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To study intercellular communication, the pharmacological agents carbenoxolone (CBX) and 18\u03b2\u2010glycyrrhetinic acid (18\u03b2GA) are used widely as connexin inhibitors and gap junction blockers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We investigated the effects of CBX and 18\u03b2GA on intercellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      waves, evoked by inositol 1,4,5\u2010trisphosphate (IP\n                      <jats:sub>3<\/jats:sub>\n                      ) in the endothelium of intact mesenteric resistance arteries.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Acetycholine\u2010evoked IP\n                      <jats:sub>3<\/jats:sub>\n                      \u2010mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release and propagated waves were inhibited by CBX (100 \u03bcM) and 18\u03b2GA (40 \u03bcM). Unexpectedly, the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signals were inhibited uniformly in all cells, suggesting that CBX and 18\u03b2GA reduced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release. Localised photolysis of caged IP\n                      <jats:sub>3<\/jats:sub>\n                      (cIP\n                      <jats:sub>3<\/jats:sub>\n                      ) was used to provide precise spatiotemporal control of site of cell activation. Local cIP\n                      <jats:sub>3<\/jats:sub>\n                      photolysis generated reproducible Ca\n                      <jats:sup>2+<\/jats:sup>\n                      increases and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      waves that propagated across cells distant to the photolysis site. CBX and 18\u03b2GA each blocked Ca\n                      <jats:sup>2+<\/jats:sup>\n                      waves in a time\u2010dependent manner by inhibiting the initiating IP\n                      <jats:sub>3<\/jats:sub>\n                      \u2010evoked Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010channel blockers. Furthermore, CBX and 18\u03b2GA each rapidly and reversibly collapsed the mitochondrial membrane potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      CBX and 18\u03b2GA inhibit IP\n                      <jats:sub>3<\/jats:sub>\n                      \u2010mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18\u03b2GA may block cell\u2013cell communication by acting at sites that are unrelated to gap junctions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15329","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T01:57:27Z","timestamp":1606960647000},"page":"896-912","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Carbenoxolone and 18\u03b2\u2010glycyrrhetinic acid inhibit inositol 1,4,5\u2010trisphosphate\u2010mediated endothelial cell calcium signalling and depolarise mitochondria"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7961-4544","authenticated-orcid":false,"given":"Charlotte","family":"Buckley","sequence":"first","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0790-4291","authenticated-orcid":false,"given":"Xun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2500-0632","authenticated-orcid":false,"given":"Calum","family":"Wilson","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-3984","authenticated-orcid":false,"given":"John G.","family":"McCarron","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,17]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14750"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14752"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14753"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14749"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1983.tb00038.x"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-111-5-1683"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211946109"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2010.02244.x"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2017.07.003"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01814.x"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.112.007351"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006432"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986710793348563"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004240100588"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000343358"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02947.x"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14905"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.4.631"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2011.08.003"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200604016"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"issue":"3","key":"e_1_2_12_23_1","first-page":"1104","article-title":"Glycyrrhetinic acid derivatives: A novel class of inhibitors of gap\u2010junctional intercellular communication. 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