The bee venom peptide tertiapin underlines the role of I(KACh) 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 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 I(KACh), to evaluate the role of I(KACh) in Langendorff preparations challenged with ACh. ACh (0.5 microM) 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 I(KACh) with an IC(50) of 30+/-4 nM with no significant effect on the major currents classically associated with cardiac repolarisation process (I(Kr), I(Ks), I(to1), I:(sus), I(K1) or I(KATP)) or AV conduction (I(Na) and I(Ca(L))). In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I(KACh).
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Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
Diochot
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Terrenoire
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Romey
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Lazdunski
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D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects / Q000502:physiology; D001514:Bee Venoms / Q000494:pharmacology*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006327:Heart Block / Q000139:chemically induced* / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D009865:Oocytes; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011817:Rabbits; D014982:Xenopus laevis
D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C029738:tertiapin; D000109:Acetylcholine