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PubMed2005

Sorptive loss of volatile and gaseous anesthetics from in vitro drug application systems.

In in vitro pharmacological experiments, determination of effective concentration values for various anesthetics depends on understanding the exact concentration of the drugs dissolved in physiological solutions. Actual anesthetic concentration may differ from expectations because of drug adsorption, absorption or other loss, especially in tubing. We tested the hypothesis that delivered concentrations of anesthetics decrease when solutions pass through laboratory tubing and investigated such loss by measuring the entering and exiting dissolved concentrations of two volatile (sevoflurane and isoflurane) and two gaseous (nitrous oxide and xenon) anesthetics. We tested solutions passed through tubes (1 m x 2 mm ID x 4 mm OD) made of five different materials (glass, Teflon, polyethylene (PE), polyvinyl chloride (PVC), and silicon rubber). Exiting concentrations of anesthetics were significantly reduced when they were passed through PVC (>33%) and silicon (>43%) tubes. There were no decreases in anesthetic concentrations with glass, Teflon, or PE tubes. When sevoflurane solution flowed through PVC and silicon tubes, it took 20 and 30 min, respectively, after start of flow until the anesthetic loss became negligible. These results indicate that frequently used PVC and silicon tubes, whereas flexible and easy to handle, have serious drawbacks when used in inhaled anesthetic pharmacology experiments.

Adsorption↗

PubMed2005

Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors.

Although inhaled anesthetics have diverse effects on 5-hydroxytryptamine type 3 (5-HT3A) receptors, the mechanism accounting for this diversity is not understood. Studies have shown that modulation of 5-HT3A receptor currents by n-alcohols depends on molecular volume, suggesting that steric interactions between n-alcohols and their binding sites define their action on this receptor. Electrostatic interactions also play an important role in anesthetic action on other ligand-gated receptors. We aimed to determine the contribution of molecular volume and electrostatics in defining volatile anesthetic actions on 5-HT3A receptors. Human 5-HT3A receptors were expressed in, and recorded from, Xenopus oocytes using the two-electrode voltage-clamp technique. The effects of a range of volatile anesthetics, n-alcohols, and nonhalogenated alkanes on submaximal serotonin-evoked peak currents, and full serotonin concentration-response curves were defined. Volatile anesthetics and n-alcohols, but not alkanes, smaller than 0.120 nm3 enhanced submaximal serotonin-evoked peak currents whereas all larger agents reduced currents. Most compounds tested inhibited maximal serotonin-evoked peak currents to varying degrees. However, only agents smaller than 0.120 nm3 shifted the 5-HT3A receptor's serotonin concentration-response curve to the left, whereas larger anesthetics shifted them to the right. Modulation of human 5-HT3A-mediated currents by volatile anesthetics exhibits a dependence on molecular volume consistent with the n-alcohols, suggesting that both classes of agents may enhance 5-HT3A receptor function via the same mechanism. Furthermore, the enhancing but not inhibiting effects of anesthetic compounds on 5-HT3A receptor currents are modulated by electrostatic interactions.

Administration, Inhalation↗

PubMed1984

Studies on rabbit corneal permeability of local anesthetics (I).

To elucidate the pharmacokinetics of local anesthetics with respect to corneal permeability in the rabbit, we examined the relationship between the corneal permeability velocities of three agents, cocaine X HCl, procaine X HCl and tetracaine X HCl and corneal hydration. The corneal permeability velocity constants (k) of these three ester-type local anesthetics were approximately 0.5-6.0 X 10(-6) cm/sec and the membrane permeability constants of these agents were approximately 0.5-4.0 X 10(-7) cm2/sec, whereas the rabbit corneal hydration values were 3.2-4.2. Tetracaine X HCl with the strongest topical anesthetic action showed the greatest corneal hydration and the smallest corneal permeability velocity constant among these local anesthetics. Rabbit corneal permeability decreased with increasing molecular length of the agents. Permeability of these local anesthetics in the rabbit cornea appears to result from passive transport. As corneal hydration values and the corneal permeability constant increased with greater topical anesthetic activity, it appears that the degree of inhibition of Na+-K+ ATPase activity is associated with the order of topical anesthetic activity in a similar manner as general anesthetics.

Anesthetics, Local↗

PubMed2006

Gq protein-coupled receptors as targets for anesthetics.

