Cellular Actions and Interactions of Anticholinesterases and Their Antidotes in Mammalian Autonomic Neurons

摘要

The major objectives of this study are (1) elucidation of the cellular mechanism of the facilitatory and blocking effects of organophosphorus anti-cholinesterase (anti-ChE) agent, diisopropylfluorophosphate (DFP) on sympathetic neurons and on ganglionic transmission; and (2) clarification of the site and mechanism of action of a cholinesterase (ChE) reactivator, pyridinealdoxime (2-PAM) on cholinergic transmission. Isolated rabbit superior cervical ganglia or guinea pig inferior mesenteric ganglia were used in this study. Intracellular recordings were obtained from neurons of the isolated sympathetic ganglia by means of glass microelectrodes. DFP, 2-PAM and other agents were applied to the ganglia either by superfusion in known concentrations or by pressure ejection from a micropipette containing appropriate agents. DFP exerted a dose-dependent action on nicotinic and muscarinic transmission of the sympathetic neurons. It is concluded that contrary to the long standing concept that DFP and 2-PAM affect cholinergic transmission solely by inhibiting and reactivating junctional ChE, respectively, these compounds exert direct actions on cholinergic nicotinic and muscarinic receptors/ion-channel complex that are independent of the status of junctional ChE activity. D-tubocurarine and prostaglandin reversibly and dose-dependently suppressed the spike after-hyperpolarization (AH) of rabbit and guinea pig sympathetic ganglion cells. The ability of these two compounds to suppress spike AH is interesting as they may increase the membrane excitability of sympathetic neurons and other central neurons.