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Synthetic cannabinoid, JWH-030, induces QT prolongation through hERG channel inhibition
Yun, Jaesuk,Yoon, Kyung Sik,Lee, Tac-Hyung,Lee, Hyunjin,Gu, Sun Mi,Song, Yun Jeong,Cha, Hye Jin,Han, Kyoung Moon,Seo, Hyewon,Shin, Jisoon,Park, Hye-Kyung,Kim, Hyung Soo,Kim, Young-Hoon Oxford University Press 2016 Toxicology research Vol.5 No.6
<P>The problem of new psychoactive substance (NPS) abuse, which includes synthetic cannabinoids, is emerging globally, and the cardiotoxicity of these synthetic cannabinoids has not yet been evaluated extensively. In the present study, we investigated the effects of synthetic cannabinoids on the cytotoxicity, human Ether-à-go-go-related gene (hERG) channel, action potential duration (APD), and QT interval. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that JWH-030 was more cytotoxic than JWH-210, JWH-250, and RCS4 in H9c2 cells at 0.1 μM. In addition, the cytotoxicity was associated with its pro-apoptotic effects as evidenced by the increase in caspase-3 levels. We demonstrated that a cannabinoid receptor type 2 (CB2) antagonist, AM630, inhibited JWH-030-induced cytotoxicity, whereas a CB1 antagonist, rimonabant, did not. Furthermore, fluorescence polarization assay showed JWH-030 to block the hERG channel (half-maximal inhibitory concentration, IC50 was 88.36 μM). JWH-030 significantly reduced the APD at 90% repolarization (APD90) in rabbit Purkinje fibers and decreased the left ventricular end diastolic pressure (LVEDP) in Langendorff-perfused Sprague-Dawley (SD) rat hearts at 30 μM. In addition, the electrocardiogram (ECG) measurement revealed that the intravenous injection of JWH-030 (0.5 mg kg<SUP>−1</SUP>) prolonged the QT interval in SD rats. These results suggest that JWH-030 is cytotoxic and its cytotoxicity is mediated by its action on the CB2 receptor; it prolongs the QT interval by regulating ion current channels and APD.</P>
( Hyewon Hur ),( Young Han Kim ),( Hee Young Cho ),( Yong Won Park ),( Hye Sung Won ),( Mi Young Lee ),( Bo Hyon Yun ),( Kwang Hee Lee ),( Sung Yoon Kim ),( Junsang Yoo ),( Ja Young Kwon ) 대한산부인과학회 2015 Obstetrics & Gynecology Science Vol.58 No.4
Objective: To evaluate the feasibility of five-dimensional Long Bone (5D LB), a new technique that automatically archives, reconstructs images, and measures lengths of fetal long bones, to assess whether the direction of volume sweep influences fetal long bone measurements in three-dimensional (3D) ultrasound and 5D LB, and to compare measurements of fetal long bone lengths obtained with 5D LB and those obtained with conventional two-dimensional (2D) and manual 3D techniques. Methods: This prospective study included 39 singleton pregnancies at 26+0 to 32+0 weeks of gestation. Multiple pregnancies, fetuses with multiple congenital anomalies, and mothers with underlying medical diseases were excluded. Fetal long bones of the lower extremities-the femur, tibia, and fibula were measured by 2D and 3D ultrasound, and 5D LB, by an expert and non-expert examiner. First, we analyzed the 3D ultrasound and 5D LB data according to 2 different sweeping angles. We analyzed intra- and inter-observer variability and agreement between ultrasound techniques. Paired t-test, interclass correlation coefficient, and Bland-Altman plot and Passing-Bablok regression were used for statistical analysis. Results: There was no statistical difference between long bone measurements analyzed according to 2 different volume-sweeping angles by 3D ultrasound and 5D LB. Intra- and inter-observer variability were not significantly different among all 3 ultrasound techniques. Comparing 2D ultrasound and 5D LB, the interclass correlation coefficient for femur, tibia, and fibula was 0.91, 0.92, and 0.89, respectively. Conclusion: 5D LB is reproducible and comparable with conventional 2D and 3D ultrasound techniques for fetal long bone measurement.