| Autor: |
Koki Chiba, Ryuichi Kambayashi, Mayu Onozato, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akio Matsumoto, Koichiro Tanaka, Yasunari Kanda, Takeshi Fukushima, Atsushi Sugiyama |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Journal of Pharmacological Sciences, Vol 150, Iss 3, Pp 154-162 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1347-8613 |
| DOI: |
10.1016/j.jphs.2022.07.008 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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