Arrhythmogenic effect of beta-adrenoceptor-blocking drugs in Purkinje fibres of guinea-pig hearts.
The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.
Institute of Pharmacology and Toxicology, University of Vienna, Austria.
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Lemmens-Gruber
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Zilberszac
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Heistracher
D000070:Acebutolol / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology; D004594:Electrophysiology; D004983:Ethanolamines / Q000494:pharmacology; D006168:Guinea Pigs; D007545:Isoproterenol / Q000031:analogs & derivatives / Q000494:pharmacology; D010096:Oxprenolol / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D004983:Ethanolamines; D001262:Atenolol; D010096:Oxprenolol; D000070:Acebutolol; D011433:Propranolol; D013015:Sotalol; D010869:Pindolol; C100250:nifenalol; D007545:Isoproterenol; D000638:Amiodarone; C084581:dichloroisoproterenol