{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:49:21Z","timestamp":1769550561521,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T00:00:00Z","timestamp":1547683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2019,3,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>When the human heart begins its earliest contractions from day 21, it lacks a functional autonomic nerve supply. Instead, contractions are generated by regular calcium transients later augmented by the funny current (<jats:italic>I<\/jats:italic><jats:sub>f<\/jats:sub>) produced by sinoatrial\u2010like cells. This study examined effects of blocking these currents in the early rat embryonic heart.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rat embryos were incubated in vitro with either the calcium channel blocker nifedipine and\/or the funny current (<jats:italic>I<\/jats:italic><jats:sub>f<\/jats:sub>) blocker ivabradine for 1\u2009hr to examine the effects of these drugs on the activity of the embryonic heart.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>On gestational day (GD) 10, nifedipine (0.45\u20131.8 \u03bcM) caused asystole at high concentrations (8\/10 embryos at 1.8 \u03bcM and 3\/10 embryos at 0.9 \u03bcM) and markedly increased embryonic heart rate (EHR) in all surviving embryos but likely reduced blood flow due to weak contractions. Ivabradine (1.5 \u03bcM) caused a 29% reduction in EHR in GD 10 embryos and a greater than 50% reduction in EHR for GD 11\u201314 embryos. Combined exposure to both nifedipine and ivabradine resulted in an additive effect. The increased EHR due to nifedipine was reduced by the ivabradine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results suggest that exposure to nifedipine in human pregnancy 3\u20134 weeks postfertilization may cause a direct effect on the embryonic heart resulting in reduced blood flow leading to abnormal heart and\/or blood vessel development and\/or embryonic death. Accidental exposure to ivabradine in the organogenic period would be expected to cause embryonic bradycardia, hypoxia, malformations, and embryonic death. This drug is currently contraindicated in pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.1457","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T18:21:07Z","timestamp":1547749267000},"page":"281-288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The effects of nifedipine and ivabradine on the functionality of the early rat embryonic heart. Are these drugs a risk in early human pregnancy?"],"prefix":"10.1002","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-5702","authenticated-orcid":false,"given":"Helen E.","family":"Ritchie","sequence":"first","affiliation":[{"name":"Discipline of Biomedical Sciences, Sydney School of Medical Science The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Telenius","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Histology, Sydney School of Medical Science The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elin","family":"Gustaffson","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Histology, Sydney School of Medical Science The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William S.","family":"Webster","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Histology, Sydney School of Medical Science The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,1,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.21003"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20270"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a138462"},{"key":"e_1_2_6_5_1","volume-title":"Goodman & Gilman's the pharmacological basis of therapeutics","author":"Brunton L.","year":"2006"},{"key":"e_1_2_6_6_1","volume-title":"Corlanor (ivabradine): Risk assessment and risk mitigation review","author":"Center for Drug Evaluation and Research","year":"2015"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420400510"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420400407"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420520503"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612013397744"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2018.08.018"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/01720610-201203000-00002"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2362040880"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.175.1.1750067"},{"key":"e_1_2_6_15_1","volume-title":"Procoralan, INN\u2010Ivabradine","author":"EMEA","year":"2005"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5273(85)90170-6"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.366955"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2012.06.008"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms16011429"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000056532.18710.C0"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2011.52.2.211"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-70715-8_3"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.27"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12576-010-0131-x"},{"issue":"318","key":"e_1_2_6_25_1","first-page":"1","article-title":"Mechanical regulation of cardiac development","volume":"5","author":"Lindsey S. 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