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PubMed1995

Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes.

BACKGROUND: Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma-aminobutyric acid A (GABAA) receptor-coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization-evoked release of GABA in the rat striatum were investigated. METHODS: Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with 3H-GABA (20 nM, 5 min, 37 degrees C) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing 3H-GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml.min-1, 37 degrees C) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine. RESULTS: More than 95% of 3H-GABA uptake was blocked by a 10(-3)-M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose-related, reversible, noncompetitive, inhibition of 3H-GABA uptake: IC50 = 4.6 +/- 0.3 x 10(-5) M, 5.8 +/- 0.3 x 10(-5) M, 2.1 +/- 0.4 x 10(-3) M, and 4.9 +/- 0.5 x 10(-4) M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium-dependent, concentration-related, increase from basal 3H-GABA release, +34 +/- 10% (P < 0.01) and +61 +/- 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of 3H-GABA elicited by KCl was not affected by any of the anesthetic agents tested. CONCLUSIONS: These results indicate that most of the intravenous but not the volatile anesthetics inhibit the specific high-affinity 3H-GABA uptake process in vitro in striatal nerve terminals. However, this action was observed at clinically relevant concentrations only for propofol and etomidate. In contrast, the depolarization-evoked 3H-GABA release was not affected by anesthetics. Together, these data suggest that inhibition of GABA uptake, which results in synaptic GABA accumulation, might contribute to propofol and etomidate anesthesia.

Anesthetics↗
PubMed1996

Volatile anesthetics selectively inhibit the Ca(2+)-transporting ATPase in neuronal and erythrocyte plasma membranes.

BACKGROUND: The activity of the plasma membrane Ca(2+)-transporting adenosine triphosphatase (PMCA) is inhibited by volatile anesthetics at clinical concentrations. The goal of the current study was to determine whether the inhibition is selective as compared to other adenosine triphosphatases (ATPases) and another group of general anesthetics, barbiturates. In addition, the authors determined whether the response to anesthetics of the enzymes in neuronal membranes is similar to that in erythrocyte membranes. METHODS: The effects of halothane, isoflurane, and sodium pentobarbital on four different ATPase activities were studied at 37 degrees C in two distinct plasma membrane preparations, human red blood cells and synaptosomal membranes from rat cerebellum. RESULTS: Inhibition patterns of the PMCA by halothane and isoflurane at anesthetic concentrations were vary similar in red blood cells and synaptosomal membranes. The half-maximal inhibition (I50) occurred at 0.25-0.30 mM halothane and 0.30-0.32 mM isoflurane. The PMCA in both membranes was significantly more sensitive to the inhibitory action of volatile anesthetics (I50 = 0.75-1.15 minimum alveolar concentration) than were other ATPases, such as the Na+,K+-ATPase (I50 approximately 3 minimum alveolar concentration) or Mg(2+)-ATPase (I50 > or = 5 minimum alveolar concentration). In contrast, sodium pentobarbital inhibited the PMCA in both membranes only at approximately 100-200-fold above its anesthetic concentrations. The other ATPases were inhibited at similar pentobarbital concentrations (I50 = 11-22 mM). CONCLUSIONS: The findings demonstrate analogous response of the PMCA of neuronal and erythrocyte cells to two groups of general anesthetics. The PMCA activity is selectively inhibited by volatile anesthetics at their clinical concentrations. The enzyme in vivo may then be a pharmacologic target for volatile anesthetics but not for barbiturates.

Anesthetics, Inhalation↗
PubMed2001

Different inhibitory effects of volatile anesthetics on T- and L-type voltage-dependent Ca2+ channels in porcine tracheal and bronchial smooth muscles.

