The Cardiotoxic Effect of Roundup® is not Induced by Glyphosate: A Non-specific Blockade of Human CaV1.2 Channels.

In Roundup®, the active principle glyphosate is formulated with adjuvants that help it to penetrate the plants' cell membranes. Several reports and reviews report cardiovascular effects of Roundup®, pointing the presence of arrhythmias as a potential consequence of Roundup® toxicity and death cause. However, it still remains debatable whether these cardiac events are related to glyphosate per se or to the Roundup® adjuvants. The present study aims to compare the pro-arrhythmogenic properties of Roundup® and glyphosate in an animal model and in human cardiomyocytes. In isolated guinea pig heart, the cardiotoxicity of Roundup® (significant effect on heart rate and depressive effect on ventricular contractility) was demonstrated with the highest concentrations (100 µM). In human cardiomyocytes, the cardiotoxicity is confirmed by a marked effect on contractility and a strong effect on cell viability. Finally, this Roundup® depressive effect on heart contractility is due to a concentration-dependent blocking effect on cardiac calcium channel CaV1.2 with an IC50 value of 3.76 µM. Surprisingly, no significant effect on each parameter has been shown with glyphosate. Glyphosate was devoid of major effect on cardiac calcium channel with a maximal effect at 100 µM (- 27.2 ± 1.7%, p < 0.01). In conclusion, Roundup® could induce severe cardiac toxicity by a blockade of CaV1.2 channel, leading to a worsening of heart contractility and genesis of arrhythmias. This toxicity could not be attributed to glyphosate.

Predicting cardiac safety using human induced pluripotent stem cell-derived cardiomyocytes combined with multi-electrode array (MEA) technology: A conference report.

Safety pharmacology studies that evaluate drug candidates for potential cardiovascular liabilities remain a critical component of drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have recently emerged as a new and promising tool for preclinical hazard identification and risk assessment of drugs. Recently, Pluriomics organized its first User Meeting entitled 'Combining Pluricyte® Cardiomyocytes & MEA for Safety Pharmacology applications', consisting of scientific sessions and live demonstrations, which provided the opportunity to discuss the application of hiPSC-CMs (Pluricyte® Cardiomyocytes) in cardiac safety assessment to support early decision making in safety pharmacology. This report summarizes the outline and outcome of this Pluriomics User Meeting, which took place on November 24-25, 2016 in Leiden (The Netherlands). To reflect the content of the communications presented at this meeting we have cited key scientific articles and reviews.

Action potential experiments complete hERG assay and QT-interval measurements in cardiac preclinical studies.

INTRODUCTION: The ICHS7B guideline focused on hERG and QT assays, although other factors have also been linked with the induction of severe arrhythmias. Thus, the aim of the present study was to demonstrate that two in vitro action potential recordings constitute convincing models of predictive drug-induced Torsades de pointes (TdP) and re-entry arrhythmias. METHODS: The effects of D,L-sotalol, flecainide and quinidine were investigated on potassium (hERG) and sodium (Na(V)1.5) currents transfected in HEK-293 cells to determine the repercussion of the blockade of these currents on rabbit Purkinje fibre (PF) and atrial action potentials. Atrial conduction velocity was also investigated as a model of re-entry arrhythmias. RESULTS: hERG channels were blocked by D,L-sotalol, quinidine and flecainide (IC(50): 69, 0.33 and 0.74 micromol/L, respectively). D,L-sotalol (30 micromol/L) induced reverse-use dependent increases in action potential duration (APD(90): +31.7% and +81.2% at 1 and 0.2 Hz) and triangulation (APD(90-40): +34.7% and +73.6% at 1 and 0.2 Hz) in PF but not in atria. Quinidine (10 micromol/L) also increased APD(90) (+14.5% and +68.5% at 1 and 0.2 Hz) and APD(90-40) (+73.3% and +152.1% at 1 and 0.2 Hz) in PF. Flecainide (10 micromol/L) shortened APD(90) in PF (-26.0% and - 22.2% at 1 and 0.2 Hz). Quinidine and flecainide blocked Na(V)1.5 channels by 32.3% and 73.1%, respectively, and produced decreases in dV/dt(max) which were more marked in atria (-20.4% and -31.9%) compared to PF (-12.8% and 22.4%) at 1 Hz. Finally, quinidine and flecainide decreased atrial conduction speed by 14.6% and 30.8%, respectively. CONCLUSION: Results obtained with flecainide demonstrate that use of the hERG channel alone should not be considered as a useful single assay. Rabbit Purkinje fiber action potentials can be considered as a comparable model for detection of reverse-use dependent APD prolongation and triangulation whereas the rabbit atria can be considered as a useful model for detection of sodium channel blockade associated with decreases in dV/dt(max) and conduction velocity.

