A comparison of the molecular bases for N-methyl-D-aspartate-receptor inhibition versus immobilizing activities of volatile aromatic anesthetics.

BACKGROUND: Aromatic anesthetics exhibit a wide range of N-methyl-d-aspartate (NMDA) receptor inhibitory potencies and immobilizing activities. We sought to characterize the molecular basis of NMDA receptor inhibition using comparative molecular field analysis (CoMFA), and compare the results to those from an equivalent model for immobilizing activity. METHODS: Published potency data for 14 compounds were supplemented with new values for 2 additional agents. The anesthetics were divided into a training set (n = 12) used to formulate the activity models and a test set (n = 4) used to independently assess the models' predictive capability. The anesthetic structures were geometry optimized using ab initio quantum mechanics and aligned by field-fit minimization to provide the best correlation between the steric and electrostatic fields of the molecules and one or more lead structures. Orientations that yielded CoMFA models with the greatest predictive capability (assessed by leave-one-out cross-validation) were retained. RESULTS: The final CoMFA model for the inhibition of NR1/NR2B NMDA receptors explained 99.3% of the variance in the observed activities of the 12 training set agents (F(2,)(9) = 661.5, P < 0.0001). The model effectively predicted inhibitory potency for the training set (cross-validated r(2)(CV) = 0.944) and 4 excluded test set compounds (predictive r(2)(Pred) = 0.966). The equivalent model for immobility in response to noxious stimuli explained 98.0% of the variance in the observed activities for the training set (F(2,)(9) = 219.2, P < 0.0001) and exhibited adequate predictive capability for both the training set (r(2)(CV) = 0.872) and test set (r(2)(Pred) = 0.926) agents. Comparison of pharmacophoric maps showed that several key steric and electrostatic regions were common to both activity models, but differences were observed in the relative importance of these key regions with respect to the two aspects of anesthetic activity. CONCLUSIONS: The similarities in the pharmacophoric maps are consistent with NMDA receptors contributing part of the immobilizing activity of volatile aromatic anesthetics.

Increasing the duration of isoflurane anesthesia decreases the minimum alveolar anesthetic concentration in 7-day-old but not in 60-day-old rats.

BACKGROUND: While studying neurotoxicity in rats, we observed that the anesthetic minimum alveolar anesthetic concentration (MAC) of isoflurane decreases with increasing duration of anesthesia in 7-day-old but not in 60-day-old rats. After 15 min of anesthesia in 7-day-old rats, MAC was 3.5% compared with 1.3% at 4 h. We investigated whether kinetic or dynamic factors mediated this decrease. METHODS: In 7-day-old rats, we measured inspired and cerebral partial pressures of isoflurane at MAC as a function of duration of anesthesia. In 60-day-old rats, we measured inspired partial pressures of isoflurane at MAC as a function of duration of anesthesia. Finally, we determined the effect of administering 1 mg/kg naloxone and of delaying the initiation of the MAC determination (pinching the tail) on MAC in 7-day-old rats. RESULTS: In 7-day-old rats, both inspired and cerebral measures of MAC decreased from 1 to 4 h. The inspired MAC decreased 56%, whereas the cerebral MAC decreased 33%. At 4 h, the inspired MAC approximated the cerebral MAC (i.e., the partial pressures did not differ appreciably). Neither administration of 1 mg/kg naloxone nor delaying tail clamping until 3 h reversed the decrease in MAC. In 60-day-old rats, inspired MAC of isoflurane was stable from 1 to 4 h of anesthesia. CONCLUSIONS: MAC of isoflurane decreases over 1-4 h of anesthesia in 7-day-old but not in 60-day-old rats. Both pharmacodynamic and a pharmacokinetic components contribute to the decrease in MAC in 7-day-old rats. Neither endorphins nor sensory desensitization mediate the pharmacodynamic component.

Obesity modestly affects inhaled anesthetic kinetics in humans.

