British Journal of Anaesthesia, Vol 81, Issue 4 569-577, Copyright © 1998 by The Board of Management and Trustees of the British Journal of Anaesthesia
G. W. Nietgen, C. W. Honemann, C. K. Chan, G. L. Kamatchi and M. E. Durieux
Muscarinic acetylcholine signalling plays major roles in regulation of
consciousness, cognitive functioning, pain perception and circulatory
homeostasis. Halothane has been shown to inhibit m1 muscarinic signalling.
However, no comparative data are available for desflurane, sevoflurane or
isoflurane, nor have the anaesthetic effects on the m3 subtype (which is
also prominent in the brain) been studied. Therefore, we have investigated
the effects of these compounds on isolated m1 and m3 muscarinic receptor
function. Defolliculated Xenopus oocytes expressing recombinant m1 or m3
muscarinic or (for comparison) AT1A angiotensin II receptors were voltage
clamped, and Ca(2+)-activated Cl- currents (ICl(Ca)) induced by
acetyl-beta-methylcholine (Mch) or angiotensin II were measured in the
presence of clinically relevant concentrations of halothane, sevoflurane,
desflurane or isoflurane. To determine the site of action of the volatile
anaesthetics we compared anaesthetic effects on m1, m3 and AT1A receptor
function and studied the effects of volatile anaesthetics on signalling
induced by intracellular injection of the second messenger IP3. Desflurane
had a biphasic effect on m1 signalling, enhancing at a concentration of
0.46 mmol litre-1 but depressing at 0.92 mmol litre-1. A similar, although
not significant, trend was observed with m3 signalling. Isoflurane had no
effect on m1 signalling, but profoundly inhibited m3 signalling.
Sevoflurane depressed the function of m1 and m3 signalling in a dose-
dependent manner. Halothane, similar to its known effect on m1 signalling,
dose-dependently depressed m3 function. ICl(Ca) induced by intracellular
injections of IP3 were unaffected by all four anaesthetics. Similarly, none
of the anaesthetics tested affected AT1A signalling. Absence of
interference with AT1A signalling and intracellular pathways suggest that
the effects of anaesthetics on muscarinic signalling most likely result
from interactions with the m1 or m3 receptor molecule. Multiple interaction
sites with different affinities may explain the biphasic response to
desflurane. Anaesthetic- specific effects on closely related receptor
subtypes suggest defined sites of action for volatile anaesthetics on the
receptor protein.
LABORATORY INVESTIGATIONS
Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function
Department of Anaesthesiology, University of Virginia Health Sciences Center, PO Box 10010, Charlottesville, VA 22903-0010, USA
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