Corbier_1989_Arch.Int.Pharmacodyn.Ther_300_218

The purpose of this study was to determine whether an anticholinesterase organophosphorous compound, methylphosphonothiolate (VX), could display direct effects on isolated guinea-pig ventricular muscle, and to compare these possible effects with those of carbachol (CCH) and physostigmine (PHYS). Our results confirm the direct positive inotropic effect of CCH (stimulation frequency; 2 Hz) in a concentration range from 10(-7) to 10(-3) M; lack of PHYS or VX-induced modifications was set. In the presence of an adrenergic agonist, isoproterenol (ISO) 10(-7) M, CCH or PHYS modulated the positive inotropic effect of ISO. Even with elevated concentrations of CCH (10(-4) M) or PHYS (10(-3) M), arrhythmias were never depicted. VX-induced modifications are different. Under VX, the development of (1) a positive inotropic effect and (2) two contractile events in response to each stimulation were observed. Electrophysiological studies revealed that VX led to the development of delayed after-depolarizations, and eventually triggered activity. We conclude that, in addition to its anticholinesterase activity, VX could induce a Na+/K+ ATPase inhibition. This effect could be at the onset of ventricular arrhythmias that are observed in vivo in organophosphorous compounds poisoning.