Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Abstract

Lidocaine is a class I antiarrhytmic drug that blocks Na+ channels and exists in both neutral and charged forms at a physiological pH. In this work, a mathematical model of pH and the frequency-modulated effects of lidocaine has been developed and incorporated into the Luo-Rudy model of the ventricular action potential. We studied the effects of lidocaine on Na+ current, maximum upstroke velocity, and conduction velocity and demonstrated that a decrease of these parameters was dependent on pH, frequency, and concentration. We also tested the action of lidocaine under pathological conditions. Specifically, we investigated its effects on conduction block under acute regional ischemia. Our results in one-dimensional fiber simulations showed a reduction of the window of block in the presence of lidocaine, thereby highlighting the role of reduced conduction velocity and safe conduction. This reduction may be related to the antifibrillatory effects of the drug by hampering wavefront fragmentation. In bidimensional acute ischemic tissue, lidocaine increased the vulnerable window for reentry and exerted proarrhythmic effects. In conclusion, the present simulation study used a newly formulated model of lidocaine, which considers pH and frequency modulation, and revealed the mechanisms by which lidocaine facilitates the onset of reentries. The results of this study also help to increase our understanding of the potential antifibrillatory effects of the drug.