Use-dependent blocking action of newly developed lidocaine-analogs on maximum rate of rise of action potentials in guinea pig papillary muscle.
The mode of antiarrhythmic actions of the newly developed antiarrhythmic drugs, tocainide, mexiletine and SUN1165, which bear the N-2,6-dimethylbenzene ring as a common structural unit, were examined by comparing the use-dependent blocking actions on the maximum rate of rise of action potentials (Vmax) in guinea pig ventricular muscle. The time course of the use-dependent reduction of Vmax after stimulation and its recovery after cessation of stimulation were fitted by double exponential curves to avoid the effects of the rapid stimulation (2 Hz) on the level of the membrane diastolic potential. The onset rates constants of the use-dependent block were 0.29 +/- 0.07 per action potential for tocainide (10(-4) M), 0.07 +/- 0.02 (mean +/- SE, n = 5) per action potential for SUN1165 (10(-5) M) and were too rapid to be accurately fitted for mexiletine (10(-5) M). The time constants of the Vmax recovery from the use-dependent block were prolonged to 0.67 +/- 0.32, 0.27 +/- 0.13 and 96 +/- 11 (mean +/- SE, n = 5) sec in the presence of tocainide, mexiletine and SUN1165, respectively. These data indicate that tocainide and mexiletine should be classified as lidocaine-like drugs, while SUN1165 may be a quinidine-like drug which interacts with Na+ channels and has slower kinetics than lidocaine-like drugs.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003864:Depression, Chemical; D006168:Guinea Pigs; D007700:Kinetics; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008801:Mexiletine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016677:Tocainide
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D016677:Tocainide; D008012:Lidocaine; C042288:pilsicainide