Electrophysiological interactions between carbachol and class I antiarrhythmic drugs (lidocaine, quinidine)--experimental studies in rabbit atrial myocardium

Cholinergic agents exert no direct effect on the fast Na+ inward current but may influence the binding characteristic of class I antiarrhythmic drugs in atrial myocardium by shortening the action potential (AP) duration or by increasing the resting potential (RP). In order to examine such possible interactions we performed experiments using conventional intracellular microelectrodes on isolated preparations of rabbit atrial myocardium (Ke 2.7 mM, temperature 32 degrees C). At first the influence of the cholinergic agent carbachol (1 mg/l = 6.7 x 10(-6) M) on the RP and AP was examined at different stimulation rates (1.0, 2.5, and 3.3 Hz). Thereafter measurements were repeated under the influence of lidocaine (10 mg/l = 2.2 x 10(-5) M) or quinidine (5 mg/l = 2.2 x 10(-5) M) alone and in combination with carbachol (1 mg/l).

(statistically significant differences, p less than 0.05): Carbachol increased the RP by about 10 mV and shortened the AP by about 60%. The maximal upstroke velocity of the AP (Vmax) was not significantly altered at 1.0 and 2.5 Hz, but increased under carbachol at 3.3 Hz. After addition of carbachol to the lidocaine-containing solution, Vmax increased to its control level at all stimulation rates. In experiments with quinidine, Vmax also increased after addition of carbachol but remained significantly below the control values.

Carbachol effects on Vmax are most likely attributable to earlier recovery (caused by the shortening of the AP) and to faster recovery kinetics (due to hyperpolarization). The attenuation of the class I effect of lidocaine by carbachol can thus be considered mainly a consequence of the shortening of the inactivated state which results in a reduced affinity of lidocaine to its receptor and allows earlier dissociation of the drug. Minor binding of the drug due to hyperpolarization may play the major role in interactions between carbachol and quinidine.