title: Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig.
abstract: Quinidine is a class Ia Na(+) channel blocker that prolongs cardiac repolarization owing to the inhibition of I(Kr), the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. osadchiy@hst.aau.dk
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Osadchii
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004562:Electrocardiography / Q000187:drug effects*; D004699:Endocardium / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D010496:Pericardium / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology* / Q000633:toxicity; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000139:chemically induced
chemical_list: D011802:Quinidine