BACKGROUND: Few studies have determined the effect of obesity on inhaled anesthetic pharmacokinetics. We hypothesized that the solubility of potent inhaled anesthetics in fat and increased body mass index (BMI) in obese patients interact to increase anesthetic uptake and decrease the rate at which the delivered (FD) and inspired (FI) concentrations of an inhaled anesthetic approach a constantly maintained alveolar concentration (end-tidal or FA). This hypothesis implies that the effect of obesity would be greater with a more soluble anesthetic such as isoflurane versus desflurane. METHODS: In 107 ASA physical status I-III patients, anesthesia was induced with propofol, tracheal intubation facilitated with neuromuscular blockade, and ventilation controlled with 50% nitrous oxide in oxygen to maintain end-tidal carbon dioxide concentrations between 35 and 45 mm Hg. Isoflurane or desflurane was administered in a 1 L/min inflow rate at FD concentrations sufficient to maintain FA at 0.6 minimum alveolar anesthetic concentration (0.7% or 3.7%, respectively). FD, FI, and FA were measured 5, 10, 20, 40, 60, 90, 120,150, and 180 min after starting potent inhaled anesthetic delivery. RESULTS: Fifty-nine patients received isoflurane and 48 received desflurane. BMI ranged between 18 and 63 kg/m(2) and demographic variables did not differ between anesthetic groups. For isoflurane, FD/FA or FI/FA weakly (but significantly) correlated with BMI at 9/18 time points whereas for desflurane FD/FA or FI/FA correlated significantly with BMI at only one time point (P < 0.01). After dividing each group into nonobese (BMI < 30) and obese (BMI > or = 30) patients, with isoflurane, FD/FA or FI/FA was higher in obese patients at four time points whereas there was no difference between nonobese and obese patients for desflurane. Patients receiving isoflurane took longer to respond to command after discontinuing anesthesia but obesity did not increase or decrease awakening time for either isoflurane or desflurane. When BMI was used to normalize FI/FA and FD/FA the median values for isoflurane consistently exceeded the median value for desflurane by factors ranging from 3 to 5, values comparable to the ratios of their blood/gas (3.1), muscle/gas (4.6), and fat/gas (5.4) partition coefficients. CONCLUSION: BMI modestly affects FD/FA and FI/FA, and this effect is most apparent for an anesthetic having a greater solubility in all tissues. An increased BMI increases anesthetic uptake and, thus, the need for delivered anesthetic to sustain a constant alveolar anesthetic concentration, particularly with a more soluble anesthetic. However, the increase with an increased body mass is small.

Intrathecal veratridine administration increases minimum alveolar concentration in rats.

BACKGROUND: Results from several studies point to sodium channels as potential mediators of the immobility produced by inhaled anesthetics. We hypothesized that the intrathecal administration of veratridine, a drug that enhances the activity or effect of sodium channels, should increase MAC. METHODS: We measured the change in isoflurane MAC caused by intrathecal infusion of various concentrations of veratridine into the lumbothoracic subarachnoid space of rats. We compared these result with those obtained from intracerebroventricular infusion. RESULTS: As predicted, intrathecal infusion of veratridine increased MAC. The greatest infused concentration (25 microM) also produced neuronal injury in the hindlimbs of two rats and decreased the peak effect on MAC. A concentration of 1.6 microM produced the largest (21%) increase in MAC. Intraventricular infusion of 1.6 and 6.4 microM veratridine did not alter MAC. Rats given 25 microM died. CONCLUSIONS: Intrathecal administration of veratradine increases MAC of isoflurane, a finding consistent with a role for sodium channels as potential mediators of the immobility produced by inhaled anesthetics.

Increases in spinal cerebrospinal fluid potassium concentration do not increase isoflurane minimum alveolar concentration in rats.

