Non-invasive monitoring of CN oxygenation prior to, during, and after thoracoabdominal aortic repair is feasible. Lumbar CN oxygenation levels directly respond to compromise of aortic blood circulation.

Background and purpose: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. Experimental approach: We have investigated the effects of three halogenated structural analogues of propofol on voltageoperated human skeletal muscle sodium channels (Na V 1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na V 1.2) heterologously expressed in human embryonic kidney cell line 293. Key results: 4-Iodo-, 4-bromo-and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC 50 for block of resting channels at À150 mV was 2.3, 3.9 and 11.3 mM in Na V 1.4, respectively, and 29.2 mM for 4-chloropropofol in Na V 1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na V 1.4, and 450 nM for 4-chloropropofol in Na V 1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). Conclusions and implications:Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. (2008) 155, 265-275; doi:10.1038/bjp.2008 published online 23 June 2008 Keywords: sodium channels; voltage-operated; local anaesthetics; propofol analogues Abbreviations: ECI 50 , half-maximum effect in inactivated channels; ECR 50 , half-maximum effect on resting channels; k, Boltzmann parameter, slope factor of the availability curve; Na V 1.2, voltage-gated neuronal sodium channel (brain type IIA); Na V 1.4, voltage-gated skeletal muscle sodium channel; n H , Hill coefficient; V 0.5 , Boltzmann parameter, voltage of half-maximum channel availability; DV 0.5 , shift in the voltage dependence of channel availability British Journal of Pharmacology

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These results, which show that 2,6-dimethyl-4-chlorophenol blocks voltage-operated sodium channels in a lidocaine-like manner while having a several fold higher potency than the non-halogenated parent compound, highlight a potentially meaningful principle of increasing the sodium channel blocking potency of phenol derivatives.

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