The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene.

UNLABELLED: The differences in potencies of optical isomers of anesthetics support the hypothesis that anesthetics act by specific receptor interactions. Diastereoisomerism and geometrical isomerism offer further tests of this hypothesis but have not been explored. They are the subject of this report. We quantified the nonimmobilizing and convulsant properties of the cis and trans diastereomers of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane). Although the lipophilicity of the diastereomers predicts complete anesthesia at the partial pressures applied, neither diastereomer had anesthetic activity alone, and the cis form may have a small (10%) capacity to antagonize anesthesia, as defined by additive effects on the MAC (the minimum alveolar concentration required to suppress movement to a noxious stimulus in 50% of rats) of desflurane. Both diastereomers produced convulsions, the cis form being nearly twice as potent as the trans form: convulsant 50% effective dose (mean +/- SD) was 0.039 +/- 0.009 atmospheres (atm) for the purified cis and 0.064 +/- 0.009 atm for the purified trans isomer. The MAC value for cis-1,2-dichloroethylene equaled 0.0071 +/- 0.0006 atm, and MAC for trans-1,2-dichloroethylene equaled 0.0183 +/- 0.0031 atm. In qualitative accord with the Meyer-Overton hypothesis, the greater cis potency was associated with a greater lipophilicity. However, the product of MAC x solubility differed between the cis and trans isomers by 40%-50%. We conclude that neither the cis nor trans isomers of 2N have anesthetic properties, but isomerism does influence 2N's convulsant properties and the anesthetic properties of dichloroethylene. These isomeric effects may be as useful in defining receptor-anesthetic interactions as those found with optical isomers. IMPLICATIONS: Cis-trans isomerism can influence the convulsant properties of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) and the anesthetic properties of dichloroethylene. Such isomeric effects may be as useful as those found with optical isomers in defining receptor-anesthetic interactions.

Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart.

UNLABELLED: All series of volatile and gaseous compounds contain members that can produce anesthesia, as defined by the minimum alveolar anesthetic concentration (MAC) required to produce immobility in response to a noxious stimulus. For unhalogenated n-alkanes, cycloalkanes, aromatic compounds, and n-alkanols, potency (1 MAC) increases by two-to threefold with each carbon addition in the series (e.g., ethanol is twice as potent as methanol). Total fluorination (perfluorination) of n-alkanes essentially eliminates anesthetic potency: only CF4 is anesthetic (MAC = 66.5 atm), which indicates that fluorine atoms do not directly influence sites of anesthetic action. Fluorine may enhance the anesthetic action of other moieties, such as the hydrogen atom in CHF3 (MAC = 1.60 atm), but, consistent with the notion that the fluorine atoms do not directly influence sites of anesthetic action, adding -(CF2)n moieties does not further increase potency (e.g., CHF2-CF3 MAC = 1.51 atm). Similarly, adding -(CF2)n moieties to perfluorinated alkanols (CH2OH-[CF2]nF) does not increase potency. However, adding a second terminal hydrogen atom (e.g., CHF2-CHF2 or CH2OH-CHF2) produces series in which the addition of each -CF2- "spacer" in the middle of the molecule increases potency two- to threefold, as in each unhalogenated series. This parallel stops at four or five carbon atom chain lengths. Further increases in chain length (i.e., to CHF2[CF2]4CHF2 or CHF2[CF2]5CH2OH) decrease or abolish potency (i.e., a discontinuity arises). This leads to our hypothesis that the anesthetic moieties (-CHF2 and -CH2OH) interact with two distinct, spatially separate, sites. Both sites must be influenced concurrently to produce a maximal anesthetic (immobility) effect. We propose that the maximal potency (i.e., for CHF2[CF2]2CHF2 and CHF2[CF2]3CH2OH) results when the spacing between the anesthetic moieties most closely matches the distance between the two sites of action. This reasoning suggests that a distance equivalent to a four or five carbon atom chain, approximately 5 A, separates the two sites. IMPLICATIONS: Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.

Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties.

UNLABELLED: The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82+/-0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. IMPLICATIONS: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.

Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms.

UNLABELLED: Some inhaled compounds cause convulsions. To better appreciate the physical basis for this property, we correlated the partial pressures that produced convulsions in rats with the lipophilicity (nonpolarity) and hydrophilicity (polarity) of 45 compounds: 3 n-alkanes, 18 n-haloalkanes, 3 halogenated aromatic compounds, 3 cycloalkanes and 3 halocycloalkanes, 13 halogenated ethers, and 2 noble gases (He and Ne). In most cases, convulsions were quantified by averaging the alveolar partial pressures just below the pressures that caused and slightly higher pressures that did cause clonic convulsions (ED50). The ED50 did not correlate with hydrophilicity (the saline/gas partition coefficient), nor was there an obvious correlation with molecular structure. For 80% of compounds (36 of 45), the ED50 correlated closely (r2 = 0.99) with lipophilicity (the olive oil/gas partition coefficient). Perhaps because they block the effect of GABA on GABA(A) receptors, five compounds were more potent than would be predicted from their lipophilicity. Conversely, four compounds may have been less potent than would be predicted because they (like conventional inhaled anesthetics) enhance the effect of GABA on GABA(A) receptors. IMPLICATIONS: Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. One correlates with lipophilicity (nonpolarity), and the other correlates with an action on GABA(A) receptors.

Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics)

UNLABELLED: We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. IMPLICATIONS: It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect.

Molecular similarity analysis: an alternative approach to studying molecular mechanisms of anaesthesia.

(1) The discovery of the non-anaesthetics has provided a unique opportunity for using novel modelling techniques to study the molecular mechanisms of anaesthesia. (2) We have selected the molecular similarity approach to investigate the importance of three-dimensional molecular fields, such as geometric shape and electrostatic potential, in (a) determining whether an agent exhibits anaesthetic activity and (b) in determining the in vivo potencies of active agents. (3) The results to date are both provocative and highly promising.

Effects of inhaled nonimmobilizer, proconvulsant compounds on desflurane minimum alveolar anesthetic concentration in rats.

UNLABELLED: Anesthetics depress the central nervous system, whereas nonimmobilizers (previously called nonanesthetics) and transitional compounds having the same physical properties (e.g., solubility in lipid) do not produce anesthesia (nonimmobilizers) or are less potent anesthetics than might be predicted from their lipophilicity (transitional compounds). Potential explanations for the absent or decreased anesthetic effect of nonimmobilizer and transitional compounds include the theories that the nonimmobilizers are devoid of anesthetic effect and that transitional compounds have a decreased capacity to produce anesthesia; that the effects of these compounds are not apparent because the concentrations examined are too low; or that anesthesia, or lack thereof, results from a balance between depression and excitation (all nonimmobilizer and transitional compounds produce convulsions). To examine these issues further, we tested the effect of various multiples of the convulsive 50% effective dose (ED50) of three nonimmobilizers and one transitional compound on the minimum alveolar anesthetic concentration (MAC) of desflurane in rats. The nonimmobilizer 2,3-dichlorooctafluorobutane (NI-1), from 0.7 to 1.1 times its convulsive ED50, increased the MAC of desflurane by 14%-27%, but at 1.6 times its convulsive ED50 caused no change in MAC; the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (NI-2) did not change MAC at concentrations up to its convulsant ED50, but it increased MAC by 25% and 36% at 1.3 and 1.7 times its convulsant ED50, respectively. The nonimmobilizer flurothyl (NI-3) decreased the MAC of desflurane by 20% +/- 6% (mean +/- SD) at 0.5 times its convulsant ED50, but it caused no change at higher partial pressures (up to 7.8 times its convulsant ED50), and the transitional compound CF3CCl2-O-CF2Cl (T-1) significantly decreased MAC by 16% +/- 7% at 0.8 times its convulsant ED50, but the 6%-8% decreases in MAC at 0.4 and 1.6 times its convulsant ED50 were not significant. Thus, neither nonimmobilizer nor transitional compounds produced a consistent dose-related effect on the MAC of desflurane, and any changes were small. These results suggest that the excitation produced by transitional compounds or nonimmobilizers does not explain their limited ability or inability to produce anesthesia. The data are consistent with a decreased anesthetic efficacy of transitional compounds and the lack of efficacy of nonimmobilizers. IMPLICATIONS: Inhaled compounds that do not cause anesthesia (nonimmobilizers) are used to test theories of anesthetic action. Their use presumes that a trivial explanation, such as cancelling stimulatory and depressant effects, does not explain the absence of anesthesia. The present results argue against such an explanation.