BACKGROUND: Previous studies demonstrated that MAC for isoflurane directly correlates with the concentration of Na(+) in cerebrospinal fluid surrounding the spinal cord, the primary site for mediation of the immobility produced by inhaled anesthetics. If this correlation resulted from increased irritability of the cord, then infusion of increased concentrations of potassium (K(+)) might be predicted to act similarly. However, an absence of effect of K(+) might be interpreted to indicate that K(+) channels do not mediate the immobility produced by inhaled anesthetics whereas Na(+) channels remain as potential mediators. Accordingly, in the present study, we examined the effect of altering intrathecal concentrations of K(+) on MAC. METHODS: In rats prepared with chronic indwelling intrathecal catheters, we infused solutions deficient in K(+) and with an excess of K(+) into the lumbar space and measured MAC for isoflurane 24 h before, during, and 24 h after infusion. Rats similarly prepared were tested for the effect of altered osmolarity on MAC (accomplished by infusion of mannitol) and for the penetration of Na(+) into the cord. RESULTS: MAC of isoflurane never significantly increased with increasing concentrations of K(+) infused intrathecally. At infused concentrations exceeding 12 times the normal concentration of KCl, i.e., 29 mEq/L, rats moved spontaneously at isoflurane concentrations just below, and sometimes at MAC, but the average MAC in these rats did not exceed their control MAC. At the largest infused concentration (58.1 mEq/L), MAC significantly decreased and did not subsequently return to normal (i.e., such large concentrations produced injury). Infusions of lower concentrations of K(+) had no effect on MAC. Infusion of osmotically equivalent solutions of mannitol did not affect MAC. Na(+) infused intrathecally measurably penetrated the spinal cord. CONCLUSIONS: The results do not support a mediation or modulation of MAC by K(+) channels.

Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats.

BACKGROUND: We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By "divergently," we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and gamma-aminobutyric acid type A, glycine, N-methyl-D-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-D-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation.

A method for recording single unit activity in lumbar spinal cord in rats anesthetized with nitrous oxide in a hyperbaric chamber.

The limited potency of nitrous oxide mandates the use of a hyperbaric chamber to produce anesthesia. Use of a hyperbaric chamber complicates anesthetic delivery, ventilation, and electrophysiological recording. We constructed a hyperbaric acrylic-aluminum chamber allowing recording of single unit activity in spinal cord of rats anesthetized only with N(2)O. Large aluminum plates secured to each other by rods that span the length of the chamber close each end of the chamber. The 122 cm long, 33 cm wide chamber housed ventilator, intravenous infusion pumps, recording headstage, including hydraulic microdrive and stepper motors (controlled by external computers). Electrical pass-throughs in the plates permitted electrical current or signals to enter or leave the chamber. In rats anesthetized only with N(2)O we recorded extracellular action potentials with a high signal-to-noise ratio. We also recorded electroencephalographic activity. This technique is well-suited to study actions of weak anesthetics such as N(2)O and Xe at working pressures of 4-5 atm or greater. The safety of such pressures depends on the wall thickness and chamber diameter.

Anesthetic properties of carbon dioxide in the rat.

BACKGROUND: Carbon dioxide decreases halothane minimum alveolar concentrations (MAC) in dogs when Paco(2) exceeds 95 mm Hg. We sought to confirm these findings for several potent inhaled anesthetics in rats. METHODS: Groups of eight rats were anesthetized with halothane, isoflurane, or desflurane. MAC was determined for each anesthetic alone, and then with increasing concentrations of inspired CO(2). A fourth group was given CO(2) alone to determine the MAC of CO(2). RESULTS: Increasing inspired CO(2) concentrations produced a linear dose-dependent decrease in MAC of each potent inhaled anesthetic. With elimination of CO(2), the MAC of isoflurane and desflurane returned to the original MAC. As determined by extrapolating these data to 0% of the inhaled anesthetic, the MAC of CO(2) was approximately 50% of 1 atm. Given alone, CO(2) proved lethal. CONCLUSIONS: Unlike dogs, no threshold for the CO(2)-MAC response arose with halothane, isoflurane, or desflurane in rats. The ED(50) for CO(2) is also approximately 50% greater in rats than reported in dogs.

Concentrations of isoflurane exceeding those used clinically slightly increase the affinity of methane, but not toluene, for water.

