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PubMed1993

Anesthetic potency and cardiopulmonary effects of enflurane, halothane, and isoflurane in goats.

Anesthetic requirements, as defined by the minimum alveolar anesthetic concentration (MAC) that prevents gross, purposeful movement in 50% of animals, have not been determined in goats. Therefore, we determined anesthetic potency of enflurane (N = 6), halothane (N = 8), and isoflurane (N = 7) in goats by using the tail clamp and dew-claw clamp as the noxious stimuli and then measured the cardiovascular and respiratory effects of these agents. The MAC was 2.0 +/- 0.4%, 1.3 +/- 0.1%, and 1.5 +/- 0.3% (mean +/- SD) for enflurane, halothane, and isoflurane, respectively. At 1 MAC, when ventilation was changed from controlled to spontaneous, blood pressure decreased in goats anesthetized with isoflurane (98 +/- 17 to 78 +/- 13 mm Hg) and halothane (95 +/- 10 to 83 +/- 14 mm Hg) but did not significantly change in goats anesthetized with enflurane; heart rate increased in goats anesthetized with halothane (117 +/- 12 to 127 +/- 10 beats/min) but was not significantly different in goats anesthetized with enflurane or isoflurane; and cardiac output increased in goats anesthetized with enflurane (5.70 +/- 1.23 to 7.05 +/- 2.02 liters/min) and halothane (6.14 +/- 0.94 to 7.91 +/- 2.45 liters/min) but not with isoflurane. During spontaneous breathing, respiratory depression was manifested by apnea in two animals and an elevated PaCO2: 57 +/- 15 mm Hg, 55 +/- 13 mm Hg, and 59 +/- 14 mm Hg, respectively, for enflurane, halothane, and isoflurane. Minute ventilation during spontaneous breathing was approximately 50% of controlled ventilation for each anesthetic agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1994

Effects of various anesthetic regimens on tissue antioxidant enzyme activities.

It has been suggested that oxidative processes are involved in a variety of pathological conditions, notably ischemia-reperfusion injury. Moreover, anesthetics appear to exert differential effects on the severity of such injury, these being unlikely wholly attributable to their differential effects on cardiovascular or microcirculatory status. It is possible that these variable effects of anesthetics on this type of injury may be due, at least in part, to changes in the production of free radicals and/or in their detoxification by endogenous antioxidant enzymes. We have attempted to explore the latter possibility by measuring activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase in normal heart tissue and red cells obtained from rats anesthetized using a variety of agents (CO2, halothane, pentobarbital or ether). For comparison, analyses were also performed on tissues from unanesthetized animals rendered unconscious by stunning prior to sacrifice. Results indicated that myocardial SOD activity was significantly greater in halothane-anesthetized as compared with CO2-anesthetized animals. Red cell SOD activities did not show such differences. However, red cell GPX activity was found to be greater in halothane-anesthetized than in pentobarbital-anesthetized rats. In general, however, antioxidant enzyme activities measured ex vivo were minimally affected by the use of anesthetics prior to euthanasia. Our findings, therefore, do not support the proposal that the influence of anesthetics on the course of ischemia-reperfusion injury involves effects at the level of enzymatic antioxidant components.

Animals↗
PubMed2006

Brain protection by anesthetic agents.

PURPOSE OF REVIEW: Patients at risk for perioperative stroke, or those who have suffered recent cerebral injury, may benefit from neuroprotective properties of anesthetic agents during surgery. This manuscript reviews recent clinical and experimental evidence for neuroprotective effects of common anesthetic agents, and presents potential mechanisms involved in anesthetic neuroprotection. RECENT FINDINGS: Although strong experimental data support a neuroprotective potential of several anesthetic agents, specifically isoflurane and xenon, consistent long-term protection by either agent has not been demonstrated. Unfortunately, there is a lack of clinical studies that would support the use of any one anesthetic agent over the others. Mechanisms of neuroprotection by anesthetic agents appear to involve suppression of excitatory neurotransmission, and potentiation of inhibitory activity, which may contribute to the reduction of excitotoxic injury. Activation of intracellular signaling cascades that lead to altered expression of protective genes may also be involved. SUMMARY: Solid experimental evidence supports neuroprotection by anesthetic agents. It is too early to recommend any specific agent for clinical use as a neuroprotectant, however. Further study is warranted to unravel relevant mechanisms and to appreciate the potential clinical relevance of experimental findings.