The mechanisms of action of anesthetics are unclear. Much attention has been focused on ion channels in the central nervous system as targets for anesthetics. During the last decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR) signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M(1), metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2A, and substance P receptors. Nearly 160 GPCRs have been identified, based on their gene sequence and ability to interact with known endogenous ligands. However, an estimated 500-800 additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not yet been identified. Given that known GPCRs are targets for anesthetics, these oGPCRs represent a rich group of receptor targets for anesthetics. This article highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors are targets for anesthetics.

Anesthetics↗

PubMed2004

Anesthetic indices of sevoflurane and isoflurane in unpremedicated dogs.

OBJECTIVE: To compare the anesthetic index of sevoflurane with that of isoflurane in unpremedicated dogs. DESIGN: Randomized complete-block crossover design. ANIMALS: 8 healthy adult dogs. PROCEDURE: Anesthesia was induced by administering sevoflurane or isoflurane through a face mask. Time to intubation was recorded. After induction of anesthesia, minimal alveolar concentration (MAC) was determined with a tail clamp method while dogs were mechanically ventilated. Apneic concentration was determined while dogs were breathing spontaneously by increasing the anesthetic concentration until dogs became apneic. Anesthetic index was calculated as apneic concentration divided by MAC. RESULTS: Anesthetic index of sevoflurane (mean +/- SEM, 3.45 +/- 0.22) was significantly higher than that of isoflurane (2.61 +/- 0.14). No clinically important differences in heart rate; systolic, mean, and diastolic blood pressures; oxygen saturation; and respiratory rate were detected when dogs were anesthetized with sevoflurane versus isoflurane. There was a significant linear trend toward lower values for end-tidal partial pressure of carbon dioxide during anesthesia with sevoflurane, compared with isoflurane, at increasing equipotent anesthetic doses. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that sevoflurane has a higher anesthetic index in dogs than isoflurane. Sevoflurane and isoflurane caused similar dose-related cardiovascular depression, but although both agents caused dose-related respiratory depression, sevoflurane caused less respiratory depression at higher equipotent anesthetic doses.

Analysis of Variance↗

PubMed2001

Differential sensitivity of expressed L-type calcium channels and muscarinic M(1) receptors to volatile anesthetics in Xenopus oocytes.

Since volatile anesthetics inhibited high voltage-gated calcium channels and G-protein-coupled M(1) muscarinic signaling, their effects upon M(1) receptor-induced modulation of L-type (alpha1C) calcium channel was investigated. Voltage-clamped Ba(2+) currents (I(Ba)) were measured in Xenopus oocytes coexpressed with L-type channels and M(1) muscarinic receptors. M(1) receptor agonist, acetyl-beta-methylcholine (MCh) inhibited the peak and late components of I(Ba) in a dose-dependent manner. Analysis of I(Ba) after the treatment with MCh or volatile anesthetics revealed that the inactivating component, its time constant, and the noninactivating current were all decreased by these agents. MCh-induced inhibition followed a second messenger pathway that included G-proteins, phospholipase C, inositol-1,4,5-trisphosphate, and intracellular calcium [Ca(2+)](i). Although halothane or isoflurane inhibited I(Ba,) their effect was not mediated through these intracellular second messengers. By using volatile anesthetics and MCh sequentially, and in various combinations, the susceptibility of L-type currents and their modulation by M(1) receptors to volatile anesthetics were investigated. When MCh and volatile anesthetics were administered together simultaneously, a pronounced inhibition that was approximately equal to the sum of their individual effects was seen. Halothane or isoflurane further inhibited the I(Ba) when either volatile anesthetic was administered following the inhibition produced by prior administration of MCh. However, when MCh was administered following either volatile anesthetic, its effect was significantly reduced. Thus, whereas volatile anesthetics appear to directly inhibit L-type channels, they also interfere with channel modulation by G-protein-coupled receptors, which may have functional implications for both neuronal and cardiovascular tissues.

Anesthetics, Inhalation↗

PubMedDate not supplied

Managing patients with local anesthetic complications using alternative methods.

