Tedisamil and lidocaine enhance each other's antiarrhythmic activity against ischaemia-induced arrhythmias in rats

Abstract

1. Combinations of the action potential-widening drug tedisamil (Class III antiarrhythmic activity), and the inactivated state sodium channel blocker lidocaine (Class Ib antiarrhythmic activity) were assessed for antiarrhythmic actions in a rat model of ischaemia-induced arrhythmias and for electrophysiological actions in normal rat myocardial tissue. 2. Both tedisamil and lidocaine dose-dependently suppressed ischaemia-induced arrhythmias. The ED(50) values were 3.0+/-1.3 and 4.9+/-0.6 micro mol kg(-1) min(-1), respectively. 3. Combinations of the two drugs acted synergistically such that the ED(50) for tedisamil was reduced to 0.8+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) lidocaine. Similarly, the ED(50) for lidocaine was reduced to 0.7+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) tedisamil (both P<0.05). 4. In a separate series of experiments in which normal ventricular tissue was electrically stimulated, 2 micro mol kg(-1) min(-1) lidocaine produced a leftward shift in the dose-response curve for tedisamil's effect on effective refractory period (P<0.05). This dose of lidocaine had no effect on its own. These data indicate that the synergistic actions of combinations of tedisamil and lidocaine were mediated, at least in part, by extension of effective refractory period in normal myocardial tissue. 5. In contrast to the strategy of developing drugs that are selective for a single electrophysiological mechanism, the results of the present study suggest that effective antiarrhythmic drugs might be developed by optimising the combination of two complimentary electrophysiological mechanisms (i.e., action potential-prolonging activity and inactivated state sodium channel blockade).

Figure 1

Antiarrhythmic dose–response curves for tedisamil and combinations of tedisamil and lidocaine as compared to vehicle control (a), or relative to the antiarrhythmic protection produced by the dose of lidocaine that was coadministered (b). Each point is the mean per cent protection±s.e.m., n=5. The data were fit to a two-parameter logistic function as described in the Methods section. The curve fit parameters are summarised in Table 3.

Figure 2

Antiarrhythmic dose–response curves for lidocaine and combinations of tedisamil and lidocaine as compared to vehicle control (a), or relative to the antiarrhythmic protection produced by the dose of tedisamil that was coadministered (b). Each point is the mean per cent protection±s.e.m., n=5. The data were fit to a two-parameter logistic function as described in the Methods section. The curve fit parameters are summarised in Table 3.

Figure 3

Isobologram for combinations of lidocaine and tedisamil. Each point is the antiarrhythmic ED₅₀ determined from the antiarrhythmic dose–response curves shown in Figure 1 and Figure 2. The hatched line connecting the ED₅₀'s for tedisamil and lidocaine is the line of additivity. Points below the line of additivity indicate synergy, while points above indicate functional antagonism.

Figure 4

Dose–response curves for the effect of tedisamil and lidocaine, alone or in combination, on effective refractory period. Each point is the mean±s.e.m., n=5, as described in the Methods section. The open symbols at time 0 and 5 min show the values before starting the experiment and after administration of lidocaine or lidocaine–vehicle, respectively. Infusion of lidocaine or lidocaine–vehicle was maintained throughout the remainder of the protocol and was followed by increasing infused doses of tedisamil (0.016–2 μmol kg⁻¹ min⁻¹). *denotes statistical significance at P<0.05 from vehicle control (repeated measures ANOVA), while # denotes statistical significance between tedisamil alone and tedisamil plus lidocaine groups as well as from vehicle control.

Figure 5

Dose–response curves for the effect of tedisamil and lidocaine, alone or in combination, on effective refractory period determined at pacing rates of 7.5(a), 9.5 (b) and 11.5 Hz (c). Each point is the mean±s.e.m., n=3, except where no error bars are presented in which case n=1. The open symbols at time 0 and 5 min show the values before starting the experiment and after administration of lidocaine or lidocaine–vehicle, respectively. Infusion of lidocaine or lidocaine–vehicle was maintained throughout the remainder of the protocol and was followed by increasing infused doses of tedisamil (0.016–2 μmol kg⁻¹ min⁻¹). *denotes statistical significance at P<0.05 from vehicle control (repeated-measures ANOVA). While the tedisamil and tedisamil plus lidocaine groups were significantly different by ANOVA (P<0.05). at each pacing rate, the Tukey test did not have the power to detect which points were significantly different.