Anesthetics↗
PubMed2002

General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.

General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene-targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABA(A) receptor. In these mice, the suppression of noxious-evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. beta3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA(A) receptor-mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA(A) receptor beta3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.

Anesthetics, Inhalation↗
PubMed1999

Mouse strain modestly influences minimum alveolar anesthetic concentration and convulsivity of inhaled compounds.

UNLABELLED: In this study, we measured the minimum alveolar anesthetic concentration (MAC) in several mouse strains, including strains used in the construction of genetically engineered mice. This is important because defined genetic modifications are used increasingly to test mechanisms of inhaled anesthetic action, and background variability in MAC can potentially influence the interpretation of these studies. We investigated the effect of strain on MAC for desflurane, isoflurane, halothane, ethanol, the experimental anesthetic 1-chloro-1,2,2-trifluorocyclobutane, and convulsive 50% effective dose (the dose required to produce convulsions in 50% of animals) of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane. These drugs were studied in eight inbred strains, including both laboratory and wild mouse strains (129/J, 129/SvJ, 129/Ola Hsd, C57BL/6NHsd, C57BL/6J, DBA/2J, Spret/Ei, and Cast/Ei), one hybrid strain (B6129F2/J, derived from the C57BL/6J and 129/J strains), and one outbred strain (CD-1). To test our ability to detect effects in a genetically modified mouse, we compared these data with those for a mouse lacking the gamma (neuronal) isoform of the protein kinase C gene (PKCgamma). We also assessed whether amputating the tail tip of mice (a standard method of obtaining tissue for genetic analysis) increased MAC (e.g., by sensitization of the spinal cord). MAC and convulsant 50% effective dose values differed modestly among strains, with a range of 17% to 39% from the lowest to highest values for MAC using conventional anesthetics, and up to 48% using the experimental anesthetic 1-chloro-1,2,2-trifluorocyclobutane. Convulsivity to the nonimmobilizer varied by 47%. Amputating the tail tip did not affect MAC. PKCgamma knockout mice had significantly higher MAC values than control animals for isoflurane, but not for halothane or desflurane, which implies that protein phosphorylation by PKCgamma can alter sensitivity to isoflurane. IMPLICATIONS: Anesthetic potency differs by modest amounts among inbred, outbred, wild, and laboratory mouse strains. Absence of the neural form of protein kinase C increases minimum alveolar anesthetic concentration for isoflurane, indicating that protein phosphorylation by the gamma-isoform of protein kinase C (PKCgamma) can influence the potency of this anesthetic.

Anesthesia, Inhalation↗
PubMed2001

Anesthetic effects on mitochondrial ATP-sensitive K channel.

BACKGROUND: Volatile anesthetics show an ischemic preconditioning-like cardioprotective effect, whereas intravenous anesthetics have cardioprotective effects for ischemic-reperfusion injury. Although recent evidence suggests that mitochondrial adenosine triphosphate-regulated potassium (mitoK(ATP)) channels are important in cardiac preconditioning, the effect of anesthetics on mitoK(ATP) is unexplored. Therefore, the authors tested the hypothesis that anesthetics act on the mitoK(ATP) channel and mitochondrial flavoprotein oxidation. METHODS: Myocardial cells were isolated from adult guinea pigs. Endogenous mitochondrial flavoprotein fluorescence, an indicator of mitochondrial flavoprotein oxidation, was monitored with fluorescence microscopy while myocytes were exposed individually for 15 min to isoflurane, sevoflurane, propofol, and pentobarbital. The authors further investigated the effect of 5-hydroxydeanoate, a specific mitoK(ATP) channel antagonist, on isoflurane- and sevoflurane-induced flavoprotein oxidation. Additionally, the effects of propofol and pentobarbital on isoflurane-induced flavoprotein oxidation were measured. RESULTS: Isoflurane and sevoflurane induced dose-dependent increases in flavoprotein oxidation (isoflurane: R2 = 0.71, n = 50; sevoflurane: R2 = 0.86, n = 20). The fluorescence increase produced by both isoflurane and sevoflurane was eliminated by 5-hydroxydeanoate. Although propofol and pentobarbital showed no significant effects on flavoprotein oxidation, they both dose-dependently inhibited isoflurane-induced flavoprotein oxidation. CONCLUSIONS: Inhalational anesthetics induce flavoprotein oxidation through opening of the mitoK(ATP) channel. This may be an important mechanism contributing to anesthetic-induced preconditioning. Cardioprotective effects of intravenous anesthetics may not be dependent on flavoprotein oxidation, but the administration of propofol or pentobarbital may potentially inhibit the cardioprotective effect of inhalational anesthetics.

