Session P7C.2

The pH Dependence on the Electrophysiological Effect of Lidocaine in Ventricular Myocardium: A Computer Modelling Study

K Cardona, J Saiz*, JM Ferrero, M Martinez,
G Moltó, JM Alonso

Universidad Politécnica de Valencia
Valencia, Spain

Lidocaine is a class I antiarrhythmic drug that partially blocks the fast sodium channels. This drug is a tertiary amine and exists as an uncharged free amine and also in cationic protonated form at physiologic pH. The protonation of each species depends on the ambient of pH. A clear understanding of the influence of external pH on the blocking action of local anesthetic drugs in cardiac muscle is important for a number of reasons. The substantial fall in external pH during myocardial ischemia changes the kinetics of drug binding to the Na+ channels and may partially explain the more depressant effect of this drug during myocardial ischemia. Experimental data have shown that the rate of development and recovery of block is slowed at low pH. Slow recovery at low pH is generally believed to result from an increase in the fraction of charged drug at the receptor site.
The main goal of this work is to introduce the effect of pH in the mathematical model of lidocaine developed previously by our group. We use this model for studying the effect of different drug concentrations on the characteristics of action potentials at different pH.
We have used the model proposed by Starmer and Courtney to solve the equations for the drug and proton dissociation. In our model, we have assumed that the binding and unbinding of charged drug form is controlled by the activation gate with the channel necessarily being open, whereas the neutral drug form can bind and unbind in all states of the sodium channel. We assume that the charged form is responsible for the slow component of the block, in agreement with experimental observations. The estimation of the association and dissociation rate constants is based on experimental results found by Schwartz. The model developed has been included in the Luo Rudy model (LRd00) of guinea pig action potential. A strand of 200 cells was used in the simulations. The excitation was applied to cell #0. We tested the effect of different lidocaine concentrations on maximum upstroke velocity (dV/dt), action potential duration (APD), conduction velocity (CV) and effective refractory period (ERP).
Our results show that 50 micromol/L of lidocaine reduces the dV/dt by 36 %, 49 % and 71 % for pH of 7.4, 6.9 and 6.4, respectively. This is consistent with experimental data where lidocaine produces greater depression of dV/dt in ischemic compared with normal conditions. Furthermore, lidocaine blocks more slowly the channel when the pH was decreased. Indeed, the time constant was 1338, 840 and 460 ms for pH 6.4, 6.9 and 7.4, correspondingly. Also, we have found that the depression of CV was affected by the pH too. For 50 micromol/L of lidocaine at pH 6.4, the CV was 0.27 m/s while, at pH 7.4 it was 0.23 m/s. However, the pH-dependence of lidocaine does not influence the ERP.
In conclusion, the simulations have shown the effect of lidocaine on dV/dt and CV is increased by low pH, and its blockage is slowed by the reduction in pH.

(Abstract Control Number: 136)