Convulsant activity of nonanesthetic gas combinations.

Most nonanesthetics (inhaled compounds that neither cause anesthesia when given alone nor decrease the partial pressure of a known inhaled anesthetic required to produce anesthesia) and transitional compounds (inhaled compounds that are less potent than would be predicted by the Meyer-Overton hypothesis) cause convulsions. A possible exception is the perfluoroalkane series of nonanesthetics. The present study tested whether perfluoroalkanes do provide an exception. Further, we tested whether the convulsant effects of nonanesthetic and transitional compounds were additive. The nonanesthetic perfluoropropane caused convulsions at 7.5 +/- 0.7 atm (mean +/- SD). Convulsions also were produced by perfluorocyclobutane (0.976 +/- 0.002 atm), 1,2-dichlorotetrafluoroethane (0.358 +/- 0.011 atm), 2,3-dichlorooctafluorobutane (0.085 +/- 0.007 atm), 1,2-dichlorohexafluorocyclobutane (0.055 +/- 0.007 atm), and flurothyl (0.00156 +/- 0.00039 atm). Of these, 1,2-dichlorotetrafluoroethane is a transitional compound, the remainder being nonanesthetics. The combination of flurothyl plus 1,2-dichlorohexafluorocyclobutane gave evidence of antagonism (a 17% +/- 21% deviation from additivity; P < 0.05), whereas the combination of 1,2-dichlorotetrafluoroethane plus 2,3-dichlorooctafluorobutane gave evidence of synergy (a -13% +/- 8% deviation from additivity; P < 0.05). The combinations of perfluoropropane plus perfluorocyclobutane (-4% +/- 15%), and perfluoropropane plus 1,2-dichlorohexafluorocyclobutane (-1% +/- 26%) did not produce results that deviated significantly from additivity. We conclude that pairs of these compounds either produce convulsions in an additive manner, a finding consistent with (but not proving) a common mode of action; or deviate modestly from additivity, a finding suggesting that at least a portion of the mechanistic basis for convulsions might differ, particularly for flurothyl plus other nonanesthetics, or for the combination of non-anesthetics and transitional compounds.

Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis.

We examined the anesthetic and convulsant properties of 16 unfluorinated to completely fluorinated aromatic compounds, having six to nine carbon atoms (e.g., benzene to 1,3,5-tris(trifluoromethyl)benzene), and four cycloalkanes (cyclopentane to cyclooctane). Benzene, fluorobenzene, toluene, p-xylene, ethylbenzene, and cyclopentane caused excitation (twitching, jerking, and hyperactivity), and three aromatic compounds (perfluorotoluene, p-difluorotoluene and 1,3,5-tris(trifluoromethyl)benzene) and three cycloalkanes (cyclohexane, cycloheptane, and cyclooctane) produced convulsions. Cyclooctane and 1,3,5-tris(trifluoromethyl)benzene were nonanesthetics. Except for nonanesthetics and perfluorotoluene (too toxic to test for anesthetic potency), all compounds produced anesthesia or decreased the minimum alveolar anesthetic concentration of desflurane. Aromatic compounds were more potent and lipid-soluble than n-alkanes (data from previous report) and cycloalkanes. All three series increasingly disobeyed the Meyer-Overton hypothesis as molecular size increased. For a particular number of carbons (e.g., cyclohexane, n-hexane, and benzene), the deviation was cycloalkanes > or = normal alkanes > aromatic compounds. These results suggest that molecular shape (including "bulkiness") and size provide limited clues to the structure of the anesthetic site of action.

Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis.

Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.

Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis.

Neither lipophilicity nor vapor pressure of larger n-alkanes appear to correlate with their anesthetizing partial pressures in inspired gas. Such results suggest that the Meyer-Overton hypothesis and Ferguson's rule may not apply to these compounds. An alternative explanation might be that a large difference in inspired-to-arterial partial pressure exists, i.e., that the inspired partial pressure misrepresents the effective partial pressure. To test this explanation, we investigated the kinetics of five consecutive even-numbered n-alkanes (C2H6 to C10H22) in rats. The ratio of end-tidal-to-inspired (PA/PI), arterial-to-end-tidal (Pa/PA), and arterial-to-inspired (Pa/PI) partial pressures decreased with increasing carbon chain length, consistent with our separate finding that blood solubility increased. Using Pa/PI and the minimum inspired concentration (MIC) obtained previously, we calculated the true effective potency, minimum alveolar anesthetic concentration (MAC); of these n-alkanes as (Pa/PI)(MIC). This markedly improved, but did not perfectly correct, the correlation of MAC with lipid solubility (the Meyer-Overton hypothesis) and vapor pressure (Ferguson's rule). A coefficient of variation of 76.7% was found for the product of MAC and the olive oil/gas partition coefficient. More importantly, the correlation of the logarithm of MAC and oil solubility had a slope of -0.724 (i.e., deviated from -1.0), whereas the slope for eight conventional anesthetics was -1.046 (approached-1.0). These data imply that olive oil does not adequately mimic the nature of the anesthetic site of action of n-alkanes.

Pharmacokinetics do not explain the absence of an anesthetic effect of perfluoropropane or perfluoropentane.

In conflict with the prediction of the Meyer-Overton hypothesis, perfluoropropane (C3F8) and perfluoropentane (C5F12) have no anesthetic effect in rats. To test whether this resulted from a failure of the inspired drugs to reach the brain, we determined the increase in partial pressures of C3F8 and C5F12 in the blood and brains of rats exposed to 0.65 ata of each drug. C3F8 and C5F12 blood/gas partition coefficients equaled 0.00125 +/- 0.00037 (mean +/- SD, n = 9) and 0.00277 +/- 0.00082 (n = 4), and brain/gas partition coefficients equaled 0.0119 +/- 0.0002 (n = 4) and 0.0229 +/- 0.0055 (n = 7), respectively. As a fraction of the inspired value (Pa/PI), the partial pressures of C3F8 and C5F12 in blood (Pa) were 0.99 +/- 0.12 and 0.69 +/- 0.19, respectively, 30 min after administration. The increases in cerebral (Pb) partial pressures of both drugs paralleled the arterial increases (Pb/PI = 0.85 +/- 0.02, and 1.05 +/- 0.03, respectively at 30 min), with C3F8 reaching a plateau at 2 h of 96% +/- 4% of the partial pressure of inspired gas. We conclude that failure of C3F8 and C5F12 to reach the brain does not account for the absence of an anesthetic effect of these compounds.

A cutoff in potency exists in the perfluoroalkanes.

Anesthetic potencies (minimum alveolar anesthetic concentration [MAC]) of perfluoroalkanes from perfluoromethane to perfluorooctane were assessed in male rats to determine whether a cutoff in anesthetic effect (i.e., an absence of any anesthetic effect) exists for the larger compounds in this series. Although hyperbaric measurements suggested a MAC of 38.9 +/- 6 atm (mean +/- SD) for CF4, this pressure was nearly identical to the lethal pressure of 41.1 +/- 5.8 atm. Hyperbaric studies of C2F6 caused death without causing anesthesia, the lethal pressure being 23.8 +/- 2.6 atm. Results from studies of additivity with desflurane suggested that the MAC of CF4 was 66.5 +/- 13.4 atm at an average CF4 test partial pressure of 17.7 +/- 4.0 atm (i.e., 17.7 atm of CF4 decreased the MAC of desflurane by 26.6%). Studies of additivity with desflurane, isoflurane, or halothane did not reveal an anesthetic effect of C2F6 at a pressure of 7.2 +/- 0.4 atm, or of larger perfluoroalkanes near to or at their saturated vapor pressures. We conclude that a cutoff in anesthetic potency for perfluoroalkanes exists between perfluoromethane and perfluoroethane.