ATP-Binding Cassette Transporters↗
PubMed2005

Long-term exposure to local but not inhalation anesthetics affects neurite regeneration and synapse formation between identified lymnaea neurons.

BACKGROUND: General and local anesthetics are used in various combinations during surgical procedures to repair damaged tissues and organs, which in almost all instances involve nervous system functions. Because synaptic transmission recovers rapidly from various inhalation anesthetics, it is generally assumed that their effects on nerve regeneration and synapse formation that precede injury or surgery may not be as detrimental as that of their local counterparts. However, a direct comparison of most commonly used inhalation (sevoflurane, isoflurane) and local anesthetics (lidocaine, bupivacaine), vis-a-vis their effects on synapse transmission, neurite regeneration, and synapse formation has not yet been performed. METHODS: In this study, using cell culture, electrophysiologic and imaging techniques on unequivocally identified presynaptic and postsynaptic neurons from the mollusc Lymnaea, the authors provided a comparative account of the effects of both general and local anesthetics on synaptic transmission, nerve regeneration, and synapse formation between cultured neurons. RESULTS: The data show that clinically used concentrations of both inhalation and local anesthetics affect synaptic transmission in a concentration-dependent and reversal manner. The authors provided the first direct evidence that long-term overnight treatment of cultured neurons with sevoflurane and isoflurane does not affect neurite regeneration, whereas both lidocaine and bupivacaine suppress neurite outgrowth completely. The soma-soma synapse model was then used to compare the effects of both types of agents on synapse formation. The authors found that local but not inhalation anesthetics drastically reduced the incidence of synapse formation. The local anesthetic-induced prevention of synapse formation most likely involved the failure of presynaptic machinery, which otherwise developed normally in the presence of both sevoflurane and isoflurane. CONCLUSION: This study thus provides the first comparative, albeit preclinical, account of the effects of both general and local anesthetics on synaptic transmission, nerve regeneration, and synapse formation and demonstrates that clinically used lidocaine and bupivacaine have drastic long-term effects on neurite regeneration and synapse formation as compared with sevoflurane and isoflurane.

Action Potentials↗
PubMed1987

Anesthetic agents in trauma surgery: are there differences?

Overall, no ideal induction or maintenance technique is available for the traumatized, hypovolemic patient. As a result of the multiple insults that produce hypovolemia and the heterogeneous population of patients sustaining trauma, it is unlikely that a controlled human study of this anesthetic dilemma will ever be performed. One must balance the potential incidence of recall of operation or unacceptable sympathectomy-induced vasodilation against the anesthetic techniques available. Bogetz and Katz addressed the recall issue by documenting how many patients sustaining major trauma and requiring operation were really anesthetized. They stressed that many of the patients evaluated were too hemodynamically unstable to tolerate the usual dose of anesthetics administered during elective operations. They postulated that hypotension, hypothermia, and acute alcohol intoxication found in many trauma patients should make recall infrequent. Two groups of patients were analyzed for incidence of recall. The groups were separated based on the continuity of anesthetic administered. In 37 patients given ketamine for induction and low-dose inhalational agent for maintenance, with no gaps in anesthetic administration of over 20 minutes, 4 of 37 (11%) patients had recall. Recall was reported by 6 of 14 (43%) patients in whom it was considered clinically unwise to administer an anesthetic for intubation or whose anesthetic needed to be interrupted for more than 20 minutes secondary to hemodynamic instability. If these figures are representative of the worldwide incidence of recall in our traumatized patients, we may need to redefine the role of anesthesia in trauma. We may need to consider ourselves, not inappropriately, resuscitologists rather than anesthesiologists.

