P635Proarrhythmic drugs exert hERG-independent slowing of relaxation and irregular beating in rat engineered heart tissue

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Background: The assessment of proarrhythmic risks of drugs remains challenging. We evaluated the suitability of rat engineered heart tissue (EHT).Methods: Contractile activity of EHTs was monitored under physiological conditions (37 °C, auxotonic contractions, 50 nM epinephrine), selected compounds under electrical pacing. Drug selection (total 77): Reference blockers of IKr, IKsand Ito, 6 antiarrhythmics, 5 withdrawn from the market for torsade-de-pointes arrhythmias (TdP), 7 with measurable incidence of TdP, 13 isolated TdP reports,13 drugs considered safe (1-10-100x free therapeutic plasma concentrations; FTPC), 28 new chemical entities (NCE; 0.1-10 μM).Results: Specific blockers of IKr (dofetilide, ibutilide, E-4031) or IKs (HMR-1556) had no effect, but dramatically prolonged relaxation time (T2) when combined at >100x IC50 (1 μM E-4031+HMR-1556). The Ito-blocker 4-aminopyridine (4AP; 10 mM) increased T2 >5-fold and caused after-contractions, which were abolished by blockers of ryanodine receptors (RyR2; JTV-519) or sodium calcium exchanger (NCX; SEA0400), respectively. 15/33 drugs associated with TdP and two drugs considered non-torsadogenic (ebastine, diltiazem) induced concentration-dependent, reversible prolongations of T2. Bepridil, desipramine, imipramine, thioridazine and erythromycin induced irregular beating. Threshold concentrations were generally 100x FTPC (3x 10-fold). 3/28 NCE prolonged T2, 3 reduced force.Conclusion: Drug-induced relaxation slowing and after-contractions in rat EHTs are surrogates of prolonged repolarization and involve RyR2 and NCX. The insensitivity to blockers of IKr and IKs, a disadvantage for general drug screening, makes the technology well suited for the detection of Ito-related drug effects that appear to more frequent than generally anticipated.

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