Evidence for a direct noncholinergic effect of an organophosphorous compound on guinea-pig papillary muscles: are ventricular arrhythmias related to a Na+/K+ ATPase inhibition?
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.
Corbier
A
A
Centre d'Etudes du Bouchet, Division of Pharmacology, Vert-Le-Petit, France.
Robineau
P
P
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000201:enzymology; D001341:Autonomic Nervous System / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010830:Physostigmine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013564:Sympathetic Nervous System / Q000187:drug effects
D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D011976:Receptors, Muscarinic; C051451:methylphosphonothiolate; D002217:Carbachol; D010830:Physostigmine; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol