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. 2005 Jan;144(1):98-107.
doi: 10.1038/sj.bjp.0705942.

Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons

Martin Weber  1 , Leonid Motin, Simon Gaul, Friederike Beker, Rainer H A Fink, David J Adams
Affiliations

Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons

Martin Weber et al. Br J Pharmacol. 2005 Jan.

Erratum in

  • Br J Pharmacol. 2005 Jan;144(1):144

Abstract

The effects of intravenous (i.v.) anaesthetics on nicotinic acetylcholine receptor (nAChR)-induced transients in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and membrane currents were investigated in neonatal rat intracardiac neurons. In fura-2-loaded neurons, nAChR activation evoked a transient increase in [Ca(2+)](I), which was inhibited reversibly and selectively by clinically relevant concentrations of thiopental. The half-maximal concentration for thiopental inhibition of nAChR-induced [Ca(2+)](i) transients was 28 microM, close to the estimated clinical EC(50) (clinically relevant (half-maximal) effective concentration) of thiopental. In fura-2-loaded neurons, voltage clamped at -60 mV to eliminate any contribution of voltage-gated Ca(2+) channels, thiopental (25 microM) simultaneously inhibited nAChR-induced increases in [Ca(2+)](i) and peak current amplitudes. Thiopental inhibited nAChR-induced peak current amplitudes in dialysed whole-cell recordings by approximately 40% at -120, -80 and -40 mV holding potential, indicating that the inhibition is voltage independent. The barbiturate, pentobarbital and the dissociative anaesthetic, ketamine, used at clinical EC(50) were also shown to inhibit nAChR-induced increases in [Ca(2+)](i) by approximately 40%. Thiopental (25 muM) did not inhibit caffeine-, muscarine- or ATP-evoked increases in [Ca(2+)](i), indicating that inhibition of Ca(2+) release from internal stores via either ryanodine receptor or inositol-1,4,5-trisphosphate receptor channels is unlikely. Depolarization-activated Ca(2+) channel currents were unaffected in the presence of thiopental (25 microM), pentobarbital (50 microM) and ketamine (10 microM). In conclusion, i.v. anaesthetics inhibit nAChR-induced currents and [Ca(2+)](i) transients in intracardiac neurons by binding to nAChRs and thereby may contribute to changes in heart rate and cardiac output under clinical conditions.