BACKGROUND: Inhaled anesthetics may affect proteins at the interface between membrane lipids and the surrounding aqueous phase. The underlying solution chemistry is not known. Because the hydrophobicity of nonpolar protein components importantly influences their conformation, we tested the hypothesis that isoflurane affects the solubility of two nonpolar compounds, methane and toluene, in saline. METHODS: Using a serial dilution technique, we determined the saline:gas partition coefficients (PCs) of methane and toluene at 37 degrees C in the absence of isoflurane and in the presence of approximately 1%, 5%, and 15% isoflurane. We also measured the effect on the vapor pressure of benzene produced by saturating benzene with either cyclopropane or chloroethane, anesthetics used in a previous study to demonstrate that their equilibration with benzene decreased the solubility of benzene in water. RESULTS: Clinically relevant concentrations of isoflurane (1% and 5%) did not affect the saline:gas PC of methane and toluene, but 15%-20% isoflurane increased the PC of methane (P < 0.05) but not toluene. Saturating benzene with cyclopropane or chloroethane, decreased the vapor pressure of benzene in proportion to the amount of anesthetic dissolved in the benzene. CONCLUSION: Isoflurane has a weak antihydrophobic effect at concentrations far above the clinically relevant range, and this effect is unlikely to explain how anesthetics act. A previous study, which found that cyclopropane and chloroethane decreased the solubility of benzene in water, probably erred in its conclusion that these anesthetics interfered with the interaction of benzene and water. Instead, the anesthetics simply decreased the vapor pressure of benzene, doing so in accordance with Raoult's Law.

Lidocaine, MK-801, and MAC.

BACKGROUND: Previous studies have found that the local anesthetic/sodium channel blocker lidocaine decreased MAC by maximum amounts approximately equal to the decreases produced by dizocilpine (MK-801), a N-methyl-d-aspartate (NMDA) receptor antagonist. Blockade of sodium channels by inhaled anesthetics has been suggested as a possible cause for impairment of transmission through NMDA receptors. We postulated that the net effect of lidocaine and MK-801 on MAC would be the same, albeit by affecting NMDA neurotransmission at different points. METHODS: We measured the effect of various lidocaine infusions on the MAC of cyclopropane, halothane, isoflurane, and o-difluorobenzene in rats. We also measured the effect of concurrent lidocaine-MK-801 infusion on the MAC of isoflurane and o-difluorobenzene. RESULTS: Our data contradicted our predictions. (a) We found no limit to the effect of lidocaine infusion, in some cases finding that lidocaine, alone, produced immobility; (b) lidocaine infusion did not decrease the MAC of o-difluorobenzene differently from the MAC of other inhaled anesthetics; and (c) the addition of MK-801 equally affected the decrease in MAC produced by lidocaine infusion for isoflurane versus o-difluorobenzene. CONCLUSION: Lidocaine does not primarily decrease MAC by decreasing the release of glutamate from nerve terminals.

The excitatory and inhibitory effects of nitrous oxide on spinal neuronal responses to noxious stimulation.

BACKGROUND: Because of the logistical obstacles to measurement under hyperbaric conditions, the effect of nitrous oxide (N2O) alone on spinal neuronal responses has not been tested. We hypothesized that, like other inhaled anesthetics, N2O would depress spinal neuronal responses to noxious stimulation. METHODS: The lumbar spinal cord was exposed in rats anesthetized with isoflurane. Mechanically ventilated rats were placed into a hyperbaric chamber and needle electrodes were inserted into the hindpaws. Isoflurane administration was discontinued and anesthesia converted to N2O by pressurizing the chamber with N2O. A microelectrode was inserted into the lumbar cord using computer-controlled motors and a hydraulic microdrive. Neuronal responses to electrical stimulation of the hindpaw were sought at 1.5, 2, and 2.5 atm N2O (0.8-1.3 minimum alveolar concentration). RESULTS: Increasing N2O partial pressures variably affected neuronal responses to a 2 s 100-Hz electrical stimulus. Neuronal depth and neuronal response were correlated, with superficial neurons tending to be facilitated, while deeper neurons were depressed; (overall responses were 1331 +/- 408, 1594 +/- 383, and 1578 +/- 500 impulses/min at 1.5, 2, and 2.5 atm N2O, respectively; mean, standard error). N2O did not affect neuronal responses to a repetitive "windup" stimulus. Infusion of the N-methyl-d-aspartate blocker MK-801 into separate rats increased the neuronal response to the 100-Hz stimulus (from 781 +/- 216 to 1352 +/- 269 impulses/min, P < 0.05). CONCLUSIONS: N2O facilitated superficial spinal neuronal responses to noxious stimulation while depressing deeper neurons. These results suggest that anesthetic partial pressures of N2O have divergent effects on spinal neuronal responses to noxious stimulation, the specific responses depending on the depth of the spinal neurons.