BACKGROUND: The distal airway is more important in the regulation of airflow resistance than is the proximal airway, and volatile anesthetics have a greater inhibitory effect on distal airway muscle tone. The authors investigated the different reactivities of airway smooth muscles to volatile anesthetics by measuring porcine tracheal or bronchial (third to fifth generation) smooth muscle tension and intracellular concentration of free Ca2+ ([Ca2+]i) and by measuring inward Ca2+ currents (ICa) through voltage-dependent Ca2+ channels (VDCs). METHODS: Intracellular concentration of free Ca2+ was monitored by the 500-nm light emission ratio of Ca2+ indicator fura-2. Isometric tension was measured simultaneously. Whole-cell patch clamp recording techniques were used to investigate the effects of volatile anesthetics on ICa in dispersed smooth muscle cells. Isoflurane (0-1.5 minimum alveolar concentration) or sevoflurane (0-1.5 minimum alveolar concentration) was introduced into a bath solution. RESULTS: The volatile anesthetics tested had greater inhibitory effects on carbachol-induced bronchial smooth muscle contraction than on tracheal smooth muscle contraction. These inhibitory effects by the anesthetics on muscle tension were parallel to the inhibitory effects on [Ca2+]i. Although tracheal smooth muscle cells had only L-type VDCs, some bronchial smooth muscle cells (approximately 30%) included T-type VDC. Each of the two anesthetics significantly inhibited the activities of both types of VDCs in a dose-dependent manner; however, the anesthetics had greater inhibitory effects on T-type VDC activity in bronchial smooth muscle. CONCLUSIONS: The existence of the T-type VDC in bronchial smooth muscle and the high sensitivity of this channel to volatile anesthetics seem to be, at least in part, responsible for the different reactivities to the anesthetics in tracheal and bronchial smooth muscles.

Anesthetics, Inhalation↗
PubMed2002

Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways.

BACKGROUND: Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) or sarcolemmal K(ATP) (sarcK(ATP)) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. METHODS: A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker, HMR-1098, a selective sarcK(ATP) channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoK(ATP) channel activity. RESULTS: Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoK(ATP) channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoK(ATP) channel activity, implying a priming effect of volatile anesthetics on mitoK(ATP) channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue-positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcK(ATP) channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine-G(i) signaling pathways. CONCLUSIONS: Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoK(ATP) channels through multiple triggering protein kinase C-coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.

Adenosine Triphosphate↗
PubMed2001

The effects of anesthetics on cortical spreading depression elicitation and c-fos expression in rats.

The effects of anesthetics on the generation of cortical spreading depression (CSD) were investigated. Volatile anesthetics halothane, isoflurane, sevoflurane (0.5, 1.0, and 2.0 MAC), and the intravenous anesthetic pentobarbital were studied. Cortical spreading depression was induced by 3M-KCl applied to a surface of brain cortex for 30 minutes. Direct current (DC) potential was recorded, and the number, amplitude, and duration of CSDs were observed. With increasing concentrations of each volatile anesthetic, there was a dose-related reduction in CSD frequency but not in CSD amplitude. At 2.0 MAC of sevoflurane the suppression of CSD was less than with the other volatile anesthetics. In addition, the influence of anesthetics on expression of c-fos mRNA was investigated. Additional animals anesthetized by isoflurane or sevoflurane were studied. Five CSDs were elicited by electric stimulation (0.5 mV, 1 second) in each animal. In situ hybridization with 35S-labeled oligonucleotides was used to evaluate the level of c-fos mRNA. The expression of c-fos was observed in the hemisphere in which CSD was elicited, but there was no difference in expression of c-fos among the groups. We conclude that volatile anesthetics can induce suppression of CSD elicitation in a dose dependent manner, but that at high concentrations sevoflurane is significantly less effective than other volatile agents. Pentobarbital has the least effect on KCl-induced CSD. These data suggest that the choice of anesthetics can impact the results of studies examining membrane depolarization and the ionic changes initiated by CSD.

Anesthetics↗
PubMed2006

Cardioprotection by volatile anesthetics: new applications for old drugs?

PURPOSE OF REVIEW: Pharmacological interventions may play a prominent role in reducing organ damage in response to physiologic stress. A growing body of evidence indicates that volatile anesthetics exert protective effects against ischemia-reperfusion injury in vivo. Administration of volatile anesthetics before prolonged coronary artery occlusion and reperfusion has been shown to produce cardioprotection, a phenomenon termed anesthetic-induced preconditioning. Endogenous signal transduction proteins, reactive oxygen species, mitochondria, and ion channels have been implicated in anesthetic-induced preconditioning, and new data regarding the triggering and effector roles for these various components have been discovered that advance our understanding of the mechanisms responsible for anesthetic-induced preconditioning. This review will update and integrate these recent data into the current mechanistic model of anesthetic-induced preconditioning. RECENT FINDINGS: Despite a wealth of data from animal studies, the mechanism by which preconditioning with volatile anesthetics alleviates ischemic injury remains incompletely understood. Recent data have identified important interactions between reactive oxygen species and key intracellular signal transduction enzymes and proteins implicated in anesthetic-induced preconditioning. SUMMARY: This review highlights the major recent findings examining mechanisms of volatile anesthetic cardioprotection.

