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PubMed2002

General anesthetic actions on norepinephrine, dopamine, and gamma-aminobutyric acid transporters in stably transfected cells.

UNLABELLED: The effects of general anesthetics on neurotransmitter uptake by plasma membrane transporters are controversial. We analyzed the effects of representative volatile and IV general anesthetics on recombinant transporters for norepinephrine (human NET), dopamine (rat DAT), or gamma-aminobutyric acid (rat GAT-1) stably expressed in a porcine kidney cell line (LLC-PK(1)). This approach avoids complicating factors associated with neuronal preparations, such as the involvement of multiple transporters and the indirect effects of membrane potential. At clinical concentrations, human NET was inhibited only by halothane (50% inhibitory concentration [IC(50)] = 0.54 mM), rat DAT was sensitive to both halothane and isoflurane (IC(50) = 0.60 and 0.64 mM, respectively), and rat GAT-1 was insensitive to both volatile anesthetics. Human NET was inhibited in a dose-dependent fashion by propofol (IC(50) = 41 micro M), ketamine (IC(50) = 150 micro M), and etomidate (IC(50) > 200 micro M), but not by pentobarbital. Only propofol inhibited NET at a clinically relevant concentration (5 micro M). Rat DAT was inhibited in a dose-dependent fashion by propofol (IC(50) = 120 micro M), etomidate (IC(50) = 100 micro M), and ketamine (IC(50) = 210 micro M), but not by pentobarbital. None of these anesthetics was predicted to inhibit DAT at concentrations that produce anesthesia. Propofol inhibited rat GAT-1, but only at the largest concentration tested. General anesthetics have drug- and subtype-selective actions on neurotransmitter transporters. We conclude that effects on catecholamine, but not gamma-aminobutyric acid, transporters may contribute to secondary synaptic actions of certain anesthetics but are unlikely to be essential to their anesthetic properties. IMPLICATIONS: Previous studies have implicated neurotransmitter transporters as targets for general anesthetic effects on synaptic transmission. Recombinant transporters for norepinephrine and dopamine were sensitive to certain volatile and IV anesthetics, whereas gamma-aminobutyric acid transporters were insensitive. These anesthetic- and neurotransmitter-specific effects may underlie some of the secondary effects of general anesthetics.

Anesthetics, General↗
PubMed1986

Dual effect of local anesthetics on the function of excitable rod outer segment disk membrane.

The effects of local anesthetics and a divalent cation, Ca2+, on the function of rhodopsin were estimated from the measurements of light-induced proton uptake. The light-induced proton uptake by rhodopsin in the rod outer segment disk membrane was enhanced at lower pH (4) but depressed at higher pHs (6 to 8) by the tertiary amine local anesthetics lidocaine, bupivacaine, tetracaine, and dibucaine. The order of local anesthetic-induced depression of the proton uptake followed that of their clinical anesthetic potencies. The depression of the proton uptake versus the concentration of the uncharged form of local anesthetic nearly describes the same curve for small and large dose of added anesthetic. Furthermore, a neutral local anesthetic, benzocaine, depressed the proton uptake at all pHs between 4 and 7. These results indicate that the depression of the proton uptake is due to the effect of only the uncharged form. It is hypothesized that the uncharged form of local anesthetics interacts hydrophobically with the rhodopsin in the disk membrane. The dual effect of local anesthetics on the proton uptake, on the other hand, suggests that the activation of the function of rhodopsin may be caused by the charged form. There was no significant change in the light-induced proton uptake by rhodopsin when 1 mM of Ca2+ was introduced into the disk membrane at varying pHs in the absence or presence of local anesthetics. This fact indicates that Ca2+ ion does not influence the diprotonating process of metarhodopsin; neither does it interfere with the local anesthetic-induced changes in the rhodopsin molecule.

Anesthetics, Local↗
PubMed1992

Stereoselective inhibition of neuronal sodium channels by local anesthetics. Evidence for two sites of action?

