Synaptic inhibitory effects of edrophonium on sympathetic ganglionic transmission

Abstract

Laboratory Reports Synaptic inhibitory effects of edrophonium on sympathetic ganglionic transmissionPurpose: To evaluate the effect of edrophonium on synaptic transmission in the superior cervical ganglion.Methods: In anaesthetized rats the effect of edrophonium on synaptic transmission was studied in vitro by testing whether it blocks the compound action potential recorded from postganglionic fibres evoked by stimulation of preganglionic axons. The superior cervical ganglion was excised and the cervical sympathetic trunk and internal carotid nerve were used for stimulating and recording, respectively. Drugs superfused included edrophonium ( 0.1-500 pM), neostigmine (0. I -I 0/~M), and muscarinic M and M 2 antagonists pirenzepine and AFDX-I 16 (200 nM-I 0 pM), respectively. To eva uate a presynapt c act on, the effect of edrophonium on basal and high-K + (35 mM) evoked re ease of [3H]ACh from the superior cervical ganglion was studied in vitro. To evaluate a postsynaptic action, edrophonium's effect on postganglionic nerve discharge in response to arterial injection of ACh (100 pg) into the superior cervical ganglion was determined in vivo.

Effects of the Anticholinesterase Edrophonium on Spectral Analysis of Heart Rate and Blood Pressure Variability in Humans

“…Block of the synaptic transmission was shown to occur postsynaptically, as edrophonium inhibited postganglionic cell firing in response to exogenously administered ACh (Stein et al, 1998). It is relevant that in other models of cholinergic transmission, mouse tumor cells (Wachtel, 1990), and Xenopus laevis oocytes (Yost and Maestrone, 1994) with expressed nicotinic receptors, clinically relevant doses of edrophonium (ED 50 3.8 and 82 M, respectively) decrease ACh-activated channel open time (Wachtel, 1990) and DMPP (a selective nicotinic agonist)-activated currents (Yost and Maestrone, 1994), indicating a postsynaptic blocking effect.…”

“…For example, it is well established clinically that the fall in heart rate produced by edrophonium is significantly smaller than that produced by neostigmine (Fogdall and Miller, 1973;Cronnelly et al, 1982). It has been proposed that the modest bradycardic effect of edrophonium occurs because the enhancement of parasympathetic drive, secondary to the anticholinesterase action, is diminished by the inhibitory effect of the drug on autonomic cholinergic transmission (Backman et al, 1997;Stein et al, 1998). Animal studies suggest that the enhancement (anticholinesterase action) occurs at lower doses compared with the reduction (block of cholinergic receptors) of autonomic cholinergic transmission that occurs at high doses (Backman et al, 1996a;Stein et al, 1998).…”

“…It is relevant that in other models of cholinergic transmission, mouse tumor cells (Wachtel, 1990), and Xenopus laevis oocytes (Yost and Maestrone, 1994) with expressed nicotinic receptors, clinically relevant doses of edrophonium (ED 50 3.8 and 82 M, respectively) decrease ACh-activated channel open time (Wachtel, 1990) and DMPP (a selective nicotinic agonist)-activated currents (Yost and Maestrone, 1994), indicating a postsynaptic blocking effect. Edrophonium may also block transmission in the peripheral autonomic pathway by blocking release of ACh from preganglionic terminals in the autonomic ganglia (Stein et al, 1998) and by blocking inhibitory cardiac muscarinic (M2) receptors (Endou et al, 1997). The inhibitory effect of edrophonium on autonomic outflow, regardless of the site of action, is reminiscent of the model of autonomic failure achieved with blockage of cholinergic ganglionic transmission Shannon et al, 1998).…”

“…The evidence for a ganglion-blocking effect of edrophonium was obtained from studies in the rat sympathetic superior cervical ganglion, where clinically relevant doses of edrophonium [10 -500 M, ED 50 163 M; clinical peak serum concentration 50 -60 M with bolus dose of 1.0 mg ⅐ kg Ϫ1 edrophonium (Stein et al, 1998;Wachtel, 1990)] decreased the compound action potential amplitude recorded from the postganglionic axons in the internal carotid nerve in response to electrical stimulation of preganglionic axons in the cervical sympathetic trunk (Stein et al, 1998). Block of the synaptic transmission was shown to occur postsynaptically, as edrophonium inhibited postganglionic cell firing in response to exogenously administered ACh (Stein et al, 1998).…”

“…However, recent studies suggest that anticholinesterases may have additional effects at cholinergic synapses within the autonomic peripheral pathway. For example, in vivo and in vitro animal studies suggest that neostigmine and edrophonium directly activate (Backman et al, 1993a(Backman et al, , 1996a and inhibit (Backman et al, 1997;Stein et al, 1998), respectively, these cholinergic receptors. Thus, the parasympathomimetic action of the anticholinesterases must be understood within the context of their anticholinesterase activity on the one hand, and their direct interaction with cholinergic receptors on the other.…”