D L Downie1, N P Franks, W R Lieb. 1. Biophysics Section, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Abstract
BACKGROUND: With the exception of gamma-aminobutyric acidA (GABAA) receptors, the major molecular targets underlying the anesthetizing actions of thiopental have yet to be established. Neuronal nicotinic acetylcholine receptors (nAChRs) are closely related to GABAA receptors and hence might also be major targets. If so, they might be expected to be substantially inhibited by surgical concentrations (EC50 = 25 micrometer) of thiopental and to display the same stereoselectivity as does general anesthesia. METHODS: Neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs were expressed in Xenopus oocytes. Peak acetylcholine-activated currents were measured at -70 mV using the two-electrode voltage clamp technique. Racemic thiopental and its two optical isomers were applied with and without preincubation and at high and low concentrations of acetylcholine. RESULTS: Inhibition of all three nAChRs was enhanced by preincubation with thiopental, a protocol that mimics the pharmacologic situation in vivo. Using this protocol, inhibition was further enhanced by high concentrations of acetylcholine, with IC50 = 18 +/- 2, 34 +/- 4, and 20 +/- 2 micrometer (mean +/- SEM) thiopental for the neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs, respectively, with Hill coefficients near unity. Neither the neuronal alpha7 nor the muscle alphabetagammadelta nAChR differentiated between the optical isomers of thiopental. However, R(+)-thiopental was significantly more effective than the S(-) isomer at inhibiting the neuronal alpha4beta2 nAChR; interestingly, this is diametrically opposite to their stereoselectivity for general anesthesia. CONCLUSIONS: Both central neuronal and peripheral muscle nAChRs can be substantially inhibited by thiopental at surgical EC50 concentrations but with either no stereoselectivity or one opposite to that for general anesthesia. Thus, nAChRs are probably not crucial targets for producing thiopental anesthesia, although nAChRs may play a part in the side effects produced by this agent.
BACKGROUND: With the exception of gamma-aminobutyric acidA (GABAA) receptors, the major molecular targets underlying the anesthetizing actions of thiopental have yet to be established. Neuronal nicotinic acetylcholine receptors (nAChRs) are closely related to GABAA receptors and hence might also be major targets. If so, they might be expected to be substantially inhibited by surgical concentrations (EC50 = 25 micrometer) of thiopental and to display the same stereoselectivity as does general anesthesia. METHODS: Neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs were expressed in Xenopus oocytes. Peak acetylcholine-activated currents were measured at -70 mV using the two-electrode voltage clamp technique. Racemic thiopental and its two optical isomers were applied with and without preincubation and at high and low concentrations of acetylcholine. RESULTS: Inhibition of all three nAChRs was enhanced by preincubation with thiopental, a protocol that mimics the pharmacologic situation in vivo. Using this protocol, inhibition was further enhanced by high concentrations of acetylcholine, with IC50 = 18 +/- 2, 34 +/- 4, and 20 +/- 2 micrometer (mean +/- SEM) thiopental for the neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs, respectively, with Hill coefficients near unity. Neither the neuronal alpha7 nor the muscle alphabetagammadelta nAChR differentiated between the optical isomers of thiopental. However, R(+)-thiopental was significantly more effective than the S(-) isomer at inhibiting the neuronal alpha4beta2 nAChR; interestingly, this is diametrically opposite to their stereoselectivity for general anesthesia. CONCLUSIONS: Both central neuronal and peripheral muscle nAChRs can be substantially inhibited by thiopental at surgical EC50 concentrations but with either no stereoselectivity or one opposite to that for general anesthesia. Thus, nAChRs are probably not crucial targets for producing thiopental anesthesia, although nAChRs may play a part in the side effects produced by this agent.
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