Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin–dopamine antagonists against insomnia and nocturnal delirium
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Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J–Tpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of Tpeak–Tend, whereas J–Tpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J–Tpeakc was prolonged by each dose, but Tpeak–Tend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.
KeywordsPerospirone Blonanserin LQT3 J–Tpeakc Ca2+ overload
This study was supported in part by research grants from Japan Society for the Promotion of Science, Japan (JSPS KAKENHI grant number JP16K08559); Daiichi Sankyo Research Contribution Program 2018, Japan; Okinaka Memorial Institute for Medical Research, Japan; and Japan Agency for Medical Research and Development, Japan (AMED grant number JP17am0101122 and JP18mk0104117j0001). The authors thank Dr. Yuji Nakamura, Dr. Kentaro Ando, Mrs. Yuri Ichikawa, and Mr. Shota Tsuda for their technical assistances.
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Conflicts of interest
The authors declare no conflicts of interest.
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