Kinetics of nicotinic acetylcholine ion channels in the presence of intravenous anaesthetics and induction agents.

1. Single channel currents activated by 250 nM acetylcholine were recorded from cell-attached patches of BC3H1 mouse tumour cells grown in culture. Channels were recorded in the absence and presence of alphaxalone, diazepam, etomidate, fentanyl, ketamine, meperidine, or propofol. 2. All of the anaesthetics tested shortened channel open time but did not alter single channel current amplitude. Drug concentrations calculated to reduce the time constant of open-time distributions by 50% were 99 microM alphaxalone, 66 microM diazepam, 57 microM etomidate, 26 microM fentanyl, 15 microM ketamine, 16 microM meperidine, or 81 microM propofol. 3. Ketamine, meperidine, and propofol reduced channel open time at concentrations comparable to plasma levels attained during therapeutic use of these agents, while alphaxalone, diazepam, etomidate, and fentanyl reduced channel open time only at levels higher than those encountered clinically. 4. The potency of these drugs in decreasing channel open time appears to be directly correlated with their octanol/buffer partition coefficients. In contrast to expectations, however, agents with higher partition coefficients were less potent in altering channel open time. 5. Ketamine and meperidine produced a prominent third component in closed-time distributions, which were otherwise well described by the sum of two exponential components. Alphaxalone, diazepam, and etomidate also produced a small third component, while no additional component was seen with propofol or fentanyl. These additional components probably arise from creation of an additional closed state of the channel. 6. We conclude that these agents are not altering channel properties merely by exerting non-specific effects via the lipid bilayer and that they are probably not all acting by similar mechanisms.

Propofol potentiates both pre- and postsynaptic effects of vecuronium in the rat hemidiaphragm.

We have measured twitch tension in response to train-of-four stimulation in rat isolated phrenic nerve-hemidiaphragm preparations. Propofol inhibited nerve evoked twitch tension, with 50% inhibition occurring at 420 (SD 29) mumol litre-1. Although propofol 100 mumol litre-1 by itself had no effect on nerve evoked twitch tension, it potentiated the neuromuscular blocking effects of vecuronium. The decrease in train-of-four ratio with vecuronium was directly proportional to the degree of twitch inhibition, regardless of whether twitch was depressed by vecuronium alone or in combination with propofol. The finding that the train-of-four ratio was a function of the degree of block, rather than simply a function of vecuronium concentration, indicates that propofol also contributed to train-of-four fade and potentiated both pre- and postsynaptic effects of the neuromuscular blocker. The concentrations of propofol used in this study are much greater than human therapeutic blood concentrations, which are typically 25-35 mumol litre-1 (4-6 micrograms ml-1) immediately after a bolus dose of 2 mg kg-1, suggesting that neither muscle weakness nor potentiation of vecuronium-induced neuromuscular block should be of concern at propofol concentrations occurring clinically.

Mechanism of volatile anesthetic action on ion channels.

Single channel recording techniques have been used to study effects of halothane and isoflurane on the properties of nicotinic channels activated by 250 nM acetylcholine in cell-attached patches of BC3H1 mouse tumor cells grown in culture. Halothane and isoflurane were diluted in air and delivered as vapors in the atmosphere above the cells. Both halothane and isoflurane shortened the duration of individual opening events and caused openings to appear grouped together in bursts. The slower time constant of channel open-time distributions was decreased 50% by approximately 0.25% isoflurane (0.12 mM) or 0.30% halothane (0.15 mM) at room temperature. Total open time per burst was also decreased by each agent, an effect that is not consistent with a sequential channel blocking model. Effects of halothane and isoflurane can be explained by a sequential blocking model only if anesthetics also enhance the rate at which open channels normally close. Alternatively, results are also consistent with a cyclic blocking model in which blocked channels may close directly without having to pass back through the open state.