P635Proarrhythmic drugs exert hERG-independent slowing of relaxation and irregular beating in rat engineered heart tissue. (15th July 2014)

• Record Type: Journal Article
• Authors: Eder, A; Hansen, A; Neuber, C; Schaaf, S; Vos, MA; Eschenhagen, T
• Is Part Of: Cardiovascular research. Volume 103(2014)Supplement 1
• Page Start: S115
• Page End: S115
• Publication Date: 2014-07-15
• Subjects: Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu098.62
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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 Drug selection (total 77): Reference blockers of IKr, IKsand Ito, 6 antiarrhythmics, 5 withdrawn from the market for torsade-de-pointes arrhythmias (TdP), 7 with measurable incidence of TdP, 13 isolated TdP reports, 13 drugs considered safe (1-10-100x free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.