METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,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 IKr 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 IKr 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.
CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.
PATIENTS & METHODS: DPP4, WFS1 and KCNJ11 gene polymorphisms were genotyped in a cohort study of 662 T2DM patients treated with DPP-4 inhibitors sitagliptin, vildagliptin or linagliptin. Genotyping was performed by Applied Biosystems TaqMan SNP genotyping assay.
RESULTS: Patients with triglyceride levels less than 1.7 mmol/l (odds ratio [OR]: 2.2.; 95% CI: 1.031-4.723), diastolic blood pressure (DBP) less than 90 mmHg (OR: 1.7; 95% CI: 1.009-2.892) and KCNJ11 rs2285676 (genotype CC) (OR: 2.0; 95% CI: 1.025-3.767) were more likely to response to DPP-4 inhibitor treatment compared with other patients, as measured by HbA1c levels.
CONCLUSION: Triglycerides, DBP and KCNJ11 rs2285676 are predictors of the DPP-4 inhibitor treatment response in T2DM patients.
Methods: Chemical compounds fromDendrocalamus asperbamboo shoots were purified and identified as major palmitic acids mixed with other minor fatty acids, palmitic acid, 4-hydroxybenzaldehyde, lauric acid, 4-hydroxybenzoic acid and cholest-4-ene-3-one. The response of synthetic 4-hydroxybenzoic acid was tested on Kv1.4 potassium channel which was injected into viable oocytes that was extracted fromXenopus laevis. The current were detected by the two-microelectrode voltage clamp, holding potential starting from -80 mV with 20 mV step-up until +80 mV. Readings of treatments with 0.1% DMSO, 4-hba concentrations and K channel blockers were taken at +60 mV. The ratio of tail/peak amplitude is the index of the activity of the Kv1.4 channels withn≥ 6 (number of oocytes tested). The decreases of the ratios of five different concentrations (1 μM, 10 μM, 100 μM, 1 mM and 2.5 mM) were compared with 0.1% DMSO as the control.
Results: All concentration showed statistically significant results withP< 0.05 except for 100 μM. The normalised current of the 4-hba concentrations were compared with potassium channel blockers (TEA and 4-AP) and all groups showed statistically significant results. This study also showed that time taken for each concentration to affect Kv1.4 does not play any significant roles.
Conclusion: 4-hydroxybenzoic acid was found to be able to enhance the inactivation of Kv1.4 by lowering the membrane potential so that the abnormal neuronal firing can be inhibited. With IC50 slightly higher than 10 μM, increasing concentrations (100 μM, 1 mM and 2.5 mM) had shown to exhibit toxicity effects. The best concentration from this study is 10 μM with Hill slope of 0.1799.