This article discusses various alternative methods of treating the patient who encounters problems with local anesthetics. Those alternative methods include: acupuncture, hypnosis, sedation, general anesthesia, and antihistamines as a substitute for local anesthetics with more of a focus in using antihistamines as an effective local anesthetic agent. Although not frequently encountered in the clinical setting, allergic reactions to local anesthetics do occur. Various surveys indicate the number of deaths attributed to local anesthesia range from 1:1,500,000 to 1:4,000,000, with oral surgery offices having higher mortality rates than general dentistry offices. This occurs despite clinicians' attention to patient medical histories, aspiration of the local anesthetic syringe during injections, and minimizing the dosage of local anesthetic solutions. Generally speaking, local anesthetics can be divided into two groups: ester of benzoic and aminobenzoic derivatives (cocaine, benzocaine, procaine, tetracaine, butacaine, etc.) or amide-derivatives of xylidine and toluidine groups (lidocaine, mepivacaine, prilocaine a.k.a. Citanest, etc.). Adverse effects include allergic or toxic reactions, as well as negative effects of any vasoconstrictors contained within the local anesthetic solution. This article will concentrate on how to successfully manage patients who have previously encountered allergic reactions.

Acupuncture Analgesia↗

PubMedDate not supplied

[Role of inhalation anesthetics in current anesthesiological practice].

Inhalational anesthetic agents represented for long time the sole or mainly anesthetic technique in general anesthesia. In the last twenty years, however, their use has been also related to toxicity among operating room personnel, chronically exposed to the volatile agents. This toxicity could induce the anesthesiologist to give up the volatile anesthetic agents in favour of a total intravenous anesthetic technique. Nevertheless well constructed prospective studies have clearly demonstrated that there is no significant correlation between morbidity index and chronic exposure to inhalational anesthetics. Furthermore a valid air exchange in the operating room, as well as more appropriate anesthesiologic procedures, have significantly reduced the concentration of volatile anesthetic agents in the operating areas. Nowadays inhalational anesthetic agents represent one of the different choices to perform general anesthesia. The anesthesiologist, however, according to patient's physical status and surgical procedure, must choose the anesthetic technique compatible with minimal risk both for patient and operating room personnel.

Abnormalities, Drug-Induced↗

PubMed2004

Comparison of the depressive effects of four anesthetic regimens on ventilatory and cardiovascular variables in the guinea pig.

BACKGROUND AND PURPOSE: Guinea pigs are one of the most difficult rodents to anesthetize safely, and as a consequence, there is a paucity of reports regarding the effects of anesthesia on their cardiorespiratory variables. We used long-term indwelling cannulas for studying the guinea pig in the conscious state, and subsequently investigated the effects of four types of injectable anesthetic regimens on cardiorespiratory variables. METHODS: Using barometric plethysmography (conscious: long-term cannulated, n = 11; no cannulation, n = 28) or trachea-out plethysmography (anesthetized: n = 7 for each of the four groups), we recorded ventilatory, cardiovascular, metabolic, and arterial gas variables during air breathing and in response to 10 min of hypoxia (8% O2) and 10 min of hypercapnia (8% CO2). The four anesthetic regimens tested were: Saffan (infused at 9.75 mg/kg of body weight/h, i.v.); ketamine/xylazine (14.6/3.7 mg/kg/h, i.v.); pentobarbitone (8.3 mg/kg/h, i.v.) plus Innovar Vet (0.15 mg/kg every 1 to 1.5 h, s.c.); or pentobarbitone alone (22 mg/kg/h, i.v.). RESULTS: The least depressive anesthetic with regard to ventilation (VE) was ketamine/xylazine. Air breathing was depressed by only 17% (cf approx 50 to 60% for all other regimes), and the VE responses to hypoxia and hypercapnia were attenuated the least. All anesthetics equally depressed mean arterial blood pressure (from 70 mmHg to 56 mmHg) and ketamine/xylazine was the only anesthetic to reduce heart rate (from 260 beats/min to 198 beats/min). CONCLUSION: Although all anesthetics induce cardiorespiratory depression to some extent, the use of ketamine/ xylazine is recommended for future use in respiratory studies of the guinea pig where anesthesia cannot be avoided.

Alfaxalone Alfadolone Mixture↗

PubMed2005

[The effects of anesthetics on G-protein-coupled receptors].

Although anesthetics have been often used clinically, the mechanisms of action of anesthetics have not yet been clarified. Recently, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR)-mediated signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M1, metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2 A, and substance P receptors. Many additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not been identified yet. Given that known GPCRs are targets for anesthetics, these oGPCRs may represent a rich group of receptor targets for anesthetics. This review highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors, and proteins that convey GPCR signals are also targets for anesthetics.

