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

1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I-KACh 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 I-KACh in Langendorff preparations challenged with ACh. 2 ACh (0.5 mu M) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n = 12). 3 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). 4 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. 5 Tertiapin blocked I-KACh with an IC50 of 30 +/- 4 nM with no significant effect on the major currents classically associated with cardiac repolarisation process (I-Kr, I-Ks, I-tol, I-sus, I-KI or I-KATP) Or AV conduction (I-Na and I-Ca(L)) 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I-KACh.