Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors
Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Journal of Pharmacological Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861322000603 |
| _version_ | 1811274551750819840 |
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| author | Koki Chiba Ryuichi Kambayashi Mayu Onozato Ai Goto Hiroko Izumi-Nakaseko Yoshinori Takei Akio Matsumoto Koichiro Tanaka Yasunari Kanda Takeshi Fukushima Atsushi Sugiyama |
| author_facet | Koki Chiba Ryuichi Kambayashi Mayu Onozato Ai Goto Hiroko Izumi-Nakaseko Yoshinori Takei Akio Matsumoto Koichiro Tanaka Yasunari Kanda Takeshi Fukushima Atsushi Sugiyama |
| author_sort | Koki Chiba |
| collection | DOAJ |
| description | Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4). Effects of imatinib on each phase of isovolumetric contraction, ejection, isovolumetric relaxation and filling were studied, whereas its electrophysiological effects on early and late repolarization were analyzed by measuring J-Tpeak and Tpeak-Tend, respectively. The low and high doses of imatinib provided peak plasma concentrations of 3.23 and 17.39 μg/mL, reflecting clinically-relevant and supratherapeutic concentrations, respectively. Neither lethal ventricular tachyarrhythmia nor cardiohemodynamic collapse was observed. Imatinib decreased amplitude of peak −dP/dt, indicating suppression of isovolumetric relaxation, whereas no significant change was detected in the other phases. Imatinib prolonged QTc and J-Tpeakc without altering Tpeak-Tend, indicating increase of net inward current, which leads to intracellular Ca2+ overload. Thus, imatinib suppressed ventricular active relaxation and early repolarization, which may suggest the association of mitochondrial dysfunction-associated inhibition of ATP production. Since those findings were also reported for dasatinib, sunitinib and lapatinib, they could be common cardiac phenotype of tyrosine kinase inhibitors in vivo. |
| first_indexed | 2024-04-12T23:21:07Z |
| format | Article |
| id | doaj.art-fd87e9c0826943c79c0ee21cfceafe87 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-04-12T23:21:07Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-fd87e9c0826943c79c0ee21cfceafe872022-12-22T03:12:31ZengElsevierJournal of Pharmacological Sciences1347-86132022-11-011503154162Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitorsKoki Chiba0Ryuichi Kambayashi1Mayu Onozato2Ai Goto3Hiroko Izumi-Nakaseko4Yoshinori Takei5Akio Matsumoto6Koichiro Tanaka7Yasunari Kanda8Takeshi Fukushima9Atsushi Sugiyama10Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Traditional Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, JapanDepartment of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, JapanDepartment of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, JapanDepartment of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, JapanDepartment of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, JapanDepartment of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, JapanDepartment of Aging Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, JapanDepartment of Traditional Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, JapanDivision of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, JapanDepartment of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, JapanDepartment of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Aging Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Corresponding author. Department of Pharmacology, Faculty of Medicine, Toho University 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4). Effects of imatinib on each phase of isovolumetric contraction, ejection, isovolumetric relaxation and filling were studied, whereas its electrophysiological effects on early and late repolarization were analyzed by measuring J-Tpeak and Tpeak-Tend, respectively. The low and high doses of imatinib provided peak plasma concentrations of 3.23 and 17.39 μg/mL, reflecting clinically-relevant and supratherapeutic concentrations, respectively. Neither lethal ventricular tachyarrhythmia nor cardiohemodynamic collapse was observed. Imatinib decreased amplitude of peak −dP/dt, indicating suppression of isovolumetric relaxation, whereas no significant change was detected in the other phases. Imatinib prolonged QTc and J-Tpeakc without altering Tpeak-Tend, indicating increase of net inward current, which leads to intracellular Ca2+ overload. Thus, imatinib suppressed ventricular active relaxation and early repolarization, which may suggest the association of mitochondrial dysfunction-associated inhibition of ATP production. Since those findings were also reported for dasatinib, sunitinib and lapatinib, they could be common cardiac phenotype of tyrosine kinase inhibitors in vivo.http://www.sciencedirect.com/science/article/pii/S1347861322000603ImatinibDiastolic dysfunctionTyrosine kinase inhibitorSafety pharmacologyQTc |
| spellingShingle | Koki Chiba Ryuichi Kambayashi Mayu Onozato Ai Goto Hiroko Izumi-Nakaseko Yoshinori Takei Akio Matsumoto Koichiro Tanaka Yasunari Kanda Takeshi Fukushima Atsushi Sugiyama Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors Journal of Pharmacological Sciences Imatinib Diastolic dysfunction Tyrosine kinase inhibitor Safety pharmacology QTc |
| title | Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors |
| title_full | Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors |
| title_fullStr | Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors |
| title_full_unstemmed | Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors |
| title_short | Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors |
| title_sort | imatinib induces diastolic dysfunction and ventricular early repolarization delay in the halothane anesthetized dogs class effects of tyrosine kinase inhibitors |
| topic | Imatinib Diastolic dysfunction Tyrosine kinase inhibitor Safety pharmacology QTc |
| url | http://www.sciencedirect.com/science/article/pii/S1347861322000603 |
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