Effects of Na+ channel blockers on the restitution of refractory period, conduction time, and excitation wavelength in perfused guinea-pig heart

Abstract

Na+ channel blockers flecainide and quinidine can increase propensity to ventricular tachyarrhythmia, whereas lidocaine and mexiletine are recognized as safe antiarrhythmics. Clinically, ventricular fibrillation is often precipitated by transient tachycardia that reduces action potential duration, suggesting that a critical shortening of the excitation wavelength (EW) may contribute to the arrhythmic substrate. This study examined whether different INa blockers can produce contrasting effects on the rate adaptation of the EW, which would explain the difference in their safety profile. In perfused guinea-pig hearts, effective refractory periods (ERP), conduction times, and EW values were determined over a wide range of cardiac pacing intervals. All INa blockers tested were found to flatten the slope of ERP restitution, indicating antiarrhythmic tendency. However, with flecainide and quinidine, the beneficial changes in ERP were reversed owing to the use-dependent conduction slowing, thereby leading to significantly steepened restitution of the EW. In contrast, lidocaine and mexiletine had no effect on ventricular conduction, and therefore reduced the slope of the EW restitution, as expected from their effect on ERP. These findings suggest that the slope of the EW restitution is an important electrophysiological determinant which can discriminate INa blockers with proarrhythmic and antiarrhythmic profile.

Fig 1. Representative monophasic action potential recordings obtained upon measuring the effective refractory period.

Panel A shows monophasic action potentials (MAP) recorded from the left ventricular (LV) and the right ventricular (RV) epicardium upon extrasystolic stimulations applied at a basic drive cycle length of 550 ms. The moments of S₁ and S₂ application are shown by vertical dotted lines. The numbers (ms) shown indicate the effective refractory period (last beat in LV MAP) and the LV-to-RV conduction time (second beat in RV MAP). Panel B illustrates location of the LV and RV MAP recording electrodes (open circles), and the LV stimulating (St) electrode (filled circle).

Fig 2

Effects of flecainide (panel A), quinidine (panel B), lidocaine /panel C), and mexiletine (panel D) on LV-to-RV conduction time. Conduction times were determined in the last beat of a train of 20 regular (S₁) pulses during ERP measurements at baseline and following drug infusion. The S₁-S₁ interval in a train was progressively reduced from 550 ms to 170 ms, as described in Methods, to generate a range of diastolic intervals (DI) from about 380 ms to 40 ms. The heart was allowed to beat spontaneously for 5–10 s in between successive stimulations.

Fig 3. Effects of flecainide on the restitution of effective refractory period and excitation wavelength.

Effective refractory periods (ERP) (panel A) and the relative excitation wavelength (EW) values (panel B) were determined at baseline and after drug infusion and plotted as a function of preceding diastolic interval (DI). The restitution curves were differentiated in order to assess changes in the restitution slope over the range of DIs used (panels C and D). Mean values of the maximum restitution slope (panels E and F) were calculated using individual measurements from each experiment. *P<0.05 vs. basal value (in panels E and F). The same figure design is used in Figs 4–6.

Fig 4. Effects of quinidine on the restitution of effective refractory period and excitation wavelength.

Fig 5. Effects of lidocaine on the restitution of effective refractory period and excitation wavelength.

Fig 6. Effects of mexiletine on the restitution of effective refractory period and excitation wavelength.