Anesthetics, Inhalation↗
PubMedDate not supplied

Determination of the minimum anesthetic concentration and cardiovascular dose response for sevoflurane in chickens during controlled ventilation.

OBJECTIVE: To determine the minimum anesthetic concentration for sevoflurane and effects of various multiples of minimum anesthetic concentration on arterial pressure and heart rate during controlled ventilation in chickens. STUDY DESIGN: Prospective experimental study. ANIMALS: Seven healthy chickens, 6 to 8 months old, weighing 1.6 to 3.4 kg. METHODS: A rebreathing, semiclosed anesthetic circuit was used. Anesthesia was induced by mask with sevoflurane in oxygen. Each chicken was endotracheally intubated, then controlled ventilation was started and the end-tidal CO2 partial pressure was maintained at 30 to 40 mm Hg. Body temperature was maintained at 39.5 degrees to 41.0 degrees C. The inspired and end-tidal sevoflurane concentration were monitored with a multigas monitor. Minimum anesthetic concentration was determined as the minimal end-tidal sevoflurane concentration which prevented gross purposeful movement in response to clamping a toe for 1 minute. After the determination, the cardiovascular effects of sevoflurane at 1.0, 1.5, and 2.0 times the minimum anesthetic concentration were determined. RESULTS: The minimum anesthetic concentration for sevoflurane was 2.21% + 0.32% (mean +/- SD). Mean arterial pressure and heart rate at minimum anesthetic concentration were 84 +/- 13 mm Hg and 150 +/- 58 beats/min, respectively. There was a dose-dependent decrease in arterial pressure. The heart rate did not change significantly over the range 1 to 2 x minimum anesthetic concentration. No cardiac arrhythmias developed throughout the experiments. CONCLUSIONS AND CLINICAL RELEVANCE: The minimum anesthetic concentration for sevoflurane in chickens was within the range of minimum alveolar concentration reported in mammals. When the concentration of sevoflurane is increased during controlled ventilation in chickens, decrease in arterial pressure should be expected.

Anesthetics, Inhalation↗
PubMed2002

Prenylamine block of Nav1.5 channel is mediated via a receptor distinct from that of local anesthetics.

We have shown previously that prenylamine, a calcium channel blocker, has potent local anesthetic activity in vivo and in vitro. We now characterize the tonic and use-dependent block of prenylamine on wild-type human cardiac voltage-gated sodium channels (hNav1.5) transiently expressed in human embryonic kidney 293t cells under whole-cell voltage-clamp condition. We also determine whether prenylamine and local anesthetics interact with a common binding site on the Nav1.5 channel by analyzing prenylamine block on mutant hNav1.5 channels that have substitution mutations in amino acids at the putative local anesthetic binding sites. Prenylamine exhibits tonic block at both hyperpolarizing and depolarizing potentials on hNav1.5 channels with 50% inhibitory concentrations of 9.67 +/- 0.25 microM and 0.72 +/- 0.02 microM, respectively. Substitutions of the amino acids at the putative local anesthetic binding site (i.e., F1760, N1765, Y1767, and N406) with lysine had much lesser effects on prenylamine block of the mutant hNav1.5 channels compared with local anesthetic block. The affinity of prenylamine was reduced at most by 5.8-fold, whereas that of bupivacaine, a known local anesthetic, was reduced by as much as 68-fold compared with wild-type by the mutations at the local anesthetic receptor site. Furthermore, equilibrium results between prenylamine-bupivacaine mixtures suggest two independent receptors. Thus, the data demonstrate that prenylamine has both tonic and use-dependent block of hNav1.5 channels similar to that of local anesthetics, but the location of the prenylamine binding site on hNav1.5 differs from that of the local anesthetic binding site.

