{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:56:56Z","timestamp":1793239016732,"version":"4.5.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000325","name":"Wellbeing of Women","doi-asserted-by":"publisher","award":["ELS083"],"award-info":[{"award-number":["ELS083"]}],"id":[{"id":"10.13039\/501100000325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N020685\/1"],"award-info":[{"award-number":["MR\/N020685\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/18\/7\/33535"],"award-info":[{"award-number":["PG\/18\/7\/33535"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000682","name":"Royal College of Obstetricians and Gynaecologists","doi-asserted-by":"publisher","award":["MR\/N020685\/1"],"award-info":[{"award-number":["MR\/N020685\/1"]}],"id":[{"id":"10.13039\/501100000682","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,5,28]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale:<\/jats:title>\n                    <jats:p>Activation of the kynurenine pathway of tryptophan catabolism by infection and inflammation contributes to the development of systemic hypotension. Commercially-available kynurenine has direct vasorelaxant effects on arteries from several species and reduces systemic blood pressure when administered to normotensive or hypertensive rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>To determine whether kynurenine promotes relaxation of human resistance arteries from normotensive and hypertensive pregnant women and to identify the vascular mechanism of its effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      In isolated omental and myometrial resistance arteries from normotensive pregnant women, kynurenine (1 mmol\/L) significantly reduced U46619-induced constriction (omentum N=14,\n                      <jats:italic>P<\/jats:italic>\n                      =2.4\u00d710\n                      <jats:sup>\u22123<\/jats:sup>\n                      ; myometrium N=21\u201325,\n                      <jats:italic>P<\/jats:italic>\n                      =2.6\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) and relaxed preconstricted arteries (N=53,\n                      <jats:italic>P<\/jats:italic>\n                      =1.0\u00d710\n                      <jats:sup>\u221211<\/jats:sup>\n                      ; N=20,\n                      <jats:italic>P<\/jats:italic>\n                      =8.8\u00d710\n                      <jats:sup>\u22123<\/jats:sup>\n                      ). Vasorelaxation persisted following endothelium removal (N=7,\n                      <jats:italic>P<\/jats:italic>\n                      =1.6\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) but was completely prevented by inhibition of large-conductance Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -activated K\n                      <jats:sup>+<\/jats:sup>\n                      channels (BK\n                      <jats:sub>Ca<\/jats:sub>\n                      ) channels with iberiotoxin (N=9,\n                      <jats:italic>P<\/jats:italic>\n                      =5.7\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) or paxilline (N=10,\n                      <jats:italic>P<\/jats:italic>\n                      =2.1\u00d710\n                      <jats:sup>\u221217<\/jats:sup>\n                      ). Accordingly, in isolated vascular smooth muscle cells from omental arteries, kynurenine increased the BK\n                      <jats:sub>Ca<\/jats:sub>\n                      current (n=5\u20138,\n                      <jats:italic>P<\/jats:italic>\n                      =0.022) and the amplitude of spontaneous transient outward currents (n=6,\n                      <jats:italic>P<\/jats:italic>\n                      =0.031) but did not affect spontaneous transient outward current frequency. Kynurenine also increased Ca\n                      <jats:sup>2+<\/jats:sup>\n                      spark frequency of pressurized omental arteries (n=8,\n                      <jats:italic>P<\/jats:italic>\n                      =0.031). Vasorelaxant effects of kynurenine persisted following inhibition of ryanodine receptors (N=7,\n                      <jats:italic>P<\/jats:italic>\n                      =0.48) but were moderately reduced by inhibition of adenylate cyclase (N=9,\n                      <jats:italic>P<\/jats:italic>\n                      =0.024). In arteries from women with preeclampsia, kynurenine similarly attenuated vasoconstriction (N=15,\n                      <jats:italic>P<\/jats:italic>\n                      =1.3\u00d710\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) and induced BK\n                      <jats:sub>Ca<\/jats:sub>\n                      -mediated vasodilation (N=16,\n                      <jats:italic>P<\/jats:italic>\n                      =2.0\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). Vasorelaxation in response to kynurenine and a specific BK\n                      <jats:sub>Ca<\/jats:sub>\n                      activator, NS11021, was absent in fetal-derived placental resistance arteries in normal pregnancy and preeclampsia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Kynurenine dilates systemic arteries from multiple territories via BK\n                      <jats:sub>Ca<\/jats:sub>\n                      activation. Notably, the vasorelaxatory capacity of kynurenine is preserved in preeclampsia, suggesting this approach may have translational potential for the treatment of hypertension in pregnancy. The data warrant further investigation of the potential to exploit this endogenous vasorelaxant as a new treatment for hypertensive pathologies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.317612","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T09:19:33Z","timestamp":1614763173000},"page":"1679-1693","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["Kynurenine Relaxes Arteries of Normotensive Women and Those With Preeclampsia"],"prefix":"10.1161","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4099-6717","authenticated-orcid":true,"given":"Stephanie A.","family":"Worton","sequence":"first","affiliation":[{"name":"Maternal &amp; Fetal Health Research Centre, Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (S.A.W., S.L.G., A.E.P.H., M.W., J.E.M.)