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Figures

Figure 1
Figure 1
Clinically relevant concentrations of thiopental inhibit nAChR-mediated [Ca2+]i transients in rat intracardiac neurons. (a) Representative [Ca2+]i transients in response to focal application of 500 μM ACh obtained in the absence (control) and presence of 25 μM thiopental in the bath solution. The bath solution also contained 100 nM atropine to inhibit mAChRs. (b) Concentration–response relationship for inhibition of ACh-induced [Ca2+]i transients by thiopental in the presence of 100 nM atropine. Average [Ca2+]i responses to ACh in the presence of thiopental were normalized to average responses obtained with agonist applications before and after superfusion with thiopental in the same cells. Data points represent the mean normalized [Ca2+]i response±s.e.m. from two to seven cells. The curve of best fit to the data had an IC50=28 μM and Hill coefficient of 1.24.
Figure 2
Figure 2
Inhibition of nAChR-induced [Ca2+]i transients and membrane currents by thiopental. (a) Fura-2-loaded rat intracardiac neurons were voltage clamped at −60 mV using the perforated patch whole-cell recording configuration. Representative traces of transient increases in [Ca2+]i and whole-cell inward currents recorded simultaneously in response to 500 μM ACh in the absence and presence of 25 μM thiopental bath applied. The bath solution also contained 100 nM atropine. (b and c) Bar graphs of the changes in ACh-induced [Ca2+]i increases (Δ[Ca2+]i) and membrane currents (IACh) by thiopental together with ⩾100 nM atropine bath applied. Bath application of 25 μM thiopental significantly reduced ACh-induced increases in [Ca2+]i (P<0.05, n=4) and peak inward current amplitude (P<0.05, n=4).
Figure 3
Figure 3
Voltage-independent inhibition of nAChR-mediated membrane currents by thiopental in voltage-clamped rat intracardiac neurons. (a) Whole-cell currents evoked by 300 μM ACh in the presence of 100 nM atropine at various membrane potentials in the absence (control) and presence of 25 μM thiopental, as indicated by the horizontal bar. The dashed horizontal lines indicate control responses obtained by averaging the peak current amplitudes before and after superfusion with thiopental. (b) Current–voltage relationship for peak current (IACh) amplitude evoked by 300 ACh μM in the presence 100 nM atropine. Data points represent mean peak current amplitudes±s.e.m. of 11 cells, before, during and after superfusion with 25 μM thiopental. (c) Inhibition of ACh-induced peak current (IACh) amplitudes by thiopental and ketamine as a function of membrane potential in the presence of 100 nM atropine. Data points represent normalized mean peak current amplitudes±s.e.m. in the presence of 25 μM thiopental (triangles, n=11) and 10 μM ketamine (circles, n=3). Responses were normalized to average responses obtained before and after the superfusion with an anaesthetic in each individual cell. A linear regression of the relative peak current amplitudes and the holding potentials indicated that the slope was not significantly different from zero (P<0.3).
Figure 4
Figure 4
Clinically relevant concentrations of thiopental, ketamine and pentobarbital inhibit nAChR-mediated [Ca2+]i transients. (a) Representative [Ca2+]i transients in rat intracardiac neurons in response to focal application of 500 μM ACh obtained in the absence (control) and presence of 50 μM pentobarbital in the bath solution. The bath solution also contained 100 nM atropine to inhibit mAChRs. (b) Representative [Ca2+]i responses to 500 μM ACh focally applied in the presence of 100 nM atropine obtained in the absence (control) and presence of 10 μM ketamine in the bath solution. (c) Bar graph of Δ[Ca2+]i in response to ACh (control), ACh+25 μM thiopental (n=6), 50 μM pentobarbital (n=8) and 10 μM ketamine (n=7). Atropine (100 nM) was present in all bath solutions to inhibit mAChRs.
Figure 5
Figure 5
Caffeine-induced [Ca2+]i transients in rat intracardiac neurons are not inhibited by thiopental. Representative [Ca2+]i transients evoked upon activation of ryanodine receptors by application of 10 mM caffeine in the absence (control) and presence of 25 μM thiopental, as indicated by the horizontal bar.
Figure 6
Figure 6
Clinically relevant concentrations of i.v. anaesthetics do not inhibit voltage-dependent Ca2+ channel currents or muscarinic ACh receptor-mediated [Ca2+]i increases in rat intracardiac neurons. (a) Superimposed whole-cell Ba2+ currents obtained in response to step depolarization from −100 to −20 mV in the absence (control, black trace) and presence of 25 μM thiopental, 50 μM pentobarbital and 10 μM ketamine (grey traces). (b) Representative [Ca2+]i transients in response to 100 μM muscarine focally applied in the absence (control) and presence of 25 μM thiopental, 10 μM ketamine and 50 μM pentobarbital in the bath solution.
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References

    1. ADAMS D.J., NUTTER T.J. Calcium permeability and modulation of nicotinic acetylcholine receptor-channels in rat parasympathetic neurons. J. Physiol. (Paris) 1992;86:67–76. - PubMed
    1. AKINE A., SUZUKA H., HAYASHIDA Y., KATO Y. Effects of ketamine and propofol on autonomic cardiovascular function in chronically instrumented rats. Auton. Neurosci. 2001;87:201–208. - PubMed
    1. ANDOH T., FURUYA R., OKA K., HATTORI S., WATANABE I., KAMIYA Y., OKUMURA F. Differential effects of thiopental on neuronal nicotinic acetylcholine receptors and P2X purinergic receptors in PC12 cells. Anesthesiology. 1997;86:1199–1209. - PubMed
    1. BEKER F., WEBER M., FINK R.H.A., ADAMS D.J. Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons. J. Neurophysiol. 2003;90:1956–1964. - PubMed
    1. BERRIDGE M.J. Neuronal calcium signaling. Neuron. 1998;21:13–26. - PubMed

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