title: Prolongation of the QT interval by dofetilide modulates rate-dependent effects of mexiletine on intraventricular conduction.
abstract: Prolongation of action potential duration during treatment with agents that possess class I antiarrhythmic activity may result in a clinically relevant increase in Na+ channel block. In order to test this hypothesis in vivo, the effect of QT prolongation on intraventricular conduction was assessed during administration of mexiletine. Epicardial His bundle recordings were made in anesthetized guinea pigs. After abolition of spontaneous sinus node activity by application of high-frequency current to the sinus node area, the hearts were paced via the left atrium. Administration of the class III antiarrhythmic agent dofetilide (10 micrograms/kg i.v.; n = 6) significantly prolonged QT intervals without a significant effect on HV intervals. Infusion of mexiletine (bolus 2 mg/kg + 0.18 mg/kg per min i.v.; n = 6) produced significant increases in HV intervals at cycle lengths of 200 and 300 ms. Subsequent addition of dofetilide (20 micrograms/kg i.v.) to mexiletine induced similar increases in QT intervals as single treatment with 10 micrograms/kg dofetilide and significantly enhanced the rate-dependent conduction slowing. Upon abruptly decreasing the pacing cycle length from 500 ms to 300 ms, conduction slowing developed with a rate constant of 1.0 +/- 0.2 beat-1 after mexiletine and with a rate constant of 1.1 +/- 0.2 beat-1 after subsequent addition of dofetilide (P = n.s.). After rapid stimulation at a cycle length of 250 ms the conduction slowing produced by mexiletine recovered with a time constant of 174 +/- 24 ms. No further change of this recovery time constant was observed after subsequent addition of dofetilide to mexiletine (160 +/- 19 ms, P = n.s.). Thus action potential duration, as reflected by the QT interval, is an important modulator of the magnitude Na+ channel block in vivo. The kinetic parameters of Na+ channel block produced by mexiletine, however, remain unchanged by prolongation of action potential duration after addition of dofetilide.
authors.affiliation: Pharmakologisches Institut, Universität Wien, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Todt
authors.forename: N
authors.initials: N
authors.lastname: Zojer
authors.forename: G
authors.initials: G
authors.lastname: Raberger
authors.forename: W
authors.initials: W
authors.lastname: Schütz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000827:Animal Welfare; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D008433:Mathematics; D008801:Mexiletine / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology*; D026941:Sodium Channel Blockers; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D008801:Mexiletine; C063533:dofetilide