The objective of this study was to determine if the "tonic," resting inhibition of Na+ channels by local anesthetics results from binding at a site different from that for "phasic," use-dependent inhibition. Stereoselective actions of four local anesthetics were examined in isolated frog peripheral nerve and single Na+ channels. Using the sucrose-gap method on desheathed nerves, four actions of local anesthetics were assayed: 1) tonic depression of compound action potentials at low stimulation frequency (one per minute); 2) phasic depression of the compound action potential during trains of stimulation at 5, 10, and 20 Hz; 3) competitive antagonism of the reversible Na+ channel activator veratridine assayed through the depolarization of the compound resting membrane potential; and 4) depression of the depolarization of the compound resting membrane potential initially induced by the irreversible channel activator batrachotoxin. For assays 1, 2, and 3, all local anesthetics showed a stereoselectivity, where rectus, or (+), enantiomers were more potent than sinister, or (-), enantiomers. In contrast, for the noncompetitive antagonism of veratridine's action and the depression of batrachotoxin-induced depolarization, also a noncompetitive interaction between anesthetic and activator, the (-) enantiomer was more potent than the corresponding (+) enantiomer. Blockade of single Na+ channels activated by batrachotoxin in planar lipid bilayers was also stereoselective for the (-) enantiomer. These findings, along with previously reported voltage-clamp results, can be applied to infer properties of a local anesthetic binding site in activator-free channels. Local anesthetic molecules with more sharply angled shapes have stronger stereoselectivities than less angled, more planar drugs. The inversion of the stereopotency induced by the activators can be explained by either of two mechanisms. There may be two binding sites for local anesthetics, one of high and one of low affinity and of opposite stereoselectivity; activators may change the conformation at the high affinity site, reducing its local anesthetic affinity below that of the usual low affinity site and thereby revealing the pharmacology of the weaker site. Alternatively, only a single binding site may exist and be conformationally altered by activators such that both anesthetic affinity and stereopotency are modified. In activator-free channels, however, a single, high-affinity binding site with a constant stereoselectivity can account for both tonic and phasic inhibition by local anesthetics.

Action Potentials↗
PubMed1993

Effects of general anesthetics on intercellular communications mediated by gap junctions between astrocytes in primary culture.

BACKGROUND: Astrocytes represent a major nonneuronal cell population in the central nervous system (CNS) and are actively involved in several brain functions. These cells are coupled by gap junctions (GJ) into a syncytial-like network resulting in cellular communication through ionic and metabolic exchange between adjacent astrocytes. Whether anesthetics affect astrocyte function is not known. In the present study, the effects of general anesthetics on GJ permeability were investigated in primary cultures of mouse striatal astrocytes. METHODS: Junctional permeability was determined by using the fluorescent probe Lucifer yellow and the scrape loading/dye transfer technique. Confluent cells were preincubated 5 min with various concentrations of anesthetic agents and GJ permeability was estimated by measuring the area occupied by the dye from digitalized images taken 8 min after cell loading. RESULTS: Of the intravenous anesthetics tested, only propofol (P: 10(-4) M, P < 0.01 and 10(-5) M, P < 0.05) and etomidate (ET: 10(-4) M, P < 0.05, but not 10(-5) M) induced a significant reduction of GJ permeability. In contrast, diazepam (10(-5) M), morphine (10(-4) M), ketamine (10(-4) M), thiopental (10(-4) M), and clonidine (10(-7) M) did not affect junctional permeability. In addition, the halogenated anesthetics halothane, enflurane, and isoflurane induced a dose-dependent closure of GJ. For halothane, enflurane, and isoflurane, the maximum effect was achieved with a 10(-4) M, 1.6 x 10(-3) M, and 10(-3) M anesthetic concentration, respectively. Removal of volatile anesthetics resulted in the restoration of the control fluorescence area between 15 and 45 min. The time course of recovery of GJ permeability was examined more precisely for shorter periods of halothane administration (5 min, 1 mM). Under these conditions, the rate of dye spread returned to control values following anesthetic washout, while, during the same period of time, complete uncoupling of GJ was still observed in the presence of a 1 mM halothane concentration. CONCLUSIONS: These results indicate that general anesthetics differentially affect GJ permeability in cultured astrocytes. This uncoupling effect (closure of gap junctions) may contribute to the mechanisms of action of some anesthetic agents (primarily volatile anesthetics) at the level of the CNS by altering astrocyte communication.

Anesthetics↗
PubMed1994

Selective anesthetic inhibition of brain nitric oxide synthase.