Anesthetics↗
PubMed2003

Anesthetic treatment blocks synaptogenesis but not neuronal regeneration of cultured Lymnaea neurons.

Trauma and injury necessitate the use of various surgical interventions, yet such procedures themselves are invasive and often interrupt synaptic communications in the nervous system. Because anesthesia is required during surgery, it is important to determine whether long-term exposure of injured nervous tissue to anesthetics is detrimental to regeneration of neuronal processes and synaptic connections. In this study, using identified molluscan neurons, we provide direct evidence that the anesthetic propofol blocks cholinergic synaptic transmission between soma-soma paired Lymnaea neurons in a dose-dependent and reversible manner. These effects do not involve presynaptic secretory machinery, but rather postsynaptic acetylcholine receptors were affected by the anesthetic. Moreover, we discovered that long-term (18-24 h) anesthetic treatment of soma-soma paired neurons blocked synaptogenesis between these cells. However, after several hours of anesthetic washout, synapses developed between the neurons in a manner similar to that seen in vivo. Long-term anesthetic treatment of the identified neurons visceral dorsal 4 (VD4) and left pedal dorsal 1 (LPeD1) and the electrically coupled Pedal A cluster neurons (PeA) did not affect nerve regeneration in cell culture as the neurons continued to exhibit extensive neurite outgrowth. However, these sprouted neurons failed to develop chemical (VD4 and LPeD1) and electrical (PeA) synapses as observed in their control counterparts. After drug washout, appropriate synapses did reform between the cells, although this synaptogenesis required several days. Taken together, this study provides the first direct evidence that the clinically used anesthetic propofol does not affect nerve regeneration. However, the formation of both chemical and electrical synapses is severely compromised in the presence of this drug. This study emphasizes the importance of short-term anesthetic treatment, which may be critical for the restoration of synaptic connections between injured neurons.

Anesthetics↗
PubMed2006

Influence of different anesthetics on skin oxygenation studied by electron paramagnetic resonance in vivo.

The effects of two general anesthetics on skin oxygenation in mice are evaluated by electron paramagnetic resonance oximetry. Up to now no data on the effects of different anesthetics on skin oxygenation could be found. In this study animals were anesthetized with ketamine/xylazine or isoflurane, and partial pressure of oxygen (pO(2)) in the skin, heart rate and hemoglobin oxygen saturation were followed as a function of time and inhaled oxygen concentration. The skin pO(2) significantly increased continuously for about 60 min in mice anesthetized with isoflurane and remained constant after that. During ketamine/xylazine anesthesia, the pO(2) in the skin only slightly decreased. The skin pO(2) increased with higher inspired oxygen concentrations for both anesthetics groups. When breathing 21% oxygen, mice anesthetized with isoflurane had two-fold higher pO(2) in the skin compared to mice anesthetized with ketamine/xylazine. The heart rate was significantly lower in animals anesthetized with ketamine/xylazine, while hemoglobin saturation was almost the same in both groups at all inhaled oxygen concentrations. These results show that the type of anesthesia is an important parameter that needs to be considered in experiments where skin pO(2) is followed.

Anesthetics, Combined↗
PubMed2003

The effects of local and intravenous anesthetics on recombinant rat VR1 vanilloid receptors.

UNLABELLED: Capsaicin, acting at the vanilloid 1 receptor (VR1), may potentiate local anesthetic activity, and as a ligand-gated ion channel of the transient receptor potential family, may also be a target for IV general anesthetics. We have examined whether local (lidocaine, prilocaine, and procaine 0.1-10 mM; 10 mM represents 0.25%-0.27% wt/vol) or IV anesthetics (propofol 10 micro M, thiopental 100 micro M, and ketamine 100 micro M) interact with recombinant rat VR1 expressed in human embryonic kidney (HEK293) cells (VR1-HEK293). We have assessed receptor interaction functionally by monitoring intracellular Ca(2+) ([Ca(2+)](i)) in Fura2-loaded cells at 37 degrees C. The addition of capsaicin (60 nM) produced a time-dependent biphasic increase in [Ca(2+)](i) amounting to 50-100 nM above than basal, which was inhibited by capsazepine 10 micro M and was absent in wild type HEK293 cells. Lidocaine and prilocaine alone (e.g., at 10 mM) significantly increased [Ca(2+)](i) by 67 +/- 6 nM and 33 +/- 7 nM, respectively, and concentration-dependently inhibited the capsaicin response. The effects of procaine were obscured by anesthetic-induced quenching of Fura2. In wild type HEK293 cells, lidocaine (10 mM) alone produced a small increase in [Ca(2+)](i). All IV anesthetics failed to modify capsaicin-increased [Ca(2+)](i). In conclusion, the present data suggest that local but not IV general anesthetics interact with recombinant rat VR1 receptors with the former anesthetics having antagonistic activity. IMPLICATIONS: Vanilloid receptors (VR1) are activated by capsaicin, the pain-producing component of hot chili peppers. We suggest that local (but not IV general) anesthetics may have inhibitory actions on this receptor.

