3-O-129
チロシンキナーゼ阻害薬imatinibによる左室拡張障害の発生機序の検討
Analysis of onset mechanism for tyrosine kinase inhibitor imatinib induced-left ventricular diastolic dysfunction
〇千葉 浩輝1、長澤 美帆子2、神林 隆⼀2、後藤 愛1、原 司3、天谷 亮介3、布井 啓雄2、中瀬古 寛子1,2、松本 紋子3、松本 明郎4、杉山 篤1,2,4
Koki Chiba1, Mihoko Hagiwara-Nagasawa2, Ryuichi Kambayashi2, Ai Goto1, Tsukasa Hara3, Ryosuke Amagai3, Yoshio Nunoi2, Hiroko Izumi-Nakaseko1,2, Ayako Okado-Matsumoto3, Akio Matsumoto4, Atsushi Sugiyama1,2,4
1東邦大・院医・薬理、2東邦大・医・薬理、3東邦大・理・生物・生化学、4東邦大・医・加齢薬理
1Dept. Pharmacol., Grad. Sch. Med., Toho Univ., 2Dept. Pharmacol., Faculty Med., Toho Univ., 3Lab. Biochem., Dept. Biol., Faculty Sci., Toho Univ., 4Dept. Aging Pharm., Faculty Med., Toho Univ.
Introduction: Imatinib is a tyrosine kinase inhibitor used for treating various types of cancers. The other tyrosine kinase inhibitors sunitinib and dasatinib have been reported to induce diastolic dysfunction; however, such information is lacking for imatinib.
Methods: Exp. 1: Imatinib mesylate in doses of 1 and 10 mg/kg, i.v., were administered to the halothane-anesthetized dogs (n=4). Cardiovascular variables along with biomarkers reflecting myocardial injury were measured. Exp. 2: Mitochondria isolated from the rat heart (n=2) were incubated with tyrosine kinase inhibitors, of which effects on mitochondrial respiratory complexes were assessed.
Results: Exp. 1: The low dose decreased the total peripheral vascular resistance with prolonging the isovolumic relaxation time, prolonged the QTc and J-Tpeakc, and increased AST and LDH. Moreover, the high dose suppressed the ventricular relaxation, increased the left ventricular end-diastolic volume, prolonged HV interval and increased CPK. Exp. 2: The activity of complex II were decreased by the inhibitors.
Conclusions: Imatinib may induce myocardial injury, resulting in the left ventricular diastolic dysfunction, in which mitochondrial dysfunction might play an important role.