Anesthetics, Local↗
PubMed1999

Ubiquitin metabolism affects cellular response to volatile anesthetics in yeast.

To investigate the mechanism of action of volatile anesthetics, we are studying mutants of the yeast Saccharomyces cerevisiae that have altered sensitivity to isoflurane, a widely used clinical anesthetic. Several lines of evidence from these studies implicate a role for ubiquitin metabolism in cellular response to volatile anesthetics: (i) mutations in the ZZZ1 gene render cells resistant to isoflurane, and the ZZZ1 gene is identical to BUL1 (binds ubiquitin ligase), which appears to be involved in the ubiquitination pathway; (ii) ZZZ4, which we previously found is involved in anesthetic response, is identical to the DOA1/UFD3 gene, which was identified based on altered degradation of ubiquitinated proteins; (iii) analysis of zzz1Delta zzz4Delta double mutants suggests that these genes encode products involved in the same pathway for anesthetic response since the double mutant is no more resistant to anesthetic than either of the single mutant parents; (iv) ubiquitin ligase (MDP1/RSP5) mutants are altered in their response to isoflurane; and (v) mutants with decreased proteasome activity are resistant to isoflurane. The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity. Like zzz4 strains, zzz1 mutants are resistant to all five volatile anesthetics tested, suggesting there are similarities in the mechanisms of action of a variety of volatile anesthetics in yeast and that ubiquitin metabolism affects response to all the agents examined.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Local anesthetics induce human renal cell apoptosis.

Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Local anesthetics induce apoptosis in neuronal and lymphocytic cell lines. We examined the effects of chronic (48 h) local anesthetic treatment (lidocaine, bupivacaine and tetracaine) on human proximal tubular (HK-2) cells. Apoptosis induction was assessed by detecting poly(ADP)-ribose polymerase fragmentation, caspase activation, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, DNA laddering and by cellular morphology. Cell death was quantified by measuring neutral red dye uptake and lactate dehydrogenase released into the cell culture medium. All 3 local anesthetics caused concentration-dependent cell death, induced HK-2 cell apoptosis and potentiated TNF-alpha induced apoptosis. Local anesthetics induced HK-2 cell apoptosis by activation of caspases 3, 6, 7, 8 and 9. ZVAD-fmk, a pan-caspase inhibitor, blocked the local anesthetic induced HK-2 cell apoptosis. Local anesthetics also inhibited the activities of anti-apoptotic kinases protein kinase B (Akt) and extracellular signal regulated mitrogen-activated protein kinase. Local anesthetic's pro-apoptotic effects are independent of sodium channel inhibition as tetrodotoxin, a selective voltage-gated sodium channel blocker, failed to mimic local anesthetic-mediated induction or potentiation of HK-2 cell apoptosis. We conclude that local anesthetics induce human renal cell apoptotic signaling by caspase activation and via inhibition of pro-survival signaling pathways.

Analysis of Variance↗
PubMed1990

Pro- and anticonvulsant effects of anesthetics (Part II)

