Computer Simulation of the Effects of Organophosphate-Induced Cardiac Toxicity

摘要

Organophosphosphorous (OP) compounds are widely used in agriculture as insecticides. Their significant toxicity has severe cardiovascular ramifications upon overexposure with an estimated 98% of the agent located within or transported by the vasculature and deposited in the cardium. Toxicity is manifested with the OP binding to the acetylcholinesterase (AChE) of the cardiac tissue, preventing hydrolysis of the acetylcholine (ACh) and resulting in an ACh overload. Negative inotropy and arrhythmia, not only in the atria (bradyarrhythmia), the Purkinje fibers and the ventricles is accompanied by conduction abnormalities. An ancillary effect of the toxicity is an increase in the calcium influx resulting in an increase in the intracellular calcium concentration. An increase in the vagal tone also ensues contributing to atrial fibrillation. OP toxicity also results in the elevation of the extracellular potassium concentration that influences the transmembrane resistance of Purkinje fibers and sodium ion concentration, mimicking ischemia. Moderate elevation of extracellular potassium increases the conduction velocity but in concentrations of 8-16 mM, a decrease with eventual cessation of signal transmission is noted. This results in modulation and possible dissolution of the action potential. The electrophysiologic changes of organophosphate (OP)-produced acetylcholine (ACh) overload in atrial tissue was studied by computer simulation. Cellular processes were expressed as a system of differential equations. In a tissue of 3 cm by 3 cm, changes in the action potential dynamics due to the heterogeneity of the substrate resulting from OP deposition in the tissue were produced, and the conditions for the generation and persistence of reentry waves were determined. It was shown that modulation of cardiac cell membrane currents can be used to modulate conditions leading to reentry suggesting avenues to prophylaxis.