Anesthetics, Intravenous↗
PubMed2002

Evaluation of the bispectral index as an indicator of degree of central nervous system depression in isoflurane-anesthetized horses.

OBJECTIVE: To determine whether the bispectral index (BIS) can be used as an indicator of degree of CNS depression in isoflurane-anesthetized horses. ANIMALS: 10 Standardbred and 6 Norwegian cold-blooded trotter stallions admitted for routine castration. PROCEDURE: A 2-channel referential electrode configuration was used to record EEG for calculation of BIS by the EEG monitor. The BIS was calculated before (awake) and after (sedated) administration of detomidine (0.01 mg/kg of body weight, IV) and butorphanol (0.01 mg/kg, IV). Anesthesia was induced with ketamine hydrochloride (2.5 mg/kg, IV) and diazepam (0.04 mg/kg, IV) and maintained with isoflurane delivered in oxygen. The BIS was calculated after 30 minutes of equilibration at an end-tidal isoflurane concentration of 1.4% (n = 8) or 1.9% (8) and recorded continuously during surgery. RESULTS: Bispectral index was significantly less in sedated and anesthetized horses, compared with awake horses. However, BIS was not significantly different between sedated and anesthetized horses. Mean BIS in horses anesthetized at 1.9% isoflurane was significantly greater, compared with horses anesthetized at an end-tidal concentration of 1.4%. Four horses in the 1.4% group moved during surgery, and BIS increased immediately prior to movement in 2 of these horses. CONCLUSIONS AND CLINICAL RELEVANCE: BIS is not a precise indicator of degree of CNS depression in isoflurane-anesthetized horses. Thus, determination of BIS may not be a useful technique for monitoring anesthetic depth in isoflurane-anesthetized horses.

Analgesics↗
PubMed2004

[Effects of intravenous and inhalational anesthetics on short-latency somatosensory evoked potentials].

OBJECTIVE: To choose suitable general anesthetics dosages when short-latency somatosensory evoked potentials (SLSEP) is monitored during operation. METHODS: 150 ASA I-II neurosurgical patients undergoing elective operations were randomly divided into intravenous anesthesia group of 90 patients and inhalation anesthesia group of 60 patients. The intravenous anesthesia group was further divided into 9 subgroups of 10 patients treated with different anesthetics of different dosages: propofol (1.5 mg/kg, 2 mg/kg, and 3 mg/kg), midazolam (0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg), and etomidate (0.15 mg/kg, 0.3 mg/kg, and 0.4 mg/kg). The intravenous anesthetics were given and upper limb SLSEP was monitored continuously. The inhalation anesthesia group was further divided into enflurane, isoflurane and desflurane subgroups of 20 patients each. The inhalational anesthetics were given at the concentrations corresponding to the end-expiratory concentrations of 0 to 0.3, 0.5, 0.75, 1.0 and 1.5 MAC. The changes of N(14), N(20) and central conduction time (CCT) were recorded. In addition to SLSEP, EKG, NIBP, SpO(2), P(ET) CO(2) were monitored as well as end-tidal anesthetic concentration. During the experiment SpO(2) was maintained > 95% and P(ET) CO(2) was maintained at the range of 35 - 45 mmHg by mask oxygen or assisted ventilation. RESULTS: The intravenous anesthetic propofol significantly decreased N(20) amplitude and produced less effect on the latency of N(14), N(20) and CCT. Midazolam significantly decreased the N(20) amplitude and prolonged the latency of N(20) and CCT. Etomidate significantly increased the N(20) amplitude, and the change did not recover when the patients had opened their eyes 10 minutes after medication. All three inhalational anesthetics significantly decreased the N(20) amplitude and prolonged the N(20) latency and CCT. N(20) amplitude disappeared in some patients treated with enflurane when the end-expiratory concentration was 1.0 MAC, while disappeared in some patients treated with isoflurane and desflurane when the end-expiratory concentration was 1.5 MAC for these 2 drugs. CONCLUSION: When using SLSEP monitoring, the most suitable general anesthetic is etomidate during the induction stage and isoflurane and desflurane during the maintenance stage with the end-expiratory concentration below 1.0 MAC.