BACKGROUND: It has been postulated that nitric oxide (NO) is a neurotransmitter involved in consciousness, analgesia, and anesthesia. Halothane has been shown to attenuate NO-mediated cyclic guanosine monophosphate accumulation in neurons, and a variety of anesthetic agents attenuate endothelium-mediated vasodilation, suggesting an interaction of anesthetic agents and the NO-cyclic guanosine monophosphate pathway. However, the exact site of anesthetic inhibitory action in this multistep pathway is unclear. The current study examines effects of volatile and intravenous anesthetic agents on the enzyme nitric oxide synthase (NOS) in brain. METHODS: NOS activity was determined by in vitro conversion of [14C]arginine to [14C]citrulline. Wistar rats were decapitated and cerebellum quickly harvested and homogenized. Brain extracts were then examined for NOS activity in the absence and presence of the volatile anesthetics halothane and isoflurane, and the intravenous agents fentanyl, midazolam, ketamine, and pentobarbital. Dose-response curves of NOS activity versus anesthetic concentration were constructed. Effects of anesthetics on NOS activity were evaluated by analysis of variance. RESULTS: Control activities were 57.5 +/- 4.5 pmol.mg protein-1.min-1 in the volatile anesthetic experiments and 51.5 +/- 6.5 pmol.mg protein-1.min-1 in the intravenous anesthetic experiments. NOS activity was not affected by ketamine (< or = 1 x 10(-4) M), pentobarbital (< or = 5 x 10(-5) M), fentanyl (< or = 1 x 10(-5) M), and midazolam (< or = 1 x 10(-5) M). Halothane decreased NOS activity to 36.7 +/- 2.5 (64% of control, P < 0.01 from control), 23.8 +/- 4.3 (41%, P < 0.01 from control and < 0.05 from 0.5% halothane), 25.2 +/- 3.8 (44%, P < 0.01 from control and < 0.05 from 0.5% halothane), and 19.7 +/- 2.8 (34%, P < 0.01 from control and < 0.05 from 0.5% halothane) pmol.mg protein-1.min-1 at 0.5, 1.0, 2.0, and 3.0% vapor. Isoflurane decreased NOS activity to 48.9 +/- 6.1 (85% of control), 46.0 +/- 3.2 (80%, P < 0.05 from control), 40.3 +/- 5.1 (70%, P < 0.05 from control), and 34.2 +/- 4.0 (60%, P < 0.05 from control and 0.5% and 1.0% isoflurane) pmol.mg protein-1.min-1 at 0.5, 1.0, 1.5, 2.0% vapor, respectively. CONCLUSIONS: Volatile anesthetics inhibit brain NOS activity in an in vitro system, but the intravenous agents examined have no effect at clinically relevant concentrations. This inhibition suggests a protein-anesthetic interaction between halothane, isoflurane, and NOS. In contrast, intravenous agents appear to have no direct effect on NOS activity. Whether intravenous agents alter signal transduction or regulatory pathways that activate NOS is unknown.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

Alkalinizing water-soluble local anesthetic solutions by addition of cyclodextrin.

BACKGROUND AND OBJECTIVES: The use of sodium bicarbonate for alkalinization of local anesthetics to improve their efficacy has some disadvantages including decreased stability of the solutions. The present study was performed to evaluate usefulness of cyclodextrins (CDs) in improving the solubility and stability of local anesthetic solutions at near physiologic pH without precipitation. METHODS: Solubility of local anesthetics with or without CDs in physiologic saline was investigated by monitoring cloudiness or precipitate formation visually and by recording absorbance at 620 nm. Interaction of anesthetic and CD was also studied spectrophotometrically using spectral change of the drugs associated with the inclusion complex formation. RESULTS: Cyclodextrins improved the solubility and stability of the four local anesthetics studied (dibucaine, tetracaine, bupivacaine, and lidocaine). In the neutral pH region, the effects of the CDs were more significant with dibucaine and tetracaine, which are more hydrophobic than the other two. A type of effective CD was different for each anesthetic depending partly on the tendency to form inclusion complex with local anesthetic. The local anesthetic solutions solubilized by CDs were found to remain clear for more than 72 hours without any visible precipitation or turbidity at neutral pHs. CONCLUSIONS: The improved solubility of local anesthetics by adding CD may be caused by inclusion complex formation of CD with local anesthetics. This new preparation for the alkalinized water-soluble anesthetic solutions may be useful for practical application in the clinical setting, although this awaits further study.

Anesthetics, Local↗
PubMed2005

Local anesthetics inhibit priming of neutrophils by lipopolysaccharide for enhanced release of superoxide: suppression of cytochrome b558 expression by disparate mechanisms.