Blockade of acetylcholine receptors does not change the dose of etomidate required to produce immobility in rats.

BACKGROUND: Administration of drugs blocking muscarinic plus neuronal nicotinic acetylcholine receptors (e.g., atropine and mecamylamine) does not affect the MAC of isoflurane. Although this implies that acetylcholine receptors do not mediate the immobility produced by inhaled anesthetics, another interpretation is possible. Sub-MAC concentrations of isoflurane alone profoundly block acetylcholine receptors, allowing for the possibility that atropine and mecamylamine have no effect because the receptors already are blocked. METHODS: In the present study, we indirectly tested this possibility by measuring the capacity of acetylcholine receptor blockade to decrease the anesthetic requirement for etomidate, an anesthetic thought to act solely by enhancing the effect of gamma-aminobutyric acid on gamma-aminobutyric acid(A) receptors. RESULTS: Administration of 10 mg/kg atropine plus 5 mg/kg mecamylamine did not change the infusion rate of etomidate, or the blood or brain concentrations of etomidate required to produce immobility in rats. CONCLUSION: Acetylcholine receptors do not mediate the capacity of anesthetics to produce immobility in the face of noxious stimulation.

Alterations in spinal, but not cerebral, cerebrospinal fluid Na+ concentrations affect the isoflurane minimum alveolar concentration in rats.

BACKGROUND: Previous studies demonstrated that MAC (the minimum alveolar concentration of an inhaled anesthetic that produces immobility in 50% of subjects exposed to noxious stimulation) for halothane directly correlates with the central nervous system concentration of Na+. However, those studies globally altered Na+ concentrations, and thus did not distinguish effects on the spinal cord from cerebral effects. This is an important distinction because the cord appears to be the primary site for mediation of the immobility produced by inhaled anesthetics. Accordingly, in the present study, we examined the effect of altering intrathecal versus intracerebroventricular concentrations of Na+ on MAC. METHODS: In rats prepared with chronic indwelling catheters or stylets, we infused solutions deficient in Na+ and with an excess of Na+ into the lumbar subarachnoid and intracerebroventricular spaces and measured MAC for isoflurane before, during, and after infusion. RESULTS: MAC of isoflurane correlated directly with concentrations of Na+ infused intrathecally but did not correlate with concentrations infused intracerebroventricularly. CONCLUSION: The results are consistent with a mediation or modulation of MAC by Na+ channels. These might include voltage-gated or ligand-gated channels or other Na-sensitive targets (e.g., pumps, transporters, exchangers).

Ammonia has anesthetic properties.

BACKGROUND: A recent theory of anesthesia predicts that some endogenous compounds should have anesthetic properties. This theory raises the possibility that metabolites that are profoundly elevated in disease may also exert anesthetic effects. Because in pathophysiologic concentrations, ammonia reversibly impairs memory, consciousness, and responsiveness to noxious stimuli in a manner similar to anesthetics, we investigated whether ammonia had anesthetic properties. METHODS: The effect of ammonia was studied on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A, alpha1 glycine, and NR1/NR2A N-methyl-D-aspartate receptors, and the two-pore domain potassium channel TRESK. Channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The immobilizing effect of ammonia in rats was evaluated by determining the reduction in isoflurane minimum alveolar concentration produced by IV infusion of ammonium chloride. The olive oil-water partition coefficient was measured to determine whether free ammonia (NH3) followed the Meyer-Overton relation. RESULTS: Ammonia positively modulated TRESK channels and glycine receptors. No effect was seen on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A receptors or NR1/NR2A N-methyl-d-aspartate receptors. Ammonia reversibly decreased the requirement for isoflurane, with a calculated immobilizing EC50 of 1.6 +/- 0.1 mM NH4Cl. The Ostwald olive oil-water partition coefficient for NH3 was 0.018. At a pH of 7.4, and at the anesthetic EC50, the NH3 concentration in bulk olive oil is 0.42 muM, approximately five orders of magnitude less than observed by anesthetics that follow the Meyer-Overton relation. CONCLUSIONS: These findings support the hypothesis that ammonia has anesthetic properties. Bulk oil concentration did not predict the potency of ammonia.