Adolescent↗
PubMed1977

Interaction of general anesthetics with phospholipid vesicles and biological membranes.

Low concentrations of general anesthetics, including halothane, ethrane, trilene, diethyl ether and chloroform are observed to shift the phase transitions of phospholipid vesicles to lower temperatures, and from these data partition coefficients for the anesthetic between lipid and water can be calculated. In contrast to the anesthetics, high concentrations of ethanol are required to shift the phase transition of lipids and glycerol causes no effect. Above the phase transition general anesthetics alter nuclear magnetic resonance spectra of phospholipid dispersions and increase the rotational and lateral diffusion rates of fluorescent probes located in the hydrocarbon core of the bilayer, indicating that they induce disorder in the structure. In red blood cell membranes and sarcoplasmic reticulum fragments, the rotational diffusion rate of 1-phenyl-6-phenylhexatriene is increased in the presence of general anesthetics. The 220 MHz nuclear magnetic resonance spectra of sarcoplasmic reticulum reveal some resolved lines from the lecithin fatty acid protons; addition of general anesthetic increases the contribution of these peaks. The data from the NMR and fluorescence techniques lead to the conclusion that general anesthetics increase the pool size of melted lipids in the bimolecular phospholipid layers of biological membranes; this would account for the ability of general anesthetics to increase passive diffusion rates of various substances in membranes.

Anesthetics↗
PubMed1985

Effect of positively charged local anesthetics on a membrane-bound phosphatase in Acholeplasma laidlawii.

The plasma membrane p-nitrophenylphosphatase activity of Acholeplasma laidlawii was stimulated by the spin-labeled local anesthetic 2-[N-methyl-N-(2,2,6,6-tetramethylpiperidinooxyl)]ethyl p-hexyloxybenzoate, abbreviated as C6SL, and its methylated quaternary analog, C6SLMeI. The tertiary amine C6SL (at a concentration of 5 X 10(-5) M) was more potent at pH 6.5 than at pH 7.7. In contrast, the permanently-charged C6SLMeI was equally potent, independently of pH. These results suggest that cationic forms of the anesthetics are responsible for stimulating the enzyme. Electron spin resonance studies of C6SL- and C6SLMeI-labeled membranes showed that these anesthetics in their cationic forms interacted electrostatically with components of the Acholeplasma membrane. For C6SL, this interaction was pH dependent and correlated with the pH dependency of the anesthetic-induced enzyme stimulation in the Acholeplasma membranes. Further, studies using 5-doxylstearic acid labels and non-spin-labeled anesthetics at various pH values showed that the membrane-fluidizing effect of anesthetics was not correlated with anesthetic-induced pNPPase stimulation. Our observations are consistent with the hypothesis that electrostatic interactions between cationic local anesthetics and anionic membrane components may lead to functional changes mediated by membrane proteins.

Acholeplasma laidlawii↗
PubMed1995

In vitro and in vivo effects of cocaine and selected local anesthetics on the dopamine transporter.

