Synthetic cannabinoid, JWH-030, induces QT prolongation through hERG channel inhibition

Abstract

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, IC was 88.36 μM). JWH-030 significantly reduced the APD at 90% repolarization (APD) 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) 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.

Relationship between KCNQ1 (LQT1) and KCNH2 (LQT2) gene mutations and sudden death during illegal drug use

“…reported that 9.2% of the healthy Japanese subjects that they examined using a PCR-based method carried this variant 19 . To date, no significant variation from the frequency of this polymorphism in the general Japanese population has been observed in particular groups of subjects in this country 9 . Carriage of this variant is known to differ according to ethnicity, with estimates of its frequency among Caucasians being as high as 33%.…”

“…QT prolongation leading to fatal arrhythmia has been implicated in sudden death during MP use, and this drug has also been associated with development of cardiomyopathic states, including torsades de pointes (TdP) 8 . Similarly, various NPSs have been reported to cause TdP, which may be involved in the occurrence of sudden death during the use of such drugs 9 – 11 .…”

The electrophysiological effect of cannabidiol on hERG current and in guinea-pig and rabbit cardiac preparations

“…Our results in rabbit ventricular myocytes are in good agreement with those reported by Al Kury et al on inward calcium and sodium currents in rat ventricular myocytes 9 . In a previous study hERG channel inhibition and QT lengthening were also reported in anaesthetized rats 18 by a synthetic cannabinoid compound (JWH-030). This synthetic cannabinoid compound differs from those investigated by us and inhibited hERG channel with a relatively high IC 50 (88.36 µM).…”

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy

“…A recent study assessed the potential cardiotoxicity of SCs by exposing myoblasts to different concentrations of JWH-210, JWH-030, JWH-250 and RCS4. The results indicate that all of the SCs, especially JWH-030, decreased cell viability as assessed by MTT, at doses as low as 0.1 µM, most likely act through CB2 receptors [49]. Similarly, the nephrotoxicity of JWH-122 and THJ-2201 was confirmed in vitro by means of the MTT assay, whereas the underlying mechanism, which seems to be mitochondria-related, was identified through ATP assays.…”