Ketamine inhibits synaptic transmission and nicotinic acetylcholine receptor-mediated responses in rat intracardiac ganglia in situ
Introduction
Ketamine is used as an anaesthetic and analgesic in clinical and veterinary practice, and similarly in animal research. Since its activity is rapid in onset and short lived, it is ideal for brief surgical operations and is used in conflict zones and disaster situations (Trelles Centurion et al., 2017). In addition, the risk of overdose is small and hence few complications are associated with its use. Ketamine is used in human surgery in adults and pediatric patients, being listed in the WHO Essential Medicine List since 1985 (WHO Model List of Essential Medicines, 2017). The principal target for the action of ketamine is generally held to be its antagonist action at the N-methyl-d-aspartate (NMDA) receptor (Anis et al., 1983; Lodge and Mercier, 2015). Ketamine, however, has been demonstrated to interact with several other neurotransmitter receptors and ion channels including opioid and cholinergic receptors (Zanos et al., 2018) and can have anaesthetic effects on voltage-gated Na+ channels (Sinner and Graf, 2008).
The intravenous (i.v.) dissociative anaesthetic ketamine is known to affect cardiac parameters such as heart rate and cardiac output under clinical conditions (Tweed et al., 1972) and in chronically instrumented animals (Akine et al., 2001; Blake and Korner, 1981, 1982; Inoue and Arndt, 1982). Ketamine also has a direct effect on cardiac muscle, decreasing myocardial contractility, but only at supratherapeutic ketamine doses (~100 μM) (Sprung et al., 1998). Considering autonomic regulation, excitatory neurotransmission in guinea-pig sympathetic ganglia is blunted by ketamine (Juang et al., 1980; Mahmoodi et al., 1980). This effect is overridden by the stimulation of a central sympathetic response sustaining or increasing blood pressure (Kurdi et al., 2014). However, ketamine inhibition of parasympathetic neurons involved in the regulation of cardiac function may contribute to the increase in heart rate (Inoue and König, 1988). Ketamine has been shown to inhibit nicotinic receptor excitation in cardiac preganglionic parasympathetic neurons of the nucleus ambiguus of the brainstem (Irnaten et al., 2002b). Postganglionic intracardiac neurons have also been shown to modulate heart rate in a nicotine-dependent manner, demonstrating the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) (Bibevski et al., 2000; Ji et al., 2002).
Ketamine inhibits reversibly and stereo-specifically neuronal nAChRs in rat PC12 cells (Sasaki et al., 2000) and human SH-SY5Y cells (Friederich et al., 2000). Furthermore, bath application of ketamine has been shown to cause a concentration-dependent inhibition of ACh-induced increases in intracellular Ca2+ concentration ([Ca2+]i) in rat ICG neurons (Weber et al., 2005). At a clinically relevant concentration, ketamine (10 μM) reversibly inhibited ACh-induced increases in [Ca2+]i but failed to inhibit increases in [Ca2+]i evoked by focal application (100 μM) of either muscarine or ATP. Taken together, ketamine would be predicted to reduce the excitatory postsynaptic potential (EPSP) amplitude and depress synaptic transmission in the ICG and would account for the action of ketamine on peripheral vagal transmission to the heart (Inoue and König, 1988). We have directly tested this proposal by investigating the actions of ketamine on postsynaptic responses to vagal nerve stimulation and exogenous ACh and nicotine in ICG neurons in a whole mount ganglion preparation of the excised right atrial ganglion plexus from the adult rat. A preliminary account of the results has been given in a published abstract (Harper et al., 2006).
Section snippets
Preparation
Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al., 2010). The whole mount ICG preparation has been described previously (Rimmer and Harper, 2006). Briefly, twenty young, non-pregnant, female adult Wistar rats (≥ 6 wk, 125–220 g) were used. The University of Dundee is a designated scientific establishment (certificate of designation no. 60/2602) under the Animals (Scientific Procedures) Act 1986 (‘the Act’). Rats were obtained from a designated supplier in the
The action of ketamine on the passive membrane properties of the postganglionic ICG neurons
All ICG neurons investigated had a resting membrane potential of at least −40 mV, overshooting somatic action potentials evoked by short depolarizing current pulses (2–3 ms) and received excitatory input due to transmitter release from the vagus or interganglionic nerve terminals. Recordings were stable for at least 15 min before readings were taken and the superfusing solution was altered. The passive membrane properties, resting membrane potential and input resistance, were in good agreement
Discussion
The increasing use of ketamine as a potential rapid-onset antidepressant (Zanos and Gould, 2018; Villas Boas et al., 2019) necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. Furthermore, it is recognised that abuse of or chronic treatment with ketamine cause ventricular structural and functional alterations which lead to alterations in cardiac electrophysiological properties and increase the susceptibility to arrhythmias
Authors contributions
Performed experiments and analysed the data: A.A.H., K.R., J.R.D., J.R.M., D.J.A.
Conceived and designed the studies, supervised the project and wrote the manuscript: A.A.H., D.J.A.
Funding sources
This work was supported by grants from the British Heart Foundation (A.A.H.) and National Health and Medical Research Council of Australia (D.J.A.). K. Rimmer was a Biotechnology and Biological Sciences Research Council, UK Research Student.
Declaration of competing interest
The authors declare no conflict of interests.
Acknowledgements
We thank Professor Leonard Arnolda, IHMRI, University of Wollongong, for constructive criticism of a draft of the manuscript.
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