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.

Deranged sodium to sudden death

“…A recent study investigated lidocaine (lignocaine) effects in a multiscale computational model (Cardona et al . ). The authors demonstrated both anti‐fibrillatory effects in normal tissue and predicted the potential for pro‐arrhythmia with lidocaine during pathologies including acidosis and ischaemia, as has also been demonstrated experimentally due to differential effects of drugs on channels from the normal and infarct border zones (Pu et al .…”

Multiscale computational analysis of the bioelectric consequences of myocardial ischaemia and infarction

“…According to their simulation results, pinacidil 87 was shown to be proarrhythmic (incrementing the VW) at low concentrations but protective at concentrations higher than 10 mol/L, 88 while lidocaine 89 facilitates the onset of reentry in 20 ischaemic ventricular tissue. 90 In a similar study using a 2D slice of virtual acutely ischaemic ventricular tissue, Tice et al…”

In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles

“…In our simulations, the results of quinidine on SQT1 are consistent with the clinical studies (see Discussion section). Regarding the experimental conditions, many factors that can influence the binding of a drug to ion channels are increasingly being modeled, including oxygen, the concentration of ions, temperature and pH [57,58]. However, pharmacological screening does not usually record sufficient data [58].…”