Perioperative seizures have numerous potential etiologies. In general, when seizures occur during surgery, their onset often coincides with the introduction of a specific anesthetic or analgesic drug. Conversely, postoperative seizures are more commonly due to nonanesthetic causes. However, there have been reports of postoperative convulsions that appeared to be caused by anesthetic or analgesic drugs administered intraoperatively via inhalation or injection (e.g., intravenous, epidural, or peripheral nerve block). Some anesthetics appear to possess both proconvulsant and anticonvulsant properties. One possible factor is an inherent pharmacodynamic variability in the responsiveness of inhibitory and excitatory target tissues in the CNS. This is well illustrated by the anticonvulsant and proconvulsant effects of progressively higher doses of local anesthetic drugs. This variability in neuronal responsiveness could also explain the conflicting findings for low versus high doses of fentanyl and etomidate. Furthermore, biological variation in the individual patient's responsiveness to certain anesthetic drugs could be an additional contributory factor. Differing structure-activity relationships might also explain why some anesthetic agents possess both proconvulsant and anticonvulsant properties. Relatively minor modifications in a drug's structure can influence its affinity for a specific receptor site and its intrinsic pharmacologic activity. For example, when methohexital was first introduced, convulsions were commonly encountered in patients with and without a history of epilepsy. Subsequent fractionation of the original compound into its two isomeric forms resulted in the identification of the isomer primarily responsible for this convulsive activity. In its present formulation (Brevital; Eli Lilly, Indianapolis, Ind.), the epileptogenic properties of methohexital are limited to patients with psychomotor epilepsy. However, compared with thiopental, excitatory effects are still more common with methohexital. The excitatory effects of methohexital are presumably due to its methylated structure. The inhaled anesthetic flurothyl (hexaflurodiethyl) ether and the intravenous anesthetic ketamine also illustrate how subtle changes in stereoisomerism can result in significant changes in structure-activity relationships. Flurothyl, a fluorinated ether analogue, reliably produces convulsions in nonepileptic patients, whereas its structural isomer isoindoklon has not been associated with seizure activity. Other examples of isomer or structural analogue relationships that produce differential effects on neuronal hyperexcitability include enflurane-isoflurane and meperidine-normeperidine. In conclusion, the patient population (epileptic or nonepileptic), the method of documentation (EEG study or clinical observation), and the method of EEG analysis (cortical or depth electrodes) must be considered to properly analyze the proconvulsant and/or anticonvulsant properties of an anesthetic or analgesic drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Anesthesia↗
PubMed2003

Electron paramagnetic resonance assessment of brain tissue oxygen tension in anesthetized rats.

UNLABELLED: The adequacy of cerebral tissue oxygenation (PtO(2)) is a central therapeutic end point in critically ill and anesthetized patients. Clinically, PtO(2) is currently measured indirectly, based on measurements of cerebrovascular oxygenation using near infrared spectroscopy and experimentally, using positron emission tomographic scanning. Recent developments in electron paramagnetic resonance (EPR) oximetry facilitate accurate, sensitive, and repeated measurements of PtO(2). EPR is similar to nuclear magnetic resonance but detects paramagnetic species. Because these species are not abundant in brain (or other tissues) in vivo, oxygen-responsive paramagnetic lithium phthalocyanine crystals implanted into the cerebral cortex are used for the measurement of oxygen. The line widths of the EPR spectra of these materials are linear functions of PtO(2). We used EPR oximetry in anesthetized rats to study the patterns of PtO(2) during exposure to various inhaled and injected general anesthetics and to varying levels of inspired oxygen. Rats anesthetized with 2.0 minimum alveolar anesthetic concentration isoflurane maintained the largest PtO(2) (38.0 +/- 4.5 mm Hg) and rats anesthetized with ketamine/xylazine had the smallest PtO(2) (3.5 +/- 0.3 mm Hg) at a fraction of inspired oxygen (FIO(2)) of 0.21, P < 0.05. The maximal PtO(2) achieved under ketamine/xylazine anesthesia with FIO(2) of 1.0 was 8.8 +/- 0.3 mm Hg, whereas PtO(2) measured during isoflurane anesthesia with FIO(2) of 1.0 was 56.3 +/- 1.7 mm Hg (P < 0.05). These data highlight the experimental utility of EPR in measuring PtO(2) during anesthesia and serve as a foundation for further study of PtO(2) in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia. IMPLICATIONS: Using in vivo electron paramagnetic resonance oximetry, we studied the patterns of cerebral tissue oxygenation (PtO(2)) during exposure to various inhaled and injected general anesthetics, and to varying levels of inspired oxygen. These data show that inhaled anesthetics result in larger levels of PtO(2) in the brain than do several injectable anesthetics. The results highlight the experimental utility of electron paramagnetic resonance in measuring PtO(2) during anesthesia and serve as a foundation for further study of PtO(2) in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia.

Anesthesia↗
PubMed2003

Local anesthetics differentially inhibit sympathetic neuron-mediated and C fiber-mediated synovial neurogenic plasma extravasation.

