{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:50:40Z","timestamp":1787017840673,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K17812"],"award-info":[{"award-number":["JP20K17812"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18K08856"],"award-info":[{"award-number":["JP18K08856"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>\n                    <jats:italic>Background<\/jats:italic>\n                    . We investigated the potential safety of remimazolam and propofol in malignant hyperthermia\u2010 (HM\u2010) susceptible patients using ryanodine receptor 1\u2010 (RYR1\u2010) expressing human embryonic kidney\u2010 (HEK\u2010) 293 cells.\n                    <jats:italic>Methods<\/jats:italic>\n                    . We compared the enhanced responsiveness of HEK\u2010293 cells expressing wild\u2010type\n                    <jats:italic>RYR1<\/jats:italic>\n                    with that of mutant\n                    <jats:italic>RYR1<\/jats:italic>\n                    to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC\n                    <jats:sub>50<\/jats:sub>\n                    ; i.e., the concentration required to reach half\u2010maximal activation) using an unpaired two\u2010tailed\n                    <jats:italic>t<\/jats:italic>\n                    \u2010test while a\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05 was considered significant.\n                    <jats:italic>Results<\/jats:italic>\n                    . Remimazolam and propofol did not promote the caffeine\u2010induced increase in intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels in HEK\u2010293 cells expressing mutant RYR1 even with exposure to approximately 100\u2010fold the clinically used concentration. In wild\u2010type RYR1, EC\n                    <jats:sub>50<\/jats:sub>\n                    values of remimazolam following refusion vs. nonperfusion were 2.86\u2009mM vs. 2.75\u2009mM (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76\u2009mM vs. 2.75\u2009mM, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.83). In mutant RYR1, EC\n                    <jats:sub>50<\/jats:sub>\n                    values of remimazolam refusion vs. nonperfusion were 1.58\u2009mM vs. 1.71\u2009mM, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65\u2009mM vs. 1.71\u2009mM, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.73). Remimazolam and propofol increased intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels in a concentration\u2010dependent manner, but the effect was not enhanced by RYR1. EC\n                    <jats:sub>50<\/jats:sub>\n                    values of remimazolam with non\u2010RYR1 vs. wild\u2010type RYR1 were 1.00\u2009mM vs. 0.92\u2009mM, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.91) while those of propofol were 1.09\u2009mM vs. 1.05\u2009mM, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.84).\n                    <jats:italic>Conclusions<\/jats:italic>\n                    . The increase in intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    concentration caused by remimazolam or propofol was not considered an RYR1\u2010mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH\u2010susceptible patients with\n                    <jats:italic>RYR1<\/jats:italic>\n                    \u2010mutation without causing MH and may be safely substituted for an MH\u2010triggering anesthetic when RYR1\u2010mediated MH occurs.\n                  <\/jats:p>","DOI":"10.1155\/2021\/8845129","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T15:00:49Z","timestamp":1610377249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Effects of Remimazolam and Propofol on Ca\n                    <sup>2+<\/sup>\n                    Regulation by Ryanodine Receptor 1 with Malignant Hyperthermia Mutation"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-0741","authenticated-orcid":false,"given":"Tomoyuki","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1375-5344","authenticated-orcid":false,"given":"Hirotsugu","family":"Miyoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-8299","authenticated-orcid":false,"given":"Yuko","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9838-078X","authenticated-orcid":false,"given":"Soshi","family":"Narasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-9437","authenticated-orcid":false,"given":"Atsushi","family":"Morio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-0415","authenticated-orcid":false,"given":"Yukari","family":"Toyota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2391-4783","authenticated-orcid":false,"given":"Hiroshi","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7255-852X","authenticated-orcid":false,"given":"Keiko","family":"Mukaida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7832-5516","authenticated-orcid":false,"given":"Toshimichi","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1997-082X","authenticated-orcid":false,"given":"Yasuo 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