."},{"name":"Manchester University Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom (S.A.W., A.E.P.H., A.G., J.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-0909","authenticated-orcid":true,"given":"Harry A.T.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (H.A.T.P., M.A., A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2867-4368","authenticated-orcid":true,"given":"Susan L.","family":"Greenwood","sequence":"additional","affiliation":[{"name":"Maternal &amp; Fetal Health Research Centre, Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (S.A.W., S.L.G., A.E.P.H., M.W., J.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Alakrawi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (H.A.T.P., M.A., A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E.P.","family":"Heazell","sequence":"additional","affiliation":[{"name":"Maternal &amp; Fetal Health Research Centre, Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (S.A.W., S.L.G., A.E.P.H., M.W., J.E.M.)."},{"name":"Manchester University Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom (S.A.W., A.E.P.H., A.G., J.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wareing","sequence":"additional","affiliation":[{"name":"Maternal &amp; Fetal Health Research Centre, Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (S.A.W., S.L.G., A.E.P.H., M.W., J.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Greenstein","sequence":"additional","affiliation":[{"name":"Manchester University Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom (S.A.W., A.E.P.H., A.G., J.E.M.)."},{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (H.A.T.P., M.A., A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0913-2096","authenticated-orcid":true,"given":"Jenny E.","family":"Myers","sequence":"additional","affiliation":[{"name":"Maternal &amp; Fetal Health Research Centre, Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (S.A.W., S.L.G., A.E.P.H., M.W., J.E.M.)."},{"name":"Manchester University Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom (S.A.W., A.E.P.H., A.G., J.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2092"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1179\/135100000101535357"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01149.x"},{"key":"e_1_3_5_5_2","first-page":"15","article-title":"Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma.","volume":"23","author":"Pellegrin K","year":"2005","unstructured":"Pellegrin, K, Neurauter, G, Wirleitner, B, Fleming, AW, Peterson, VM, Fuchs, D. Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma. Shock. 2005;23:15\u201315.","journal-title":"Shock"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803104"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0947-3"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00517.2016"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00384.2011"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphs.2015.07.042"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1139\/y11-120"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31822827f2"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00373.2011"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.156"},{"key":"e_1_3_5_15_2","unstructured":"Aahman E Abou-Zahr C Amoako Johnson F et al. Make every mother and child count. World Health Organization. 2005. Accessed June 2020. https:\/\/www.who.int\/whr\/2005\/en\/"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2006.01.008"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2008.01.007"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5236.633"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2017.11.004"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2019.04.007"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(96)00137-2"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00144a011"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000631"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2007.00484.x"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1159\/000481168"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.3945\/jn.112.173823"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.3177\/jnsv.60.255"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.33.2.269"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2504-2"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2506"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2017.08.027"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbw221"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14026"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903670"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.179952"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.279.6.C1751"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00040.2006"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00389"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2012.11.001"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(96)70046-7"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2002.0825"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.120.317612","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:09:50Z","timestamp":1715562590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.120.317612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":40,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,5,28]]}},"alternative-id":["10.1161\/CIRCRESAHA.120.317612"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.120.317612","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]},"assertion":[{"value":"2020-07-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}