Local anesthetics have anti-inflammatory effects in vivo and inhibit neutrophil functions in vitro, but how these agents act on neutrophils remains unclear. Phagocytosis and bactericidal activity of neutrophils are enhanced by exposure to bacterial components such as lipopolysaccharide (LPS); this process is termed priming, which for enhanced release of superoxide (O2-) causes mobilization of intracellular granules that contain cytochrome b558, a component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We studied whether local anesthetics affected LPS priming for enhanced release of O2- in response to triggering by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), and we investigated which element in the LPS signaling pathway might be the target of local anesthetics. Neutrophils were incubated with 10 ng/ml LPS and 1% plasma+/-local anesthetics, washed, and triggered with fMLP. Local anesthetics all inhibited LPS priming, and 50% inhibition was at 0.1 mM tetracaine, 0.5 mM bupivacaine, 3.0 mM lidocaine, or 4.0 mM procaine. Local anesthetics inhibited LPS-induced mobilization of specific granules and secretory vesicles. Local anesthetics inhibited LPS-induced up-regulation of cytochrome b558 but not LPS-induced translocation of p47phox. Inhibition of priming by local anesthetics was reversed by washing and incubating for 5 min. Tetracaine alone, but not the other local anesthetics, inhibited LPS activation of p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (kinases in the LPS signaling pathway). The p38 MAPK inhibitors SB203580 and PD169316 also blocked LPS priming. Thus, tetracaine and the other local anesthetics inhibit by disparate mechanisms, but all the local anesthetics impaired up-regulation of cytochrome b558 and all impaired priming of NADPH oxidase by LPS.

Anesthetics, Local↗
PubMed2004

The effect of local anesthetics on monocyte mCD14 and human leukocyte antigen-DR expression.

UNLABELLED: It has been demonstrated that local anesthetics have several effects on the immune system. Monocytes and macrophages are essential components of the host response to microbial infection; however, the effect of local anesthetics on monocyte surface receptor expression remains unclear. We designed this study to investigate the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced or staphylococcal enterotoxin B (SEB)-induced tumor necrosis factor (TNF)-alpha production. Blood samples were obtained from 10 healthy volunteers. The effects of local anesthetics on LPS- or SEB-induced TNF-alpha production were determined by using an enzyme-linked immunosorbent assay. After different doses of local anesthetics were added, the blood was stimulated with LPS (10 ng/mL) or SEB (10 micro g/mL) for 4 h. The effects of local anesthetics on monocyte mCD14 and HLA-DR expression were measured by dual monoclonal antibody staining and flow cytometry. Local anesthetics showed no effect on LPS- or SEB-induced TNF-alpha production in human whole blood. Local anesthetics suppressed monocyte HLA-DR expression in a dose-dependent manner (P < 0.05) but had no effect on monocyte mCD14 expression. This study demonstrated that local anesthetics suppress HLA-DR expression on the surface of human monocytes. IMPLICATIONS: Monocyte surface receptors have a crucial role in the host response to microbial infection. We investigated the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression. Our results show that local anesthetics suppress HLA-DR expression on the surface of human monocytes.

Adult↗
PubMed2006

Local anesthetic-induced protection against lipopolysaccharide-induced injury in endothelial cells: the role of mitochondrial adenosine triphosphate-sensitive potassium channels.

Lidocaine attenuates cell injury induced by ischemic-reperfusion and inflammation, although the protective mechanisms are not understood. We hypothesized that lidocaine and other amide local anesthetics protect against endothelial cell injury through activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels. We determined the effects of amide local anesthetics (lidocaine, ropivacaine, and bupivacaine), ester local anesthetics (tetracaine and procaine), one amide analog (YWI), and two non-amide local anesthetic analogs (JDA and ICM) on viability of human microvascular endothelial cells after exposure to lipopolysaccharide (LPS) in the absence or presence of the mitoK(ATP) channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoK(ATP) channels. Lidocaine, ropivacaine, bupivicaine, YWI, JDA, and ICM attenuated by 60% to 70% the decrease in cell viability caused by LPS. Amide local anesthetics and YWI protection was inhibited by 5-hydroxydecaonate, whereas the protection induced by JDA and ICM was not. Tetracaine and procaine did not protect against LPS-induced injury. The amide local anesthetics and the amide analog (YWI) enhanced diazoxide-induced flavoprotein fluorescence by 5% to 20%, whereas ester local anesthetics decreased diazoxide-induced flavoprotein fluorescence by 5% to 60% and the non-amide local anesthetic analogs had no effect. In conclusion, amide local anesthetics and the amide analog (YWI) attenuate LPS-induced cell injury, in part, through activation of mitoK(ATP) channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoK(ATP) channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoK(ATP) channels.

Adenosine Triphosphate↗
PubMed2006

Contrasting roles of the N-methyl-D-aspartate receptor in the production of immobilization by conventional and aromatic anesthetics.