Anesthetics↗

PubMed1975

MAC expanded: AD50 and AD95 values of common inhalation anesthetics in man.

Two important measures may be derived from patient responses to a range of anesthetic doses. The AD50, corresponding to MAC, estimates the median anesthetic concentration--that dose where half the patients are anesthetized and half are not. The AD95 approaches the theoretical "minimum" anesthetic concentration by estimating the dose that anesthetizes 95 per cent of a patient population. The AD50 and AD95 are logical extensions of the MAC concept and can be evaluated with current experimental methodology. Recomputed from available data , the AD50's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's were 5 to 40 per cent greater than the AD50's.)Key workd: Potency, anesthetic, MAC, AD50, AD95; Pharmacology, dose-response curves.)

Anesthesia, Inhalation↗

PubMed1988

Comparison of the effects of carbisocaine and other local anesthetics on 32P incorporation into individual and total phospholipids in synaptosomes.

The aim of the paper was to study the effect of carbisocaine, a new local anesthetic with high liposolubility on incorporation of 32P into individual and total phospholipids and to compare its effect with that of other local anesthetics (procaine, lidocaine, cinchocaine, heptacaine). Carbisocaine decreased 32P incorporation into neutral phospholipids and increased the incorporation into acid phospholipids, presumably by inhibiting phosphatidate phosphohydrolase, similarly as reported for other anesthetics (Brindley and Bowley 1975). The increased incorporation of 32P into phosphatidylserine induced by carbisocaine suggests that this phospholipid is also synthetised from phosphatidic acid. At low concentrations, the local anesthetics studies were found to increase 32P incorporation into total phospholipids, whereas at high concentrations they reduced 32P incorporation. This biphasic effect is in agreement with the incorporation of 14C from glucose into lipids (Lassánová et al. 1984) and with the effect of cinchocaine on glycerol incorporation into phospholipids (Allan and Michell 1975), suggesting that local anesthetics affect de novo synthesis of phosphatidic acid. Carbisocaine increased 32P incorporation into phospholipids, in concentrations lower by several orders of magnitude as compared to the other local anesthetics studied. A rough correlation was observed between the concentrations at which the local anesthetics showed stimulatory effect on 32P incorporation, and the average effective concentrations of the respective anesthetics. No such correlation could be found for carbisocaine.

Anesthetics, Local↗

PubMed1986

The postoperative adverse effects of inhalational anesthetics.

Inhalational general anesthetics can contribute to postoperative morbidity (Table II). Postoperative effects of inhalational anesthetics on the central nervous system are speculative. The "toxic" effects of these agents during the postoperative period are most often an extension of their pharmacologic and physiochemical properties. Inhalational anesthetics may produce a number of varied changes in mental status after surgery such as headache, emergence excitement, and delirium. It is very important for health professionals to be aware of the risk of perioperative myocardial infarction in patients with preexisting heart disease if early detection and treatment are to occur. Relative to the common postoperative problems of atelectasis, pneumonia, and aspiration, inhalational agents may have a contributory role especially in patients with preexisting pulmonary disease. Postoperative nausea and vomiting are other common problems in which inhalational agents may have a role in their development. Although extensively investigated, suspected halothane hepatoxicity is a very rare complication if it exists at all. The renal effects of inhalational anesthetics are usually mild and transitory, although the use of methoxyflurane can produce direct nephrotoxicity. The evidence to support a clinically significant direct immunosuppressant effect of inhalational anesthetics after surgery is inconclusive. A concensus exists that any minor, short-lived effects are in all probability overshadowed by the nonspecific stress of surgery itself. By reducing this stress, anesthetics undoubtedly have a protective effect. There are probably no major mutagenic or carcinogenic effects of inhalational anesthetics under normal conditions. Inhalational anesthetics should be avoided during pregnancy because of their teratogenic potential and their effects on the uterus.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗

PubMed1986

Anesthetic-protein interaction: surface potential of bovine serum albumin estimated by a pH-sensitive dye.