Molecular properties of the "ideal" inhaled anesthetic: studies of fluorinated methanes, ethanes, propanes, and butanes.

We examined 35 unfluorinated, partially fluorinated, and perfluorinated methanes, ethanes, propanes, and butanes to define those molecular properties that best correlated with optimum solubility (low) and potency (high). Limited additional data were obtained on longer-chained alkanes. Using standard techniques, we assessed anesthetic potency (minimum alveolar anesthetic concentration [MAC] in rats); vapor pressure; stability in soda lime; and solubility in saline, human blood, and oil. If nonflammability, stability, low solubility in blood, clinically useful vapor pressures, and potency permitting delivery of high concentrations of oxygen are essential components of an anesthetic that might supplant those presently available, our data indicate that such a drug would have three or four carbon atoms with single or dual hydrogenation of two carbons, especially terminal carbons. We conclude that: 1) smaller and larger molecules and lesser hydrogenation provide insufficient potency; 2) high vapor pressures of smaller molecules do not permit the use of variable bypass vaporizers; 3) greater hydrogenation enhances flammability, and complete hydrogenation decreases potency; 4) internal hydrogenation decreases stability; and 5) greater hydrogenation increases blood solubility.

Protection from high pressure induced hyperexcitability by the AMPA/kainate receptor antagonists GYKI 52466 and LY 293558.

The neurophysiological effects of 2 novel AMPA/kainate receptor antagonists, GYKI 52466 and LY 293558, on the high pressure neurological syndrome have been investigated in the rat and baboon (GYKI 52466) and rat (LY 293558). Rats were exposed to increasing ambient pressures of helium and oxygen at 3 ATA/min, on one occasion each. GYKI 52466 at 20 mumol/kg i.v. immediately before, followed by 70 mumol/kg/hr i.v. during compression delayed tremor by 85% and myoclonus by 30%, compared with control vehicle, and no side effects were observed. Seizure activity was not affected by any of the doses used. LY 293558 at 36 mumol/kg i.p. delayed tremor and myoclonus (44% and 12%), LY 293558 72 mumol/kg additionally delayed seizure activity (21%). Side effects, principally tranquilization at the higher dose, were also noted. Six baboons were exposed to a maximum pressure of 91 ATA at 0.3 ATA/min, in the same environment, on two occasions. One exposure was treated with an i.v. infusion of GYKI 52466 15.2 mumol/kg/hr, the other with the same volume of control vehicle. Limb and face tremor and myoclonus were delayed and the severity of signs reduced. No seizures were observed in the drug treated group before 91 ATA. EEG changes associated with exposure to pressure were not affected. It is concluded that antagonism at the AMPA/kainate receptor by GYKI 52466 and LY 293558 beneficially alters HPNS signs but in a manner which is dependent on both the drug and species being studied.

Lack of effect of lamotrigine against HPNS in rodent and primate models.