Anesthetic properties of some fluorinated oxolanes and oxetanes.

BACKGROUND: The search for new potent inhaled anesthetics has slowed, in large part because of the excellence of the two most recent additions, desflurane and sevoflurane. Nonetheless, neither desflurane nor sevoflurane are ideal anesthetics, desflurane causing cardiorespiratory stimulation, and sevoflurane having a slower (albeit rapid) recovery from anesthesia. Sevoflurane also can produce convulsions and postoperative agitation. METHODS AND RESULTS: In the present report, we describe the physical and anesthetic properties of 31 cyclic ethers halogenated solely with fluorine. Although several produced anesthesia, none had solubilities that would make them better than sevoflurane. The remaining ethers were unstable or produced obvious central nervous system irritation, including convulsions. CONCLUSIONS: We find that none of these cyclic ethers appear to provide advantages over desflurane or sevoflurane.

Hexafluorobenzene acts in the spinal cord, whereas o-difluorobenzene acts in both brain and spinal cord, to produce immobility.

BACKGROUND: Previous work demonstrated that isoflurane and halothane act on the spinal cord rather than on the brain to produce immobility in the face of noxious stimulation. These anesthetics share many effects on specific receptors, and thus do not test the broad applicability of the mediation of immobility by the cord. We sought to test such an applicability by determining whether the cord mediated the immobilizing effects of two aromatic anesthetics that differ greatly in their ability to block N-methyl-d-aspartate receptors. METHODS: We investigated the actions of hexafluorobenzene (HFB) and o-difluorobenzene (ODFB) using an intact goat model that allowed selective delivery of anesthetics to the brain. Because our results suggested a significant cerebral effect of ODFB, in other goats we administered halothane 0.5% to the brain, while determining the ODFB concentration delivered to the body (the cord) required for immobility. We chose halothane because the present and previous studies found that cerebral halothane concentrations alone required for producing immobility far exceeded those required in the cord. We also applied the above techniques to another benzene-containing anesthetic, propofol. RESULTS: Prebypass minimum alveolar concentration (MAC) for HFB was 0.82% +/- 0.14% (mean +/- sd); increased to 2.04% +/- 0.8% (P < 0.01) during selective delivery to the cranial circulation; and returned to 0.79% +/- 0.28% postbypass. Corresponding values for ODFB were 0.46% +/- 0.07%, 0.63% +/- 0.12% (P < 0.05), and 0.44% +/- 0.10%. ODFB MAC was 0.32% +/- 0.17% during selective halothane delivery to brain. But when ODFB was administered to the whole body, MAC was 0.37% +/- 0.05%, (NS). Like HFB, the halothane requirement increased threefold when delivered only to the head. In four of five animals, propofol requirements increased by 240%, but in one animal propofol requirements decreased, and the overall change was not statistically significant. CONCLUSIONS: These data suggest that HFB, like halothane, produces immobility, predominantly by a spinal cord action, and that HFB differs from ODFB with respect to brain versus spinal sites of action. Nonetheless, although ODFB can produce immobility via a cerebral action, it also can do this via an independent action in the spinal cord. Thus, our results continue to support the spinal cord as the primary site at which inhaled anesthetics, and perhaps propofol, produce immobility.

Sevoflurane concentrations in blood, brain, and lung after sevoflurane-induced death.

Sevoflurane concentrations in blood, brain, and lung were measured in an individual apparently dying from sevoflurane inhalation. Sevoflurane is a volatile nonflammable fluorinated methyl isopropyl ether inhaled anesthetic, chemically related to desflurane and isoflurane. The incidence of abuse of sevoflurane is lower than that of other drugs of abuse possibly due to its inaccessibility to the general public and less pleasurable and addicting effects. The dead subject was an anesthetist found prone in bed holding an empty bottle of sevoflurane (Ultane). Serum, urine, and liver were screened for numerous drugs and metabolites using enzyme immunoassays and gas chromatography-mass spectrometry. Analysis did not reveal presence of any drug, including ethanol, other than sevoflurane. Sevoflurane was determined by headspace gas chromatography and revealed concentrations of 15 microg/mL in blood and 130 mg/kg in brain and lung. Autopsy revealed pulmonary edema and frothing in the lung, pathological findings associated with death by sevoflurane or hypoxia. The cause of death was ruled as sevoflurane toxicity and the manner of death as accident.