It is often contended that inhalation anesthetics act on proteins via perturbation of lipid membranes. However, direct interaction between anesthetics and water-soluble proteins also has been demonstrated. We postulate that the anesthetic action is directed to the interface between water and macromolecules, irrespective of lipid membranes or proteins. The present study deals with anesthetic effects upon interfacial properties of a water-soluble, crystalline delipidated bovine serum albumin. A pH-indicator dye, bromothymol blue, was used to probe the surface potential of the protein. When a pH-indicator dye binds to a macromolecule, the pH, indicated by the color of the dye, differs from the bulk pH measured by a pH meter. This is because the pH of the microscopic area, where the dye is adsorbed, differs from the bulk due to the surface electrostatic potential that interacts with hydrogen ions (electrostatic terms), and the physical property that affects the color of the dye at the bound region is different from the bulk (nonelectrostatic terms). The mismatch between the bulk pH and the color of the bound pH indicator can be used to probe the property of the dye binding site. By screening the electrostatic effects with high ionic strength, the anesthetic effects upon the nonelectrostatic term were shown to be negligible under the present experimental conditions; the pH-color mismatch was mainly caused by the anesthetic effect upon the electrostatic potential of the macromolecular surface interacting with the dye. Accordingly, the surface potential of the dye binding site was estimated from the mismatch. It was found that inhalation anesthetics decreased the surface potential. The partial pressures of diethylether, enflurane, and methoxyflurane that decreased the surface potential by 10 mV were 2.1 X 10(-2), 1.7 X 10(-2), and 0.17 X 10(-2) bar, respectively, which were in agreement with the minimal alveolar concentrations of these anesthetics to achieve surgical anesthesia.

Anesthesia, Inhalation↗

PubMed1983

Spontaneous calcium release from sarcoplasmic reticulum. Effect of local anesthetics.

Spontaneous calcium release from purified light sarcoplasmic reticulum has been previously described (Palade, P., Mitchell, R. D., and Fleischer, S. (1983) J. Biol. Chem. 258, 8098-8107) and found to be distinct from several other forms of Ca2+ release. Ca2+ release occurs after a lag period following active Ca2+ preloading and depletion of extravesicular Ca2+. In the present study, we find that local anesthetics inhibit spontaneous Ca2+ release, in a time-dependent manner, varying considerably in the preincubation time required to exert maximal effect. At pH 7.0, hydrophilic and mostly charged local anesthetics, such as procaine, procainamide, and N-(2,6-dimethylphenyl carbamoyl methyl)triethyl ammonium bromide, inhibit Ca2+ release only after long preincubations (hours), whereas more hydrophobic local anesthetics are effective after only a short incubation (minutes) with sarcoplasmic reticulum. The more hydrophobic anesthetics take somewhat longer to reach equilibrium, as studied by inhibition of unidirectional Ca2+ efflux, and there is a direct relationship between hydrophobic partition coefficient and half-time to reach equilibrium. Agents known to inhibit permeability pathways for monovalent cations i.e. K+ channel blockers (decamethonium and n-dodecane-1, 12-N,N,N,N',N',N'-hexamethyl-bis-ammonium) or the anion blocker (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), do not inhibit spontaneous Ca2+ release. Carbonyl cyanide m-fluorophenylhydrazone, a protonophore, and gramicidin D, a monovalent cation ionophore, have no effect on Ca2+ release whether local anesthetics are present or not, while the Ca2+ ionophore A23187 relieves inhibition of Ca2+ release by local anesthetics. Ruthenium red does not inhibit spontaneous Ca2+ release. These findings suggest that the binding site(s) for local anesthetics is located on the inner face of the sarcoplasmic reticulum membrane and that local anesthetics interact directly with a Ca2+ channel rather than with other permeability pathways which might indirectly influence Ca2+ channel gating.

Amines↗

PubMed1981

Are convulsant gases also anesthetics?

