This study investigates the novel block from the cytosolic face of mRyR2 by three hERG blocking agents. For this purpose, astemizole (A), terfenadine (T) and chloroquine (C) were investigated based on their different affinities of hERG block (IC50 = 0.9 nM, 56–204 nM and 2500 nM) and differences in their proposed mechanisms of action at the cytosolic face of ion channels. As well as exhibiting high affinity block of hERG, these blockers exhibit half maximal block of multiple ion channel types at concentrations exceeding 1 × 10−6 M. Whilst mRyR2 lacks the key residues (Y652 and F656) involved in high affinity block of hERG it does possess a wide pore containing a high density of hydrophobic residues. Therefore the potential exists for mRyR2, like hERG, to be blocked by a diverse range of compounds with high affinity. The aim of this study is to examine the properties/mechanisms of mRyR2 block to identify areas within mRyR2 that may be involved in drug binding. Similar to their action in non-hERG ion channels, these compounds block mRyR2 within the micromolar range (IC50; (A) - 16.12 ± 2.12 μM; (T) - 30.04 ± 4.81 μM and (C) - 17.73 ± 5.14 μM; n = 5) at + 50 mV. Whilst all blockers reduce the single channel current amplitude to ∼ 95 % of control levels, astemizole and terfenadine induce additional blocking states, whilst also allowing channel closure during periods of block. Chloroquine exhibits briefer blocking events, indicating a faster off rate and no additional reduced conductance states observed. This work was funded by the British Heart Foundation.