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We examined whether diltiazem N\u2010oxide (DNO) has ischaemia\u2010selective antiarrhythmic activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Randomised and blinded experiments were performed in rat isolated hearts and in anaesthetised rats to determine antiarrhythmic effectiveness, adverse drug reaction (ADR) profile and mechanism of action of DNO, using diltiazem as a positive control. The ratio of the lowest concentration with antiarrhythmic activity to the highest concentration without ADRs was defined as the translational therapeutic index (TTI).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      In Langendorff\u2010perfused hearts, diltiazem (100 nM\u20136 \u00b5M) and DNO (1 \u00b5M\u20136 \u00b5M) reduced ischaemia\u2010induced VF occurrence. Diltiazem caused vasodilation (\u2265100 nM), atrioventricular (AV) block (\u22653 \u00b5M), and negative inotropy (\u22653 \u00b5M) with a TTI \u2264 1 while DNO had no adverse effects (TTI &gt; 6). Ultra\u2010high performance liquid chromatography with tandem mass spectrometry analysis of hearts perfused with 1\u2010\u03bcM DNO detected almost complete conversion of DNO to diltiazem in ischaemia, but not in normoxia.\n                      <jats:sup>31<\/jats:sup>\n                      P nuclear magnetic resonance spectroscopy (NMR) revealed ischaemia\u2010induced intracellular acidosis, decreased\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010ATP and phosphocreatine, all unaffected by either 1\u2010\u03bcM diltiazem or 1\u2010\u03bcM DNO. Diltiazem (2\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u2009+\u20090.2\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u00b7min\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) and DNO (6.5\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u2009+\u20090.65\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u00b7min\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) prevented ischaemia\u2010induced VF in anaesthetised rats, with diltiazem causing AV block and bradycardia and DNO causing no ADRs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>DNO was converted to diltiazem selectively in ischaemic cardiac tissue where it mimicked diltiazem's effect on VF, but without its associated ADRs. Neither drug affected cardiac energetics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70463","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:58:57Z","timestamp":1777870737000},"page":"4646-4662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diltiazem N\u2010oxide, a novel ischaemia\u2010activated prodrug, prevents ischaemia\u2010induced ventricular fibrillation without off\u2010target adverse effects"],"prefix":"10.1111","volume":"183","author":[{"given":"Louise M.","family":"Hesketh","sequence":"first","affiliation":[{"name":"King's College London, Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute St Thomas' Hospital  London UK"},{"name":"British Heart Foundation, Centre of Research Excellence King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel A.","family":"Watson","sequence":"additional","affiliation":[{"name":"King's College London, Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute St Thomas' Hospital  London UK"},{"name":"British Heart Foundation, Centre of Research Excellence King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mazzacuva","sequence":"additional","affiliation":[{"name":"School of Health, Sport and Bioscience University of East London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Hoare","sequence":"additional","affiliation":[{"name":"King's College London, Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute St Thomas' Hospital  London UK"},{"name":"British Heart Foundation, Centre of Research Excellence King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Eykyn","sequence":"additional","affiliation":[{"name":"British Heart Foundation, Centre of Research Excellence King's College London  London UK"},{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute St. Thomas' Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1801-4502","authenticated-orcid":false,"given":"Michael J.","family":"Curtis","sequence":"additional","affiliation":[{"name":"King's College London, Cardiovascular Division, Faculty of Life Sciences and Medicine, The Rayne Institute St Thomas' Hospital  London UK"},{"name":"British Heart Foundation, Centre of Research Excellence King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16178"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.60.2.153"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12252"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00173211"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(72)90114-2"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198908103210629"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(24)13071-4"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1987.253.2.H412"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118495148.ch23"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.50.4.518"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00830a121"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.59.2.227"},{"key":"e_1_2_12_14_1","article-title":"Extracellular phosphate and arrhythmogenesis","volume":"102","author":"Curtis M. 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