The present study investigates in vitro electrophysiological effects of therapeutic concentrations of quinidine (5-10 $ mu$M) and its combination with the Class Ib agents mexiletine and tocainide in canine Purkinje fibers with the use of standard microelectrode techniques. The frequency- and voltage-dependent depression of V$ sb{ rm max}$, used as an index of peak sodium conductance, by quinidine and the combination of quinidine and tocainide (50 $ mu$M) were assessed with the kinetics of onset of, and recovery form, rate-dependent block, and the curve relating V$ sb{ rm max}$ to membrane potential. The frequency-dependence of quinidine-induced repolarization abnormalities arising from early after-depolarizations (EADs) was characterized in the presence of low (K$ sp+$) $ sb0$ (2.7 mM) and mild acidosis (pH = 7.06 $ pm$ 0.08). Acidosis was found to favor triggered activity by directly prolonging action potential duration. Quinidine induced two types of EAD-induced triggered activity, viz. arising from phase 2 and arising from phase 3, which differed in the frequency-dependence of their characteristics (activation voltage, amplitude, and coupling interval), and their sensitivities to abolition by mexiletine. Adrenaline (1 $ mu$M) decreased the minimum cycle length for triggered activity, shortened the coupling interval of triggered responses, and transformed single triggered responses into multiple. It also induced rapid activity resembling sustained triggered activity, induced triggered responses arising from phase 2, and facilitated their transmission to ventricular muscle. The combination of quinidine with a Class Ib drug proved to be beneficial by improving its antiarrhythmic effect and preventing its bradycardia-related excessive QT prolongation. Triggered activity was found to originate only in Purkinje fibers, but electrotonic influence from ventricular muscle strongly affected its manifestation. These results provide the evidence that EAD-induced triggered
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74559 |
| Date | January 1990 |
| Creators | Valois, Maria |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001167869, proquestno: AAINN66466, Theses scanned by UMI/ProQuest. |
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