Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons.
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.
Weber
Martin
M
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.
Motin
Leonid
L
Gaul
Simon
S
Beker
Friederike
F
Fink
Rainer H A
RH
Adams
David J
DJ
D000109:Acetylcholine / Q000494:pharmacology; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001463:Barbiturates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004553:Electric Conductivity; D005456:Fluorescent Dyes; D016257:Fura-2; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006321:Heart / Q000294:innervation*; D007649:Ketamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D013874:Thiopental / Q000494:pharmacology
D000778:Anesthetics, Dissociative; D018686:Anesthetics, Intravenous; D001463:Barbiturates; D005456:Fluorescent Dyes; D011978:Receptors, Nicotinic; D007649:Ketamine; D010424:Pentobarbital; D013874:Thiopental; D000109:Acetylcholine; D002118:Calcium; D016257:Fura-2