We hypothesized that N-methyl-d-aspartate (NMDA) receptors mediate some or all of the capacity of inhaled anesthetics to prevent movement in the face of noxious stimulation, and that this capacity to prevent movement correlates directly with the in vitro capacity of such anesthetics to block the NMDA receptor. To test this hypothesis, we measured the effect of IV infusion of the NMDA blockers dizocilpine (MK-801) and (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) to decrease the MAC (the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects given a noxious stimulation) of 8 conventional anesthetics (cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon) and 8 aromatic compounds (benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene) and, for comparison, etomidate. We postulated that MK-801 or CPP infusions would decrease MAC in inverse proportion to the in vitro capacity of these anesthetics to block the NMDA receptor. This notion proved correct for the aromatic inhaled anesthetics, but not for the conventional anesthetics. At the greatest infusion of MK-801 (32 microg x kg(-1) x min(-1)) the MACs of conventional anesthetics decreased by 59.4 +/- 3.4% (mean +/- sd) and at 8 microg x kg(-1) x min(-1) by 45.5 +/- 4.2%, a decrease not significantly different from a 51.4 +/- 19.0% decrease produced in the EC50 for etomidate, an anesthetic that acts solely by enhancing gamma-amino butyric acid (GABA) receptors. We conclude that some aromatic anesthetics may produce immobility in the face of noxious stimulation by blocking the action of glutamate on NMDA receptors but that conventional inhaled anesthetics do not.

Anesthetics, Inhalation↗
PubMed2006

Inhaled anesthetic agents.

PURPOSE: The pharmacology, bioavailability and pharmacokinetics, indications, clinical efficacy, adverse effects and toxicities, and dosage and administration of the inhaled anesthetics are reviewed. SUMMARY: The inhaled anesthetics include desflurane, enflurane, halothane, isoflurane, and sevoflurane and are thought to enhance inhibitory postsynaptic channel activity and inhibit excitatory synaptic activity. The mechanism of action of inhaled anesthetics has not been completely defined. A number of factors can influence the pharmacokinetics of inhaled anesthetics, including solubility in blood, cardiac output, tissue equilibration, extent of tissue perfusion, metabolism, and age. All of the available inhaled anesthetics are effective for inducing or maintaining anesthesia or both. Most clinical trials of inhaled anesthetics have evaluated differences in induction and emergence from anesthesia by comparing (1) times to loss of reflex, extubation, and response to verbal commands; orientation to time and place; and ability to sit up without assistance, (2) need for post-surgical analgesia, and (3) time to discharge as measures of efficacy. Adverse effects and toxicities of the inhaled anesthetics include nephrotoxicity, hepatotoxicity, cardiac arrhythmias, neurotoxicity, postoperative nausea and vomiting, respiratory depression and irritation, malignant hyperthermia, and postanesthesia agitation. Safety issues surrounding these gases include occupational exposure and intraoperative fires within the delivery systems used with inhaled anesthetics. Drugs used for anesthesia during surgery can account for 5-13% of a hospital's drug budget. CONCLUSION: The inhaled anesthetics have been shown to be both safe and effective in inducing and maintaining anesthesia. These agents differ in potency, adverse-effect profile, and cost. Newer anesthetic gases, such as sevoflurane and desflurane, appear to have more favorable physico-chemical properties. These factors, as well as patient characteristics and duration and type of procedure, must be considered when selecting an inhaled anesthetic.

Anesthetics, Inhalation↗
PubMed1984

Local anesthetics in dental practice.

Local anesthetics are the most widely used drugs in dentistry today. Knowledge of the pharmacology and toxicology of these agents will result in their intelligent and judicious use. The choice of local anesthetic should be individualized for each patient. The duration of the dental procedure should be weighed against the duration of action of the local anesthetic; a decision should be made as to whether a vasoconstrictor is needed to prolong its action. However, if the duration of numbness is too long, the possibility of self-mutilation must be considered in certain patients (for example, children and the mentally retarded). In other patients with whom postoperative pain is expected, it may be beneficial to administer a long-acting local anesthetic such as bupivacaine for control of postoperative pain. The total dose of local anesthetic and vasoconstrictor must be determined for each patient based upon body weight; the maximal dosages for each agent should be known. Small children or frail individuals will require below average dosages. The use of a vasoconstrictor may constitute the limiting factor to the total number of local anesthetic cartridges that can be administered safely over a given period of time. Certain medical problems, such as cardiovascular system impairments or hyperthyroidism, may influence the choice of anesthetic and the quantity of vasoconstrictor. An understanding of the physicochemical properties of local anesthetics is also important to a rational process of selection. There are several causes for failure to achieve profound regional anesthesia. These include inflammation and/or infection, anatomic variation, intravascular injection, accessory innervation, and deflection of the needle. Inflammation and infection reduce the efficacy of a local anesthetic by reducing its bioavailability. Local anesthetics with low pKa values (for instance, mepivacaine) are the most effective in this clinical situation. Other causes of inadequate regional anesthesia are primarily related to technique of administration and can be circumvented by the use of the periodontal ligament injection. A comprehensive review of this technique and its application has been presented by the Council on Dental Materials and Equipment of the American Dental Association. Occasionally, a clinician may be unsuccessful at achieving regional anesthesia despite these additional measures. Highly anxious dental patients or patients with a genuine tolerance to local anesthetics normally pose the most problems. Transitional block or threshold block phenomena should also be suspected in these situations.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia, Dental↗
PubMed1987