UNLABELLED: Local anesthetics are used for local irrigation after many types of operations. However, recent evidence of toxic effects of local anesthetics at large concentrations during continuous administration suggests an advantage of using decreased local anesthetic concentrations for irrigation solutions. In this study, we determined whether smaller concentrations of local anesthetics may maintain an antiinflammatory and, therefore, analgesic effect without the risk of possible toxicity. Lidocaine and bupivacaine were studied for their ability to inhibit both components of neurogenic inflammation-C fiber-mediated and sympathetic postganglionic neuron (SPGN)-mediated inflammation-in the rat knee joint. Intraarticular lidocaine 0.02% reduced 5-hydroxytryptamine (5-HT)-induced (SPGN-mediated) plasma extravasation (PE) by 35%, and further decreases were obtained by perfusing larger concentrations of lidocaine. Intraarticular bupivacaine 0.025% inhibited 5-HT-induced PE by 60%, and a 95% inhibition was obtained with bupivacaine 0.05%. Larger local anesthetic concentrations were necessary to inhibit C fiber-mediated PE than those required to inhibit SPGN-mediated PE. Lidocaine 0.4% was required to reduce mustard oil-induced PE by 60%. Lidocaine 2% inhibited mustard oil-induced PE to baseline levels. Bupivacaine 0.1% was required for an 80% reduction of PE. Bupivacaine 0.25% inhibited mustard oil-induced PE to baseline levels. Our results demonstrate differential effects of local anesthetics on SPGN- and C fiber-mediated PE but confirm the concept of using smaller concentrations of local anesthetics to achieve inhibition of postoperative inflammation. IMPLICATIONS: Local anesthetic wound irrigation is often used to treat postoperative surgical pain. Large concentrations of local anesthetics are usually used, and these concentrations may have possible neurotoxic and myotoxic effects. Our results demonstrate antiinflammatory effects of lidocaine and bupivacaine at concentrations smaller than used clinically.

Anesthetics, Local↗
PubMed2004

A specific alteration in the electroretinogram of Drosophila melanogaster is induced by halothane and other volatile general anesthetics.

UNLABELLED: In higher organisms, physiological investigations have provided a valuable complement to assays of anesthetic effects on whole-animal behavior. However, although complex motor programs of Drosophila melanogaster have been used to identify genes that influence anesthesia, electrophysiological studies of anesthetic effects in this invertebrate have been limited. Here we show that the electroretinogram (ERG), the extracellular recording of light-evoked mass potentials from the surface of the eye, reveals a distinct effect of halothane, enflurane, isoflurane, and desflurane. Behaviorally relevant concentrations of these volatile anesthetics severely reduced the transient component of the ERG at lights-off. Other prominent ERG components, such as the photoreceptor potential and the lights-on transient, were not consistently affected by these drugs. Surprisingly, for most anesthetics, a diminished off-transient was obtained only with short light pulses. An identical effect was observed in the absence of anesthetic by depressing the function of Shaker potassium channels. The possibility that halothane acts in the visual circuit by closing potassium channels was examined with a simple genetic test; the results were consistent with the hypothesis but fell short of providing definitive support. Nevertheless, our studies establish the ERG as a useful tool both for examining the influence of volatile anesthetics on a simple circuit and for identifying genes that contribute to anesthetic sensitivity. IMPLICATIONS: Electroretinography (ERG) provides a useful monitor of anesthetic effects on the fruit fly. The effects of volatile anesthetics on the ERG are recapitulated by inactivation of potassium channels.

Anesthetics, Inhalation↗
PubMed2005

HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents.

General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA(A) receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (Ih) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal Ih and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of Ih involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V(1/2) and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics.

Anesthetics↗
PubMedDate not supplied

Allergy to local anesthetics in dentistry. Myth or reality?

BACKGROUND: Local anesthetics are drugs frequently used in dentistry. Although they are usually well-tolerated drugs, sometimes, they can cause adverse reactions of different kinds and severity. True incidence of local anesthetics' allergic reactions is unknown. OBJECTIVES: To evaluate the incidence of immediate adverse events in subjects who required local anesthetic injection to receive dental treatment; to assess the incidence of anaphylactic allergic reactions among those recorded as adverse events; to analyze the relationship between these patients' atopic antecedents and documented allergic reactions. MATERIAL AND METHODS: A prospective, open-label, non-comparative study including a total of 5,018 subjects who received local anesthetics during dental treatment, despite their age, was carried on in 7 either private or public odontological assistance centers. All the reactions that could appear during the first hour following the anesthetic act were assessed. RESULTS: Twenty-five adverse reactions were diagnosed, representing 0.5% of the studied population. None of them was due to an allergic cause. Most of them (22/25) were mild, quickly reversible, psychogenic or vasovagal reactions. One of the cases was related to defects of the anesthetic technique. The remaining two cases, which were initially considered as possibly due to an allergic cause, were discarded after being studied with skin and dose provocative challenge tests with the anesthetic. CONCLUSION: The allergic reactions to the local anesthetics are very rare and most of the adverse reactions are psychogenic/vasovagal. These facts should be known by the physician and by the dentist in order to minimize the frequent fears and "myths" about the use of local anesthetics at the dentist office.