This study investigated whether the convulsant gas flurothyl deviates from the correlation between anesthetic potency and lipid solubility. Flurothyl (CF3CH2OCH2CF3) produced convulsions in 50% of mice at 0.122 +/- 0.006% atm. Mice often convulsed repeatedly after exposure to flurothyl, the maximum number of convulsions occurring when the concentration was 0.24% atm. Concentrations greater than 0.6% atm produced convulsions immediately after addition of flurothyl, but rarely at later times. An ED50 value for loss of the righting reflex was obtained when the concentration was 1.22 +/- 0.19% atm. The oil/gas partition coefficient was found to be 46.9 for flurothyl at 37 C. The product of righting-reflex ED50 and oil/gas partition coefficient (0.0122 atm x 46.9 = 0.57 atm) is similar to that found for conventional anaesthetics in mice. Therefore, flurothyl does not deviate from the correlation of anesthetic potency and lipid solubility. It was also found that 0.3 to 0.8% atm flurothyl increased isoflurane MAC in dogs, but that 3 to 4% atm flurothyl decreased it. The increase of isoflurane requirement at lower concentrations of flurothyl suggests that anesthetics with a potential to cause convulsions may partly antagonize their own anesthetic effect. The decrease in isoflurane MAC in dogs at higher concentrations of flurothyl also implies that this compound has an anesthetic effect. A structural isomer of flurothyl, iso-Indoklon [(CSF3)2CHOCH3], was only anesthetic and did not have convulsant properties. Its MAC in dogs was 4.60 +/- 0.45% atm, and its righting-reflex ED50 in mice was 2.65 +/- 0.13% atm. The product of iso-Indoklon MAC in dogs and its oil/gas partition coefficient (27.0) was 1.24 atm, and the product of iso-Indoklon righting-reflex ED50 in mice and oil/gas partition coefficient was 0.72 atm. These values are close to those found for conventional anesthetic agents in dogs and mice; thus iso-Indoklon also does not deviate from the correlation between anesthetic potency and lipid solubilities.

Anesthesia, Inhalation↗

PubMed1980

Microcirculatory actions of general anesthetics.

General anesthesia, either with the inhalation or the nonvolatile anesthetics, results in significant changes in the microvasculature. The anesthetics alter microvascular diameters in the resting animal and they change the responses to stress (i.e., catecholamine stimulation or hemorrhage) also. Alterations in the microvasculature involve primarily changes in the diameters of arterioles and venules and these, combined with the associated changes in arterial pressure and cardiac output, are responsible for the changes in organ blood flow that occur during general anesthesia. General anesthetics alter the in vivo vascular smooth muscle responses to topically applied vasoactive substances such as epinephrine or norepinephrine. The microvascular responses to hemorrhage are altered by the anesthetics and the changes are most pronounced in the smaller (approximately 20 micrometers) arterioles. Anesthetic influences on the microcirculation are unique for each agent and are not the result of the general state of narcosis. Anesthetic influences on the microvasculature are both dose-dependent and tissue-specitic. The peripheral vascular effects of the anesthetics may influence the choice of anesthesia and may alter the results of experimental investigations performed in anesthetized animals.

Anesthetics↗

PubMed1995

Different subunit requirements for volatile and nonvolatile anesthetics at gamma-aminobutyric acid type A receptors.

The ability of volatile (halothane and isoflurane) and nonvolatile (alphaxalone and pentobarbital) general anesthetics to modulate radioligand binding to gamma-aminobutyric acid (GABA)A receptors was examined in an immortalized cell line (WSS-1) expressing rat alpha 1 and gamma 2 subunits. Volatile anesthetics enhance [3H]flunitrazepam binding to WSS-1 cells in a concentration-dependent manner, with potencies and efficacies comparable to those found with native GABAA receptors. Transfection of these cells with cDNAs encoding rat beta 2 or beta 3 subunits had a significant influence on anesthetic efficacy but not potency in this assay. Thus, transfection with the beta 2 subunit reduced the efficacy of both isoflurane and halothane, whereas transfection with the beta 3 subunit increased the efficacy of isoflurane but not halothane, compared with values obtained in WSS-1 cells. In contrast, alpha-xalone (an anesthetic steroid) had no effect, whereas at high concentrations pentobarbital (an anesthetic barbiturate) produced a modest inhibition of [3H]flunitrazepam binding to GABAA receptors in WSS-1 cells. Transfection of WSS-1 cells with cDNAs encoding either beta 2 or beta 3 subunits resulted in a concentration-dependent enhancement of [3H]flunitrazepam binding by these nonvolatile anesthetics. Moreover, pentobarbital was significantly more potent in enhancing [3H]flunitrazepam binding to WSS-1 cells transfected with the beta 2 subunit, compared with the beta 3 subunit. The difference in subunit requirements between volatile and nonvolatile anesthetics for enhancement of [3H]flunitrazepam binding indicates that these classes of agents affect GABAA receptor function at distinct loci. These studies also provide evidence that the beta subunit is required for these nonvolatile anesthetics to positively modulate GABAA receptors.

Anesthetics↗