{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:03:31Z","timestamp":1789506211834,"version":"build-2803163510"},"reference-count":114,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12402350"],"award-info":[{"award-number":["12402350"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U20A20388"],"award-info":[{"award-number":["U20A20388"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["1262001"],"award-info":[{"award-number":["1262001"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005024","name":"Beijing Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2025\u2010ZZ\u201018"],"award-info":[{"award-number":["2025\u2010ZZ\u201018"]}],"id":[{"id":"10.13039\/501100005024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Coordinated excitation of uterine smooth muscle cells (USMCs) is the physiological basis of labour, and several mathematical models have been developed to understand the function of USMCs. However although the key role of oxytocin in parturition has been established, most existing USMC models still rely on external electrical stimulation to initiate action potentials rather than including oxytocin as a stimulus. This study developed a multiscale dynamic model. First a pregnancy physiologically based pharmacokinetic (PBPK) model was built to describe pulsatile oxytocin release, systemic transport and clearance. This PBPK model was coupled to a cell\u2010level model via local myometrial oxytocin exposure. This model explicitly captures oxytocin binding to and dissociation from the oxytocin receptor (OXTR), as well as downstream OXTR signalling. The cell\u2010level model incorporates excitation\u2013contraction coupling, enabling the simulation of USMC excitation and contractile responses without external electrical stimulation. The model aligns with published data across multiple key endpoints, including oxytocin pharmacokinetic parameters, maternal venous and umbilical arterial and umbilical venous concentrations, and the duration and amplitude of cellular excitation and contraction. The results also show that an increased oxytocin association rate constant  lowers the half\u2010maximal effective concentration (EC\n                      <jats:sub>50<\/jats:sub>\n                      ) and is a key determinant of USMC sensitivity to oxytocin. This model provides a quantitative framework to explain oxytocin's role in uterine excitability during pregnancy and to investigate pathological conditions such as preterm labour and uterine atony.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70820-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Oxytocin is a major physiological regulator of labour contractions, but most existing uterine smooth muscle cell models still require external electrical stimulation to trigger excitation, rather than recapitulating oxytocin\u2010induced myometrial activity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We developed a multiscale physiologically based pharmacokinetic\u2010pharmacodynamic (PBPK\u2010PD) model that links pulsatile endogenous oxytocin release, maternal\u2013fetal distribution, oxytocin receptor binding, IP\n                            <jats:sub>3<\/jats:sub>\n                            \u2010mediated Ca\n                            <jats:sup>2+<\/jats:sup>\n                            signalling and excitation\u2013contraction coupling in uterine smooth muscle cells.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The model reproduced published ranges for key pharmacokinetic and pharmacodynamic endpoints, including oxytocin half\u2010life and clearance, maternal and fetal oxytocin concentrations, intracellular Ca\n                            <jats:sup>2+<\/jats:sup>\n                            responses, membrane potential, contraction duration and active stress.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Simulations showed that the oxytocin association rate constant and oxytocin receptor abundance strongly influence the oxytocin dose\u2013response relationship, shifting EC50 and modulating uterine excitability.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This work provides a quantitative framework for studying how endogenous oxytocin can induce uterine excitation and contraction, and offers a basis for investigating abnormal uterine activity such as preterm labour and uterine atony.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp291462","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:05:04Z","timestamp":1789121104000},"page":"7663-7701","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A multiscale PBPK\u2010PD model of oxytocin\u2010induced uterine excitation and contraction"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4311-8243","authenticated-orcid":false,"given":"Yongxiu","family":"Yang","sequence":"first","affiliation":[{"name":"College of Chemistry and Life Science Beijing University of Technology, and Beijing International Science 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