion model of mice and oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) model of neurons were used to explore the neuroprotection of EDHF by activating BK<jats:sub>Ca<\/jats:sub> channels in these neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Increases of BK<jats:sub>Ca<\/jats:sub> currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BK<jats:sub>Ca<\/jats:sub> channel inhibitor iberiotoxin or endothelial H<jats:sub>2<\/jats:sub>S synthase inhibitor propargylglycine. The H<jats:sub>2<\/jats:sub>S donor, NaHS\u2010induced BK<jats:sub>Ca<\/jats:sub> current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H<jats:sub>2<\/jats:sub>S acts as EDHF and activates the neuronal BK<jats:sub>Ca<\/jats:sub> channels. Besides, we found that the protective effect of endothelium\u2010derived H<jats:sub>2<\/jats:sub>S against mice cerebral ischaemia\/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BK<jats:sub>Ca<\/jats:sub> channel opener on OGD\/R\u2010induced neuron injury and the increment of intracellular Ca<jats:sup>2+<\/jats:sup> level could be inhibited by iberiotoxin but enhanced by co\u2010application with L\u2010type but not T\u2010type calcium channel inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Endothelium\u2010derived H<jats:sub>2<\/jats:sub>S acts as EDHF and exerts neuroprotective effects via activating the BK<jats:sub>Ca<\/jats:sub> channels and then inhibiting the T\u2010type calcium channels in hippocampal neurons.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15607","type":"journal-article","created":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T08:36:21Z","timestamp":1625301381000},"page":"4155-4175","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Endothelium\u2010derived hydrogen sulfide acts as a hyperpolarizing factor and exerts neuroprotective effects via activation of large\u2010conductance Ca<sup>2+<\/sup>\u2010activated K<sup>+<\/sup> channels"],"prefix":"10.1111","volume":"178","author":[{"given":"Ji\u2010Yue","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Yao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Ming","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Fei","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Si","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9131-9030","authenticated-orcid":false,"given":"Zhi\u2010Wu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.966"},{"issue":"1","key":"e_1_2_13_3_1","first-page":"S21","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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