{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T12:51:31Z","timestamp":1777294291942,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho\u2010vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and\/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho\u2010vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under \u03b2\u2010adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide\u2010induced ventricular arrhythmias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15905","type":"journal-article","created":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T05:30:12Z","timestamp":1656135012000},"page":"4549-4562","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Contribution of haemodynamic side effects and associated autonomic reflexes to ventricular arrhythmias triggering by torsadogenic hERG blocking drugs"],"prefix":"10.1111","volume":"179","author":[{"given":"Pascal","family":"Champ\u00e9roux","sequence":"first","affiliation":[{"name":"ERBC France, Chemin de Montifault  Baugy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raafat","family":"Fares","sequence":"additional","affiliation":[{"name":"ERBC France, Chemin de Montifault  Baugy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thierry","family":"Bastogne","sequence":"additional","affiliation":[{"name":"CRAN CNRS UMR 7039 Universit\u00e9 de Lorraine  Vand\u0153uvre\u2010l\u00e8s\u2010Nancy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serge","family":"Richard","sequence":"additional","affiliation":[{"name":"ERBC France, Chemin de Montifault  Baugy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean\u2010Yves","family":"Le Guennec","sequence":"additional","affiliation":[{"name":"Laboratoire PHYMEDEXP Universit\u00e9 de Montpellier, INSERM 1046, CNRS UMR 9214  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1641-5142","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Thireau","sequence":"additional","affiliation":[{"name":"Laboratoire PHYMEDEXP Universit\u00e9 de Montpellier, INSERM 1046, CNRS UMR 9214  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/27.5.861"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15537"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-199411010-00003"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2012.01.009"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14354"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13391"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2010.02.006"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13093"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.1993.tb01235.x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.04.008"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/advan.00027.2016"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100076"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eur311"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.07.038"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(86)90793-4"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.11.022"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2013.05.004"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2006.05.007"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.11.042"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003723"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.09.011"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep02100"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707297"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.84.3.1136"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/49.3.211"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.08.014"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14101"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv316"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0008-6363(02)00846-5"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270526"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.103.1.89"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-0736(99)90077-8"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(93)90876-J"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199009000-00008"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2019.01.098"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000145162.64183.C8"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.83.6.661"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000068344.54010.B3"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.000661"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15905","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.15905","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15905","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T05:39:25Z","timestamp":1692769165000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.15905"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,13]]},"references-count":43,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1111\/bph.15905"],"URL":"https:\/\/doi.org\/10.1111\/bph.15905","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,13]]},"assertion":[{"value":"2021-11-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}