Additive effects of ziprasidone and D,L-sotalol on the action potential in rabbit Purkinje fibres and on the hERG potassium current.

INTRODUCTION: Ziprasidone, an atypical antipsychotic has been shown to be devoid of cardiac adverse effects in spite of its propensity to prolong the QT-interval via a hERG current inhibition. However, the effects of ziprasidone on the action potential (AP) parameters have not been published yet. Moreover, very little information is available concerning pharmacodynamic interactions between ziprasidone and other hERG channel blockers. Thus, we investigated the putative interaction between ziprasidone and D,L-sotalol on the hERG channels at therapeutic concentrations and their consequences on the action potential prolongation. METHODS: AP were recorded at 1 and 0.2 Hz. Increasing concentrations of ziprasidone (0.01-10 micromol/L) were successively superfused for 30 min alone or in D,L-sotalol 10 micromol/L pre-treated fibres. Moreover, the effects of ziprasidone, alone or in association with d,l-sotalol, were investigated on the hERG current. RESULTS: Ziprasidone (1-10 microM) induced a concentration and reverse frequency-dependent increase in APD(90) (APD(90): +27% and +36%, respectively at 1 Hz and +50% and +70%, respectively at 0.2 Hz) due to a hERG current blockade (IC50: 0.24 micromol/L). A pre-treatment with D,L-sotalol 10 micromol/L led to an increase in APD(90) of +23% at 1 Hz, stable at 66+/-4 min. In these pre-treated fibres, ziprasidone (1 and 10 micromol/L) induced an additional AP prolongation (APD(90): +16% and +18%, respectively at 1 Hz) as compared to D,L-sotalol pre-treatment. Moreover, D,L-sotalol did not interact with the pharmacological profile of ziprasidone on the hERG channel. CONCLUSION: The present study demonstrates that ziprasidone induces an AP prolongation due to its propensity to block the hERG channel. Moreover, ziprasidone and d,l-sotalol, superfused concomitantly exhibit additive effects on the AP duration since they do not interact as competitors for the hERG channel.

Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone.

Increase in serotonin (5-HT) transmission has profound antidepressant effects and has been associated with an increase in adult neurogenesis. The present study was aimed at screening the 5-HT receptor subtypes involved in the regulation of cell proliferation in the subgranular layer (SGL) of the dentate gyrus (DG) and the subventricular zone (SVZ) and to determine the long-term changes in adult neurogenesis. The 5-HT1A, 5-HT1B, and 5-HT2 receptor subtypes were chosen for their implication in depression and their location in/or next to these regions. Using systemic administration of various agonists and antagonists, we show that the activation of 5-HT1A heteroreceptors produces similar increases in the number of bromodeoxyuridine-labeled cells in the SGL and the SVZ (about 50% over control), whereas 5-HT2A and 5-HT2C receptor subtypes are selectively involved in the regulation of cell proliferation in each of these regions. The activation of 5-HT2C receptors, largely expressed by the choroid plexus, produces a 56% increase in the SVZ, while blockade of 5-HT2A receptors produces a 63% decrease in the number of proliferating cells in the SGL. In addition to the influence of 5-HT1B autoreceptors on 5-HT terminals in the hippocampus and ventricles, 5-HT1B heteroreceptors also regulate cell proliferation in the SGL. These data indicate that multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation. Furthermore, both acute and chronic administration of selective 5-HT1A and 5-HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the DG and/or olfactory bulb, underscoring the beneficial effects of 5-HT on adult neurogenesis.