To the Editor:—

We read with great interest the elegant in vitro  study by Tanito et al.  1that demonstrates that edrophonium binds to muscarinic M2and M3receptors and acts as a competitive muscarinic antagonist. The authors speculate that this antimuscarinic effect may explain the modest bradycardia produced by edrophonium, compared with other anticholinesterase drugs, such as neostigmine. In this regard, the bradycardia resulting from enhancement of cholinergic transmission in parasympathetic autonomic ganglia and at the sinoatrial node, as a consequence of cholinesterase inhibition, would be reduced by the direct antimuscarinic action of edrophonium at the sinoatrial node.

Another mechanism to account for edrophonium's modest parasympathomimetic effect may be that it inhibits autonomic ganglionic cholinergic transmission. In studies in anesthetized cats, with tonic cardiac parasympathetic drive provided by continuous electrical stimulation of the vagus nerve, edrophonium produced a biphasic effect on the evoked bradycardia. 2At lower doses, the bradycardia was augmented, presumably as a consequence of the anticholinesterase effect, whereas at higher (but clinically relevant) doses, it was blocked. Even when the evoked  bradycardia was completely abolished by edrophonium, a small reduction in heart rate persisted, which was thought to be the consequence of the acetylcholine spontaneously released  from the intrinsic cardiac postganglionic cells. 2,3The failure of edrophonium to block this persistent bradycardia suggested that in this preparation, edrophonium does not block the M2receptors. Rather, it was hypothesized that block of the evoked bradycardia occurred in the autonomic ganglion. Indeed, using the rat sympathetic superior cervical ganglion as a model for autonomic ganglionic transmission, clinically relevant doses of edrophonium (10–500 μm, ED50163 μm) were shown to decrease the compound action potential amplitude recorded from the postganglionic axons in response to electrical stimulation of preganglionic axons. 4Block of the synaptic transmission was shown to occur postsynaptically (presumably via  block of nicotinic receptors), as edrophonium inhibited postganglionic cell firing in response to exogenously administered acetylcholine. In other models of cholinergic transmission, mouse tumor cells 5and Xenopus laevis  oocytes 6with expressed nicotinic receptors, clinically relevant doses of edrophonium (ED503.8 and 82 μm, respectively) decrease acetylcholine-activated channel open time 5and DMPP (a selective nicotinic agonist)-activated currents, 6indicating a postsynaptic nicotinic blocking effect. Edrophonium may also block ganglionic transmission by decreasing release of acetylcholine from preganglionic terminals, although this effect, if present, is likely to be small. 4 

From these facts, it is predicted that edrophonium may have the potential to reduce cardiovascular autonomic drive in both sympathetic (block of ganglionic nicotinic transmission) and parasympathetic (block of ganglionic nicotinic transmission and of muscarinic transmission at the sinoatrial node) pathways. This was recently demonstrated in a study of the effects of clinically relevant doses of edrophonium on the spectral analysis of blood pressure and heart rate variability in patients. 7Regardless of whether edrophonium blocks cholinergic transmission in autonomic ganglia, at the sinoatrial node, or both, both effects would reduce cardiovascular autonomic drive and could account for the modest parasympathomimetic effects produced by cholinesterase inhibition.

Tanito Y, Miwa T, Endou M, Hirose Y, Gamoh M, Nakaya H, Okumura F: Interaction of edrophonium with muscarinic acetylcholine M2and M3receptors. A nesthesiology 2001; 94: 804–14
Backman SB, Stein RD, Fox GS, Polosa C: Heart rate changes in cardiac transplant patients and in the denervated cat heart after edrophonium. Can J Anaesth 1997; 44: 247–54
Backman SB, Stein RD, Blank DW, Collier B, Polosa C: Different properties of the bradycardia produced by neostigmine and edrophonium in the cat. Can J Anaesth 1996; 43: 731–40
Stein RD, Backman SB, Collier B, Polosa C: Synaptic inhibitory effects of edrophonium on sympathetic ganglionic transmission. Can J Anaesth 1998; 45: 1011–8
Wachtel RE: Comparisons of anticholinesterases and their effects on acetylcholine-activated ion channels. A nesthesiology 1990; 72: 496–503
Yost CS, Maestrone E: Clinical concentrations of edrophonium enhance desensitization of the nicotinic acetylcholine receptor. Anesth Analg 1994; 78: 520–6
Deschamps A, Backman SB, Novak V, Plourde G, Fiset P, Chartrand D: Effects of the anticholinesterase edrophonium on spectral analysis of heart rate and blood pressure variability in humans. J Pharm Exp Ther 2002; 300: 112–7