The effects of selected local anesthetics on in vitro and in vivo measurements of dopamine transporter activity were determined to investigate the role of local anesthetic activity in the neuronal actions of cocaine. Cocaine inhibited [3H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1.5-naphthalenedisulfonate (CFT) binding and [3H]dopamine uptake with estimated Ki and IC50 values of 0.6 microM and 0.7 micorM, respectively. Of the local anesthetics tested, only dimethocaine showed full displacement of CFT binding (0-30 microM tested) and full inhibition of dopamine uptake (0-100 microM tested). Dimethocaine was only slightly less potent than cocaine with an estimated Ki of 1.4 micorM and an IC50 value of 1.2 microM for [3H]CFT binding and dopamine uptake. At a maximum concentration of 100 microM, the ester containing local anesthetics procaine, tetracaine, piperocaine and the amide containing local anesthetic dibucaine and bupivacaine partially inhibited dopamine uptake by 47-70%. The ester containing local anesthetic propoxycaine and the amide containing local anesthetics prilocaine, etidocaine, procainamide, and lidocaine inhibited dopamine uptake by 8-30% at 100 microM. A 10 min administration of cocaine, dimethocaine, or procaine in the dialysis solution produced dose-dependent, reversible increases in endogenous dopamine efflux from the striata of awake rats. Cocaine and dimethocaine produced similar 12-fold increases in dialysate dopamine at concentrations of 0.1 mM and 1 mM respectively. Procaine (10 mM) produced a 6-fold increase in dialysate dopamine while lidocaine (1 mM) produced a reproducible and reversible decrease (30%). These results show that the cocaine-like actions of certain local anesthetics such as dimethocaine and procaine result from their direct actions of dopamine uptake inhibitors.

Aminobenzoates↗
PubMedDate not supplied

Effect of local anesthetics on cellular respiration and thymidine transport in hepatocytes from young and old rats.

The effect of local anesthetics (procaine, nicotinoyl-procaine, tetracaine, and dibucaine) on thymidine uptake and cellular respiration was investigated in hepatocytes from 3- and 24-month-old rats. All local anesthetics inhibited the "high-affinity" as well as the "low-affinity" thymidine transport system in a non-competitive manner immediately upon addition. Nicotinoyl-procaine, tetracaine, and dibucaine showed a similar inhibition profile with an inhibition of 10--15% at 50 mumol/l, or of more than 60% at 1 mmol/l. The less-lipophilic procaine showed a distinctly lower inhibition (10% at 1 mmol/l). The inhibitory effect was reversible and not dependent on Ca2+. All local anesthetics exerted identical effects in hepatocytes from young and old rats. Nicotinoyl-procaine and tetracaine inhibited cellular respiration in young and old rats up to a maximum of 50%. Procaine did not reduce O2 consumption below 1 mmol/l. This inhibition appeared also immediately upon addition, was not reversible, and not dependent on Ca2+. It is concluded that local anesthetics impair quite different biological processes like thymidine transport and cellular respiration in hepatocytes from young and old animals even at concentrations below 100 mumol/l. The magnitude of inhibition was correlated to the lipid solubility of the local anesthetics. The mechanism seemed to be different to the anesthetic action and it is supposed that it is a direct hydrophobic interaction with membrane proteins. Thus the local anesthetic-induced increase in membrane fluidity could not improve the age-dependent impairment of thymidine transport. The reduction of respiration is considered to be due to reduced O2 diffusion. This inhibition is in striking contrast to previously observed stimulatory effects which in part lead to the use of local anesthetics in geriatrics.

Aging↗
PubMed2006

Lack of enantiomeric specificity in the effects of anesthetic steroids on lipid bilayers.

The most important target protein for many anesthetics, including volatile and steroid anesthetics, appears to be the type A gamma-amino butyric acid receptor (GABA(A)R), yet direct binding remains to be demonstrated. Hypotheses of lipid-mediated anesthesia suggest that lipid bilayer properties are changed by anesthetics and that this in turn affects the functions of proteins. While other data could equally well support direct or lipid-mediated action, enantiomeric specificity displayed by some anesthetics is not reflected in their interactions with lipids. In the present study, we studied the effects of two pairs of anesthetic steroid enantiomers on bilayers of several compositions, measuring potentially relevant physical properties. For one of the pairs, allopregnanolone and ent-allopregnanolone, the natural enantiomer is 300% more efficacious as an anesthetic, while for the other, pregnanolone and ent-pregnanolone, there is little difference in anesthetic potency. For each enantiomer pair, we could find no differences. This strongly favors the view that the effects of these anesthetics on lipid bilayers are not relevant for the main features of anesthesia. These steroids also provide tools to distinguish in general the direct binding of steroids to proteins from lipid-mediated effects.

Anesthetics↗