Cardiovascular effects of cocaine in anesthetized and conscious rats.

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.

Anesthesia↗
PubMed2001

Partition coefficients of charged and uncharged local anesthetics into dipalmitoylphosphatidylcholine bilayer membrane: estimation from pH dependence on the depression of phase transition temperatures.

Effects of the local anesthetics, dibucaine, bupivacaine and lidocaine on the phase transition temperatures of dipalmitoylphosphatidylcholine (DPPC) bilayer membrane were studied by the optical method. We focus our attention on pH dependence of the depression of main transition and pretransition temperatures. The temperatures of both transitions of DPPC bilayer membrane were depressed by the addition of anesthetics; the higher the value of pH, the larger the depression of main transition temperature and/or pretransition temperature by anesthetics. By extending the colligative thermodynamic framework to the depression of main transition temperature by an anesthetic, we can estimate the differential partition coefficient, which is defined by the difference in partition coefficients of an anesthetic into the ripple gel and liquid crystal phases. The difference in partition coefficient between the lamellar and ripple gel phases can also be estimated from the depression of pretransition temperature. Since the differential partition coefficients include both contributions of the charged and uncharged anesthetics, we could estimate the partition coefficients of the charged and uncharged anesthetic into the membranes from the pH dependence of differential partition coefficients. The liquid crystalline membrane of DPPC bilayer was more receptive to the uncharged local anesthetics than the charged species. The partition coefficients of the charged and uncharged anesthetics into the liquid crystalline phase of DPPC bilayer membrane were 3540 and 249000 (for dibucaine), 1120 and 83900 (for bupivacaine), 256 and 11700 (for lidocaine), respectively. The transfer free energy of uncharged anesthetics from the aqueous phase to the liquid crystalline membrane was well correlated to the local anesthetic potency.

Journal Article↗
PubMed1990

Absence of abundant binding sites for anesthetics in rabbit brain: an in vivo NMR study.

Using magnetic resonance spectroscopy, the authors tested whether cerebral concentrations of inhaled anesthetics do not increase proportionately at inspired concentrations exceeding 3% 1) because anesthetics bind to and saturate specific sites in the brain or 2) because anesthetic-induced depression of ventilation limits the increase in alveolar anesthetic partial pressure. New Zealand White rabbits were anesthetized with methohexital, 70% nitrous oxide, and local infiltration of 1% lidocaine. Cerebral concentrations of anesthetic were determined from 19F spectra acquired with nuclear magnetic resonance (NMR). Inspired, end-tidal, and arterial anesthetic concentrations, and end-tidal and arterial partial pressure of carbon dioxide were measured. Blood/gas partition coefficients were determined and used to convert arterial anesthetic concentration to partial pressures. In seven spontaneously breathing animals, halothane (1%; n = 5) or isoflurane (0.8%; n = 2) was administered at a constant inspired concentration for 20 min; NMR spectra were acquired between 10 and 20 min. Thereafter, the inspired concentration was increased and the process repeated until apnea occurred. Two additional rabbits were anesthetized with isoflurane and studied similarly but with higher inspired concentrations during mechanical ventilation. In spontaneously breathing animals, ventilatory depression occurred, documented by marked increases in PaCO2, and cerebral concentrations of anesthetic did not increase proportionately at inspired concentrations exceeding 3%. In contrast to an absence of a correlation of inspired and cerebral concentrations during spontaneous ventilation, arterial and cerebral concentrations correlated linearly during both spontaneous and mechanical ventilation (R2 greater than 0.969). These results are consistent with depression of ventilation, rather than binding to specific cerebral sites as an explanation for the nonlinear relationship between cerebral and inspired anesthetic concentrations.

