Evaluation of the Cardiotoxicity of Mitragynine and Its Analogues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

IntroductionMitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and ResultsThe rapid delayed rectifier potassium current (I Kr), L-type Ca2+ current (I Ca,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant I Kr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed I Kr in hiPSC-CMs by 67% ∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression,and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.ConclusionsOur study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of I Kr in human cardiomyocytes.

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

“…Chronic use results in insomnia, anorexia, weight loss, facial hyperpigmentation, dry mouth, polyuria, psychosis, or addiction [1,45,46]. Infrequent findings associated with chronic Kratom use include seizure or coma [10,24,47,48], acute respiratory distress syndrome [49], hypothyroidism [50], intrahepatic cholestasis or toxic hepatitis [38,48,51], cardiotoxicity or dysrhythmia [52], and hypertension or nephrotoxicity [38]. Fatalities have been reported in the setting of therapeutic or supratherapeutic levels of coingestants such as sympathomimetics [53,54], benzodiazepines and over the counter cold medications [55], antidepressants [56], muscle relaxers, and opioids [57,58].…”

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…The green area defines the normal QT interval range for humans. Data are shown as mean ± SD: 1, (Malan et al , 2016); 2, (Rocchetti/Sala et al , unpublished); 3, (Zhang et al , 2014); 4, (Zhang et al , 2014); 5, (Davis et al , 2012); 6, (Rocchetti/Sala et al , unpublished); 7, (Bellin et al , 2013); 8, (Sala et al , 2016); 9, (Bizy et al , 2013); 10, (Ma et al , 2013); 11, (Ma et al , 2015); 12, (Ma et al , 2015); 13, (Gibson et al , 2014a); 14, (Itzhaki et al , 2011); 15, (Gibson et al , 2014c); 16, (Lu et al , 2014); 17, (Gibson et al , 2014b); 18, (Mehta et al , 2014). (B) and (C) Composition of extracellular buffers (B) and pipette solutions (C) for current clamp experiments.…”

L-Type Calcium Channel Inhibition Contributes to the Proarrhythmic Effects of Aconitine in Human Cardiomyocytes

“…The recent scientific breakthrough has enabled the generation of human induced pluripotent stem cells (hiPSCs)-derived cardiomyocytes (hiPSC-CMs) which share important structural and functional similarities with native human cardiac myocytes. To date, hiPSC-CMs have been successfully adopted for modeling various cardiac diseases [18,19] and for drug testing [20,21]. …”