ABSTRACT: The clinically established proarrhythmic effect of bradycardia and antiarrhythmic effect of lidocaine (10 microM) were reproduced in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced over a range (80-180 ms) of baseline cycle lengths (BCLs). Action potential durations (at 90% repolarization, APD(90)s), transmural conduction times and ventricular effective refractory periods (VERPs) were then determined from monophasic action potential records obtained during a programmed electrical stimulation procedure in which extrasystolic stimuli were interposed following regular stimuli at successively decreasing coupling intervals. A novel graphical analysis of epicardial and endocardial, local and transmural relationships between APD(90), corrected for transmural conduction time where appropriate, and VERP yielded predictions in precise agreement with the arrhythmogenic findings obtained over the entire range of BCLs studied. Thus, in normokalaemic (5.2 mM K(+)) hearts a statistical analysis confirmed that all four relationships were described by straight lines of gradients not significantly (P > 0.05) different from unity that passed through the origin and thus subtended constant critical angles, theta with the abscissa (45.8 degrees +/- 0.9 degrees , 46.6 degrees +/- 0.5 degrees , 47.6 degrees +/- 0.5 degrees and 44.9 degrees +/- 0.8 degrees , respectively). Hypokalaemia shifted all points to the left of these reference lines, significantly (P < 0.05) increasing theta at BCLs of 80-120 ms where arrhythmic activity was not observed ( approximately 63 degrees , approximately 54 degrees , approximately 55 degrees and approximately 58 degrees , respectively) and further significantly (P < 0.05) increasing theta at BCLs of 140-180 ms where arrhythmic activity was observed ( approximately 68 degrees , approximately 60 degrees , approximately 61 degrees and approximately 65 degrees , respectively). In contrast, the antiarrhythmic effect of lidocaine treatment was accompanied by a significant (P < 0.05) disruption of this linear relationship and decreases in theta in both normokalaemic ( approximately 40 degrees , approximately 33 degrees , approximately 39 degrees and approximately 41 degrees , respectively) and hypokalaemic ( approximately 40 degrees , approximately 44 degrees , approximately 50 degrees and approximately 48 degrees , respectively) hearts. This extended a previous approach that had correlated alterations in transmural repolarization gradients with arrhythmogenicity in murine models of the congenital long QT syndrome type 3 and hypokalaemia at a single BCL. Thus, the analysis in terms of APD(90) and VERP provided a more sensitive indication of the effect of lidocaine than one only considering transmural repolarization gradients and may be particularly applicable in physiological and pharmacological situations in which these parameters diverge.
