The bee venom peptide tertiapin underlines the role of IKACh in acetylcholine‐induced atrioventricular blocks

Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of IKACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the effect of tertiapin, a bee venom peptide blocking IKACh, to evaluate the role of IKACh in Langendorff preparations challenged with ACh. ACh (0.5 μM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea‐pig isolated hearts (n=12). Tertiapin (10 to 300 nM) dose‐dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P<0.01). Tertiapin dose‐dependently blunted the ACh‐induced negative chronotropic response from an ACh‐induced decrease in heart rate of 39±16% in control conditions to 3±3% after 300 nM tertiapin (P=0.01). These effects were not accompanied by any significant change in QT intervals. Tertiapin blocked IKACh with an IC50 of 30±4 nM with no significant effect on the major currents classically associated with cardiac repolarisation process (IKr, IKs, Ito1, Isus, IK1 or IKATP) or AV conduction (INa and ICa(L)). In summary, tertiapin prevents dose‐dependently ACh‐induced AV blocks in mammalian hearts by inhibiting IKACh.