Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function

Muscarinic acetylcholine signalling plays major roles in regulation of consciousness, cognitive Functioning, pain perception and circulatory homeostasis. Halothane has been shown to inhibit mi 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 mi and m3 muscarinic receptor function. Defolliculated Xenopus oocytes expressing recombinant mi or m3 muscarinic or (for comparison) AT(1A) angiotensin II receptors were voltage clamped, and Ca2+-activated Cl- currents (I-Cl(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 mi, m3 and AT(1A) 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 mi 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 mi signalling, but profoundly inhibited m3 signalling. Sevoflurane depressed the function of mi and m3 signalling in a dose-dependent manner. Halothane, similar to its known effect on mi signalling, dose-dependently depressed m3 function. I-Cl(Ca), induced by intracellular injections of IP3 were unaffected by all four anaesthetics. Similarly, none of the anaesthetics tested affected AT(1A) signalling. Absence of interference with AT(1A) signalling and intracellular pathways suggest that the effects of anaesthetics On muscarinic signalling most likely result from interactions with the mi 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.