The neurophysiological effects of the novel anticonvulsant lamotrigine on the high pressure neurological syndrome, HPNS, were investigated in the rat and nonhuman primate Papio anubis. Rats were exposed to pressure at a rate of 3 ATA per min in a helium/oxygen environment. They were pretreated with either lamotrigine isethionate 15, 30, or 60 mg/kg IP or control vehicle. After 15 and 30 mg/kg there were no changes in onset pressures for any of the grades of tremor or myoclonus. After 60 mg/kg, tremor was much slower, at 7-9 Hz, than the 15-20 Hz seen in controls. Four baboons were exposed to pressure at 0.33 ATA per min in the same environment and treated with lamotrigine isethionate at 7.5 mg/kg/h i.v. Each animal underwent a control and a drug-treated exposure. No changes in the onset or severity of HPNS behavioural signs were observed. However, an increase in alpha wave amplitude of the EEG was almost prevented. In both species sustained myoclonic jerking occurred at pressures similar to those at which seizure activity was observed in control exposures. It is concluded that although lamotrigine is protective in several models of neuronal excitation, it is ineffective in protecting against behavioural signs associated with high atmospheric pressure.

The orally active NMDA receptor antagonist CGP 39551 ameliorates the high pressure neurological syndrome in Papio anubis.

The neurophysiological effects of a novel, orally active, competitive N-methyl-D-aspartate (NMDA) receptor antagonist (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester), CGP 39551, on the high pressure neurological syndrome (HPNS) were investigated in the non-human primate Papio anubis. Six animals were exposed to maximum pressures of 81 ATA in a helium and oxygen environment, on two occasions. One exposure was pretreated orally with CGP 39551 100 mg/kg 24 h before compression, the other pretreated with an equivalent volume of vehicle, in this case water. CGP 39551 significantly ameliorated the signs of HPNS, compared with controls, at pressures above 31 ATA and prevented the severe signs from occurring at the higher pressures. Onset pressures of the mild signs at low pressures were, however, unaffected. Among EEG changes, the pressure induced reduction in delta wave amplitude was prevented by CGP 39551, but the increase in the amplitude of the 7-9 Hz band was not. It is concluded that CGP 39551 may play an important role in the prophylactic treatment of HPNS.

Is there a cutoff in anesthetic potency for the normal alkanes?

Vapor pressures and anesthetizing partial pressures in rats were measured for 10 consecutive normal alkanes, methane through decane. All produced anesthesia as defined by the absence of movement in response to either the application of a tail-clamp or electrical stimulation of the tail. The anesthetizing partial pressure was calculated as the average between the concentrations just permitting and preventing movement. Although nonane and decane did not provide anesthesia when given alone at their saturated vapor pressures, their anesthetic properties could be demonstrated by their ability to decrease the anesthetic requirement for isoflurane (i.e., their anesthetic potencies could be defined by studies of additivity). Anesthetic potency increased (from 9.9 atm for methane to 0.0142 atm for decane) and vapor pressure decreased (from 38.2 atm for ethane to 0.0028 atm for decane) with increasing chain length. The decrease in vapor pressure far exceeded the increase in potency. For nonane and decane, the ratio of the partial pressure required for anesthesia to the saturated vapor pressure was less than 1, being 0.48 and 0.19, respectively. We conclude that no cutoff phenomenon (i.e., no absence of anesthetic effect with longer chain alkanes) exists from n-methane to n-decane, but that larger alkanes have vapor pressures too low to permit their potency to be evident when given alone.

Anesthesia by n-alkanes not consistent with the Meyer-Overton hypothesis: determinations of the solubilities of alkanes in saline and various lipids.

Because deviations from the Meyer-Overton rule may provide insights into the attributes of the anesthetic site of action, we characterized the solubility of the n-alkanes in various hydrophobic solvents (n-tetradecane, olive oil, n-octanol, and lecithin) as well as saline using variations on standard techniques. Increasing alkane chain length correlated with a decrease in solubility in saline and an increase in solubility in the hydrophobic solvents. The product of solubility in the hydrophobic solvents x the partial pressure (in atmospheres) required to produce anesthesia (i.e., the Meyer-Overton rule) did not produce a constant for any one of these solvents. The means and standard deviations for the products were: tetradecane, 65 +/- 103; olive oil, 33 +/- 63; n-octanol, 64 +/- 129; and lecithin, 16 +/- 26. Thus, our data suggest that the n-alkanes (especially those longer than n-heptane) do not follow the Meyer-Overton rule.