Animals↗
PubMed2000

Clinical outcomes after carotid endarterectomy: comparison of the use of regional and general anesthetics.

OBJECT: The authors analyzed their series of carotid endarterectomies (CEAs), which were performed after administration of either a general or regional anesthetic, to determine whether the choice of anesthetic affected patients' clinical outcomes and length of hospital stay. METHODS: A series of 803 consecutive CEAs performed between July 1990 and February 1999 was reviewed. Cases were analyzed for patient demographics, comorbid medical states, and perioperative complications. Contingency-table statistical analysis was used to compare the incidence of comorbid medical states and perioperative complications between patients who underwent CEA in which either a regional or general anesthetic was used. Student's t-test was used to compare the length of hospital stay and mean patient age. A regional anesthetic was used for 632 CEAs, and a general anesthetic was used for 171 operations. There were no statistically significant intergroup differences in demographics or comorbid medical states. The incidence of perioperative stroke and death did not differ significantly between the regional (2.7%) and the general anesthetic groups (2.3%). However, the incidence of nonneurological, nonfatal complications was significantly less in the regional anesthetic (1.6%) than in the general anesthetic group (14.6%, p<0.0001). Patients undergoing CEA in which a regional anesthetic was used had a significantly lower incidence of cardiopulmonary complications (myocardial infarction and postoperative intubation), cervical complications (neck hematomas and cranial nerve injuries), and urological complications (urinary retention) than patients who underwent surgery after receiving a general anesthetic. CONCLUSIONS: Patients undergoing CEA in which a regional anesthetic was used had significantly fewer nonneurological, nonfatal complications, particularly cardiopulmonary complications, than similar patients surgically treated after induction of general anesthesia.

Aged↗
PubMed2002

[Annual report of perioperative mortality and morbidity for the year 2000 at certified training hospitals of Japanese Society of Anesthesiologists: with a special reference to anesthetic methods--report of the Japanese Society of Anesthesiologists Committee on Operating Room Safety].