Do dopamine receptors mediate part of MAC?

BACKGROUND: Depletion of central nervous system catecholamines, including dopamine, can decrease MAC (the minimum alveolar concentration of an inhaled anesthetic required to suppress movement in response to a noxious stimulus in 50% of test subjects); release of central nervous system catecholamines, including dopamine, can increase MAC; and increased free dopamine concentrations in the striatum can decrease MAC. Such findings suggest that dopamine receptors might mediate part of the capacity of inhaled anesthetics to provide immobility in the face of noxious stimulation. METHODS: We measured the effect of blockade of D2 dopamine-mediated transmission with 0.3 mg/kg or 3.0 mg/kg droperidol on the MAC of cyclopropane, desflurane, halothane, isoflurane, or sevoflurane in rats, and the effect of 3.0 mg/kg droperidol on the dose or concentration of etomidate (an anesthetic known to act principally by enhancing the response of gamma-aminobutyric acid(A) receptors to gamma-aminobutyric acid) required to suppress movement in response to noxious stimulation. RESULTS: Blockade of D2 dopamine-mediated transmission with droperidol does not decrease the MAC of cyclopropane, desflurane, halothane, isoflurane, or sevoflurane or its equivalent for etomidate in rats. CONCLUSIONS: These data, plus data from studies by others about D1 dopamine receptors, indicate that dopamine receptors do not mediate the immobility produced by inhaled anesthetics.

Naloxone does not increase the minimum alveolar anesthetic concentration of sevoflurane in mice.

Several previous studies concluded that opioid receptors do not mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation because administration of naloxone (a nonspecific opioid receptor antagonist) does not increase the minimum alveolar anesthetic concentration (MAC) of inhaled anesthetic that produces immobility in 50% of subjects given a noxious stimulation. In contrast, a recent study found that 0.1 mg/kg naloxone given intraperitoneally increased sevoflurane MAC in mice by 18% (P < 0.01). We repeated the recent study with sevoflurane in the same strain of mice, administering nothing (control), 0.1 mg/kg, and 1.0 mg/kg of naloxone. Our study differed in that we also tested a parallel group given saline rather than naloxone. We were blinded to drug administration. MAC decreased 4.8% +/- 11.0% (mean+/- sd) and 2.4% +/- 12.5% with the first and second administrations of saline. Similarly, MAC decreased 4.7% +/- 7.1% and 5.5% +/- 10.0% with the administration of 0.1 mg/kg and 1.0 mg/kg of naloxone. We do not find that naloxone increases MAC. Opioid receptors do not underlie a portion of the capacity of inhaled anesthetics to produce immobility.

The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration.

TWIK-related acid-sensitive K(+)-1 (TASK-1 [KCNK3]) and TASK-3 (KCNK9) are tandem pore (K(2P)) potassium (K) channel subunits expressed in carotid bodies and the brainstem. Acidic pH values and hypoxia inhibit TASK-1 and TASK-3 channel function, and halothane enhances this function. These channels have putative roles in ventilatory regulation and volatile anesthetic mechanisms. Doxapram stimulates ventilation through an effect on carotid bodies, and we hypothesized that stimulation might result from inhibition of TASK-1 or TASK-3 K channel function. To address this, we expressed TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric, and TASK-1/TASK-3 chimeric K channels in Xenopus oocytes and studied the effects of doxapram on their function. Doxapram inhibited TASK-1 (half-maximal effective concentration [EC50], 410 nM), TASK-3 (EC50, 37 microM), and TASK-1/TASK-3 heterodimeric channel function (EC50, 9 microM). Chimera studies suggested that the carboxy terminus of TASK-1 is important for doxapram inhibition. Other K2P channels required significantly larger concentrations for inhibition. To test the role of TASK-1 and TASK-3 in halothane-induced immobility, the minimum alveolar anesthetic concentration for halothane was determined and found unchanged in rats receiving doxapram by IV infusion. Our data indicate that TASK-1 and TASK-3 do not play a role in mediating the immobility produced by halothane, although they are plausible molecular targets for the ventilatory effects of doxapram.