{"doi":"10.1038/sj.bjp.0707297","title":"Combined pharmacological block of <i>I</i><sub>Kr</sub> and <i>I</i><sub>Ks</sub> increases short‐term QT interval variability and provokes torsades de pointes","abstract":"<jats:sec><jats:title>Background and purpose:</jats:title><jats:p>Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug‐induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short‐term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> and <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP.</jats:p></jats:sec><jats:sec><jats:title>Experimental approach:</jats:title><jats:p>ECGs were recorded from conscious dogs and from anaesthetized rabbits given the <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> blocker dofetilide (DOF), the <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> blocker HMR‐1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short‐term variability of RR and QT intervals calculated.</jats:p></jats:sec><jats:sec><jats:title>Key results:</jats:title><jats:p>DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and implications:</jats:title><jats:p>STV(QT) was markedly increased by combined pharmacological block of <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> and <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2007) <jats:bold>151</jats:bold>, 941–951; doi:<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038/sj.bjp.0707297\">10.1038/sj.bjp.0707297</jats:ext-link></jats:p></jats:sec>","journal":"British Journal of Pharmacology","year":2007,"id":615174,"datarank":0.7091081728068512,"base_score":4.727387818712341,"endowment":4.727387818712341,"self_citation_contribution":0.7091081728068512,"citation_network_contribution":0.0,"self_endowment_contribution":0.7091081728068512,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":112,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1585453,"name":"A Varró","orcid":null,"position":1,"is_corresponding":false},{"id":1585454,"name":"K Tábori","orcid":null,"position":2,"is_corresponding":false},{"id":1585455,"name":"J G Papp","orcid":null,"position":3,"is_corresponding":false},{"id":1585456,"name":"I Baczkó","orcid":null,"position":4,"is_corresponding":false},{"id":1585452,"name":"C Lengyel","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Combined pharmacological block of <i>I</i><sub>Kr</sub> and <i>I</i><sub>Ks</sub> increases short‐term QT interval variability and provokes torsades de pointes","abstract":"<jats:sec><jats:title>Background and purpose:</jats:title><jats:p>Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug‐induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short‐term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> and <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP.</jats:p></jats:sec><jats:sec><jats:title>Experimental approach:</jats:title><jats:p>ECGs were recorded from conscious dogs and from anaesthetized rabbits given the <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> blocker dofetilide (DOF), the <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> blocker HMR‐1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short‐term variability of RR and QT intervals calculated.</jats:p></jats:sec><jats:sec><jats:title>Key results:</jats:title><jats:p>DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and implications:</jats:title><jats:p>STV(QT) was markedly increased by combined pharmacological block of <jats:italic>I</jats:italic><jats:sub>Kr</jats:sub> and <jats:italic>I</jats:italic><jats:sub>Ks</jats:sub> and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2007) <jats:bold>151</jats:bold>, 941–951; doi:<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038/sj.bjp.0707297\">10.1038/sj.bjp.0707297</jats:ext-link></jats:p></jats:sec>","is_dataset_classified":null,"base_score":4.727387818712341,"endowment":4.727387818712341,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"17533421","pmcid":"PMC2042930","openalex_id":"https://openalex.org/W1530248218","authors":[],"funders":[],"total_grants":0,"fwci":4.1682,"citation_percentile":0.94489332,"influential_citations":0,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":6},{"year":2014,"count":3},{"year":2015,"count":10},{"year":2016,"count":4},{"year":2017,"count":12},{"year":2018,"count":8},{"year":2019,"count":4},{"year":2020,"count":9},{"year":2021,"count":7},{"year":2022,"count":6},{"year":2023,"count":2},{"year":2024,"count":4},{"year":2026,"count":2}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1038/sj.bjp.0707297","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1038/sj.bjp.0707297","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1038%2Fsj.bjp.0707297","host_type":"publisher"},{"url":"https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0707297","host_type":"publisher"},{"url":"https://doi.org/10.1038/sj.bjp.0707297","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17533421","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2042930","host_type":"repository"}],"fields_of_study":["Cardiac electrophysiology and arrhythmias","ECG Monitoring and Analysis","Atrial Fibrillation Management and Outcomes","Animals","Blood Pressure","Chromans","Delayed Rectifier Potassium Channels","Dogs","Dose-Response Relationship, Drug","Drug Synergism","Electrocardiography","Female","Heart Conduction System","Heart Rate","Infusions, Intravenous","Long QT Syndrome","Male","Phenethylamines","Potassium","Potassium Channel Blockers","Potassium Channels, Voltage-Gated","Rabbits","Sodium","Species Specificity","Sulfonamides","Torsades de Pointes"],"mesh_terms":["Animals","Blood Pressure","Chromans","Dogs","Dose-Response Relationship, Drug","Drug Synergism","Electrocardiography","Female","Heart Conduction System","Heart Rate","Infusions, Intravenous","Long QT Syndrome","Male","Phenethylamines","Potassium","Rabbits","Sodium","Species Specificity","Sulfonamides","Torsades de Pointes","Potassium Channels, Voltage-Gated","Potassium Channel Blockers","Delayed Rectifier Potassium Channels"],"keywords":["QT interval","Torsades de pointes","Dofetilide","Prolongation","Medicine","Cardiology","Internal medicine","Electrocardiography","Long QT syndrome","Afterdepolarization","Anesthesia","Repolarization","Electrophysiology"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T19:14:00.105924Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}