The Committee on Operating Room Safety of Japan Society of Anesthesiologists (JSA) sends annually confidential questionnaires of perioperative mortality and morbidity (cardiac arrest, severe hypotension, severe hypoxia) to Certified Training Hospitals of JSA. This report is a special reference to anesthetic methods in perioperative mortality and morbidity in 2000. Five hundreds and twenty hospitals reported perioperative mortality and morbidity referred to anesthetic methods and total numbers of reported cases were 910,007. The percentage of cases reported by each anesthetic method was as follows; inhalation anesthesia 45.47%, total intravenous anesthesia (TIVA) 6.15%, inhalation anesthesia + epidural or spinal or conduction block 24.48%, TIVA + epidural or spinal or conduction block 6.33%, spinal with continuous epidural block (CSEA) 3.67%, epidural anesthesia 1.92%, spinal anesthesia 10%, conduction block 0.47% and others 1.49%. The incidence of cardiac arrest per 10,000 cases due to all etiology (anesthetic management, preoperative complications, intraoperative complications, surgery, others) is estimated to be 6.55 cases in average; 5.36 cases in inhalation anesthesia, 30.72 cases in total intravenous anesthesia (TIVA), 4.62 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.6 cases in TIVA + epidural or spinal or conduction block, 1.2 cases in spinal with continuous epidural block (CSEA), 0.57 cases in epidural anesthesia, 1.65 cases in spinal anesthesia, 2.36 cases in conduction block and 46.38 cases in other methods. However, the incidence of cardiac arrest per 10,000 cases totally attributable to anesthetic management is estimated to be 0.54 cases in average; 0.34 cases in inhalation anesthesia, 1.07 cases in TIVA, 0.58 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.17 cases in TIVA + epidural or spinal or conduction block, 0.9 cases in CSEA, 0.57 cases in epidural anesthesia, 0.99 cases in spinal anesthesia, zero case in conduction block and 1.47 cases in other methods. The incidence of severe hypotension per 10,000 cases due to all etiology is estimated to be 11.14 cases in average; 11.31 cases in inhalation anesthesia, 36.61 cases in TIVA, 9.29 cases in inhalation anesthesia + epidural or spinal or conduction block, 6.59 cases in TIVA + epidural or spinal or conduction block, 3.59 cases in CSEA, 6.3 cases in epidural anesthesia, 4.39 cases in spinal anesthesia, 2.36 cases in conduction block and 23.56 cases in other methods. On the other hand, the incidence of severe hypotension per 10,000 cases totally attributable to anesthetic management is estimated to be 1.25 cases in average; 0.97 cases in inhalation anesthesia, 0.89 cases in TIVA, 1.39 cases in inhalation anesthesia + epidural or spinal or conduction block, 1.39 cases in TIVA + epidural or spinal or conduction block, 2.09 cases in CSEA, 3.44 cases in epidural anesthesia, 1.87 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The incidence of severe hypoxia per 10,000 cases due to all etiology is estimated to be 4.8 cases in average; 6.35 cases in inhalation anesthesia, 9.64 cases in TIVA, 3.82 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.26 cases in TIVA + epidural or spinal or conduction block, 0.3 cases in CSEA, 1.15 case in epidural anesthesia, 1.21 cases in spinal anesthesia, zero case in conduction block and 5.89 cases in other methods. On the other hands, the incidence of severe hypoxia per 10,000 cases totally attributable to anesthetic management is estimated to be 1.98 cases in average; 3.09 cases in inhalation anesthesia, 2.32 cases in TIVA, 1.3 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.87 cases in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.55 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The mortality rate of cardiac arrest within 7 postoperative days per 10,000 cases due to all etiology is estimated to be 3.55 (54.2%) cases in average; 3.12 (58.1%) cases in inhalation anesthesia, 19.29 (62.8%) cases in TIVA, 1.17 (25.2%) cases in inhalation anesthesia + epidural or spinal or conduction block, 0.52 (20%) cases in TIVA + epidural or spinal or conduction block, zero cases in CSEA, zero case in epidural anesthesia, 0.33 (20%) cases in spinal anesthesia, zero case in conduction block and 39.76 (85.7%) cases in other methods. On the other hands, the mortality rate of cardiac arrest per 10,000 cases totally attributable to anesthesia is estimated to be 0.07 (12.2%) case in average, 0.07 (21.4%) case in inhalation anesthesia, 0.18 (16.8%) case in TIVA, zero case in inhalation anesthesia + epidural or spinal or conduction block, zero case in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.11 (11.1%) case in spinal anesthesia, zero case in conduction block and 0.74 (50%) case in other methods. Five major combinations of listed critical incidents, causes and anesthetic methods were as follows: 18.93 cases in TIVA, preoperative complications and severe hypotension; 18.75 cases in TIVA, preoperative complications and cardiac arrest; 11.07 cases in TIVA, surgery and severe hypotension; 6.79 cases in TIVA, surgery and cardiac arrest; 5.24 cases in inhalation anesthesia, preoperative complications and severe hypotension. In summary: 1. There was no significant difference with regard to perioperative mortality and morbidity due to anesthetic management among anesthetic methods. 2. The percentage of each anesthetic method in 2000 was not different significantly from that in 1999 in spite of increased cases reported. 3. Incidence of severe hypotension due to all etiology of TIVA in 2000 decreased significantly compared with that in 1999 (P < 0.05). This may be attributed to the decreased incidence in preoperative complication (shock) and massive bleeding due to surgery.

Anesthesia↗
PubMed1990

An evaluation of three intravenous anesthetic regimens in New Zealand rabbits.

Intravenous anesthetics can be readily administered to rabbits through the marginal ear vein. In this study, three intravenous anesthetic protocols were evaluated in New Zealand White rabbits. The three anesthetic regimens were: (a) pentobarbital (40 mg/kg); (b) ketamine-xylazine (25-5 mg/kg); (c) midazolam-xylazine-alfentanil (1-1-0.1 mg/kg). The anesthetics were injected slowly over defined time intervals. Reactions to noxious stimuli were determined before and after administration of the anesthetics. Additionally, the effects of the anesthetic agents on the rabbit's cardiopulmonary system were evaluated. Rabbits anesthetized with midazolam-xylazine-alfentanil did not have a pedal withdrawal or ear pinch reflex throughout the testing period. The ketamine-xylazine combination produced a shorter duration of non-responsiveness to noxious stimuli. Rabbits anesthetized with pentobarbital had the greatest variability in response to noxious stimuli. Apnea occurred in at least one rabbit in each group. A side effect unique to the midazolam-xylazine-alfentanil group was the occurrence of opisthotonus or seizure activity during or shortly after the administration of alfentanil. Hypotension, hypercapnia and respiratory acidosis were characteristic of the cardiopulmonary effects of the anesthetics. When choosing an anesthetic regimen for rabbits, intravenous infusion should be considered as an option. Advantages include ease of administration, possibility of redosing as required, and minimal requirements for equipment. Disadvantages of intravenous anesthetic infusion in rabbits include potential for lethal overdose and metabolic alterations after administration.

Alfentanil↗