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However, their direct and quantitative measurement\n in vivo<\/jats:italic>\n remains challenging. We established a quantitative kinetic modelling framework to estimate and independently from dynamic radiotracer data in the heart using the Nernst equation applied to the kinetics of the lipophilic cationic tracers\n [99m<\/jats:sup>\n Tc]sestamibi and [\n 99m<\/jats:sup>\n Tc]tetrofosmin. Parameters were estimated from high\u2010temporal\u2010resolution time\u2013activity curves using non\u2010linear least squares and Markov chain Monte Carlo (MCMC) fitting. Experiments were performed in isolated Langendorff\u2010perfused rat hearts under baseline, hyperkalaemic depolarization and mitochondrial uncoupling with carbonylcyanide\u20103\u2010chlorophenylhydrazone (CCCP) and\n in vivo<\/jats:italic>\n using planar scintigraphy. In perfused hearts, baseline potentials were and (mean\u00a0\u00b1\u00a0SD,\n n<\/jats:italic>\n \u00a0=\u00a04). Increasing [K\n +<\/jats:sup>\n ] caused dose\u2010dependent depolarization of in agreement with Goldman\u2013Hodgkin\u2013Katz predictions, whereas remained stable. CCCP selectively depolarized to (300\u00a0n\n m<\/jats:sc>\n ) and (600\u00a0n\n m<\/jats:sc>\n ) with minimal effect on .\n In vivo<\/jats:italic>\n , potentials were and (\n n<\/jats:italic>\n \u00a0=\u00a04), consistent with physiological values. This modelling approach enables the first non\u2010invasive, independent quantitative estimation of sarcolemmal and mitochondrial membrane potentials\n in vivo<\/jats:italic>\n . It overcomes limitations of optical probes and, with high\u2010sensitivity single\u2010photon emission computed tomography and positron emission tomography (PET) systems (including total body PET), offers new opportunities to assess bioenergetic dysfunction in cardiovascular disease and beyond.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Pharmacokinetic modelling of [\n 99m<\/jats:sup>\n Tc]sestamibi and [\n 99m<\/jats:sup>\n Tc]tetrofosmin allowed independent estimation of sarcolemmal () and mitochondrial () membrane potentials\n ex vivo<\/jats:italic>\n in the Langendorff perfused rat heart and\n in vivo<\/jats:italic>\n in the rat heart.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The method gave independent measures of membrane potentials\n ex vivo<\/jats:italic>\n when depolarized with hyperkalaemic buffers or mitochondrial uncoupling.\n <\/jats:p>\n <\/jats:list-item>\n \n \n In vivo<\/jats:italic>\n measurements of membrane potentials agreed with literature values, whereas was found to be less polarized\n ex vivo<\/jats:italic>\n in the perfused heart.\n <\/jats:p>\n <\/jats:list-item>\n \n The method uses clinically available single\u2010photon emission computed tomography\u00a0imaging agents that could be employed to measure these parameters in humans.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290295","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:26:13Z","timestamp":1773663973000},"page":"2683-2697","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sarcolemmal and mitochondrial membrane potentials measured\n ex vivo<\/i>\n and\n in vivo<\/i>\n in the heart by pharmacokinetic modelling of [\n 99m<\/sup>\n Tc]sestamibi"],"prefix":"10.1113","volume":"604","author":[{"given":"Edward C. T.","family":"Waters","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute St Thomas\u2019 Hospital London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedrich","family":"Baark","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute St Thomas\u2019 Hospital London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R.","family":"Orton","sequence":"additional","affiliation":[{"name":"Department of Radiology, MRI Unit The Royal Marsden NHS Foundation Trust London UK"},{"name":"Division of Radiotherapy and Imaging The Institute of Cancer Research London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6242-7585","authenticated-orcid":false,"given":"Michael J.","family":"Shattock","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences King's College London London UK"},{"name":"King's College London BHF Centre of Research Excellence King's College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7904-8335","authenticated-orcid":false,"given":"Richard","family":"Southworth","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute St Thomas\u2019 Hospital London UK"},{"name":"King's College London BHF Centre of Research Excellence King's College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-3808","authenticated-orcid":false,"given":"Thomas R.","family":"Eykyn","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, The Rayne Institute St Thomas\u2019 Hospital London UK"},{"name":"King's College London BHF Centre of Research Excellence King's College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0190968"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.119.226498"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(84)90069-7"},{"issue":"4","key":"e_1_2_6_5_1","first-page":"681","article-title":"Myocardial perfusion imaging with Technetium\u201099m\u2010Sestamibi \u2013 Comparative\u2010analysis of available imaging protocols","volume":"35","author":"Berman D. 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