title: Electrophysiological and arrhythmogenic effects of the histamine type 1-receptor antagonist astemizole on rabbit Purkinje fibers: clinical relevance.
abstract: Astemizole is a potent histamine H1-antagonist that has been associated with cases of life-threatening cardiac arrhythmias, including torsade de pointes and atrioventricular (AV) block. However, its effects on cardiac action potential (AP) has not been described. We examined the electrophysiological effects of astemizole on rabbit Purkinje fibers using conventional glass microelectrodes in parallel with the effects of the widely used histamine H2-antagonist cimetidine, selected because it has no known cardiac arrhythmic toxicity. Astemizole (0.01-3 microM) exerted a concentration-dependent prolonging effect on final repolarization that did not reach steady state after 3 h of exposure. This effect was more pronounced at low stimulation frequency and was less marked at high stimulation frequency. In addition, early afterdepolarizations (EADs) occurred in one third of the fibers. Increasing extracellular concentration of KCl (2.7-5.4 mM) or MgCl2 (1-5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KCl (4-2.7 mM) or MgCl2 (1-0.5 mM) concentration. At higher concentrations (3-30 microM), astemizole induced an increasing depressant effect on the maximal rate of depolarization (Vmax) that became more pronounced with high stimulation frequency. All parameters were strongly depressed at 10 microM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30 microM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30-100 microM) concentrations. These results provide evidence that astemizole exerts quinidine-like effects on cardiac APs that are compatible with the occurrence of the clinically observed arrhythmias.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016589:Astemizole / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D015636:Magnesium Chloride / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D006634:Histamine H1 Antagonists; D015636:Magnesium Chloride; D011189:Potassium Chloride; D016589:Astemizole