Adolescent↗
PubMed2005

Tribromoethanol-medetomidine combination provides a safe and reversible anesthetic effect in Sprague-Dawley rats.

Tribromoethanol typically is used alone as a general anesthetic agent for rodent surgeries. In the present study, the alpha2-adrenergic agonists xylazine and medetomidine were combined with tribromoethanol to examine their use as alternate and safe anesthetic regimes in rats. We also tested the effect of atipamezole, an alpha2-adrenergic antagonist, in reversing the anesthetic effect of the tribromoethanol-medetomidine combination. Male Sprague-Dawley rats were used to evaluate the effects of tribromoethanol (400 mg/kg intraperitoneally [i.p.]) or tribromoethanol (150 mg/kg) and medetomidine (0.5 mg/kg i.p.). Tribromoethanol (400 mg/kg)-treated rats were anesthetized for an average of 10 min, whereas rats that received tribromoethanol (150 mg/kg) and medetomidine (0.5 mg/kg) remained anesthetized for an average of 55 min. Recovery time was approximately 6 min for the tribromoethanol (400 mg/kg) group compared with 21 min for the animals that received tribromoethanol and medetomidine. In a second study, three groups of rats were given tribromoethanol (150 mg/kg) and medetomidine (0.5 mg/kg). Group 1 received atipamezole (an alpha2-antagonist; 2.5 mg/kg i.p.) 10 min after anesthetic induction, and group 2 received the same dosage at 20 min post-induction. Group 3 was allowed to recover without atipamezole treatment. The anesthetic effects in animals from groups 1 and 2 were reversed after administration of atipamezole, whereas group 3 remained anesthetized. This study demonstrates the safe and effective use of tribromoethanol-medetomidine as an anesthetic in the rat.

Adrenergic alpha-Antagonists↗
PubMed2005

[Effects of volatile anesthetics on cortical somatosensory evoked potential and Bispectral index].

OBJECTIVE: To improve the anesthetic environment in monitoring short-latency somatosensory evoked potentials (SSEP) during operation, we compared the effects of different anesthetics on SSEP and Bispectral index (BIS), which aim to select suitable anesthetics and their doses used intraoperatively. METHODS: 60 ASA I-II patients undergoing elective neurosurgery were randomly allocated into three groups: enflurane, isoflurane and desflurane group. The concentration of each volatile anesthetic was increased step by step from 0 to end-tidal 0.3, 0.5, 0.75, 1.0 and 1.5 MAC. The changes of cortical SSEP component N20 were recorded as well as Bispectral index (BIS) monitoring. The effects of three volatile anesthetics in various concentrations on short-latency SSEP and BIS were investigated. RESULTS: All three volatile anesthetics significantly decreased N20 amplitude and prolonged N20 latency. The N20 waveform disappeared in some patients when the end-tidal concentration of enflurane reached 1.0 MAC, it occurred when that of isoflurane or desflurane was at 1.5 MAC. BIS monitoring showed BIS values were all under 60 when at 1.0 MAC in three group. For some patients in enflurane group and desflurane group, BIS values were above 60 (45-64, 44-61, respectively) when at 0.75 MAC, while those in isoflurane group were still less than 60 (39-58). And the amplitude or latency of cortical SSEP correlated poorly with BIS. CONCLUSION: The effects of three volatile anesthetics on SSEP and BIS are significant in dose-dependent manner. Anesthetic regimen of 0.75 MAC isoflurane for intraoperative cortical SSEP monitoring may be optimal. It seemed that the correlation between BIS and short-latency SSEP was poor, although both are associated with the effects of anesthetics on cerebral cortex.

Adult↗