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PubMed2001

Ketamine blockade of voltage-gated sodium channels: evidence for a shared receptor site with local anesthetics.

BACKGROUND: The general anesthetic ketamine is known to be an N-methyl-D-aspartate receptor blocker. Although ketamine also blocks voltage-gated sodium channels in a local anesthetic-like fashion, little information exists on the molecular pharmacology of this interaction. We measured the effects of ketamine on sodium channels. METHODS: Wild-type and mutant (F1579A) recombinant rat skeletal muscle sodium channels were expressed in Xenopus oocytes. The F1579A amino acid substitution site is part of the intrapore local anesthetic receptor. The effect of ketamine was measured in oocytes expressing wild-type or mutant sodium channels using two-electrode voltage clamp. RESULTS: Ketamine blocked sodium channels in a local anesthetic-like fashion, exhibiting tonic blockade (concentration for half-maximal inhibition [IC50] = 0.8 mm), phasic blockade (IC50 = 2.3 mm), and leftward shift of the steady-state inactivation; the parameters of these actions were strongly modified by alteration of the intrapore local anesthetic binding site (IC50 = 2.1 mm and IC50 = 10.3 mm for tonic and phasic blockade, respectively). Compared with lidocaine, ketamine showed greater tonic inhibition but less phasic blockade. CONCLUSIONS: Ketamine interacts with sodium channels in a local anesthetic-like fashion, including sharing a binding site with commonly used clinical local anesthetics.

Algorithms↗

PubMed2002

Comparison of Amsorb, sodalime, and Baralyme degradation of volatile anesthetics and formation of carbon monoxide and compound a in swine in vivo.

BACKGROUND: Consequences of volatile anesthetic degradation by carbon dioxide absorbents that contain strong base include formation of compound A from sevoflurane, formation of carbon monoxide (CO) and CO toxicity from desflurane, enflurane and isoflurane, delayed inhalation induction, and increased anesthetic costs. Amsorb (Armstrong Ltd., Coleraine, Northern Ireland) is a new absorbent that does not contain strong base and does not form CO or compound A in vitro. This investigation compared Amsorb, Baralyme (Chemetron Medical Division, Allied Healthcare Products, St. Louis, MO), and sodalime effects on CO (from desflurane and isoflurane) and compound A formation, carboxyhemoglobin (COHb) concentrations, and anesthetic degradation in a clinically relevant porcine in vivo model. METHODS: Pigs were anesthetized with desflurane, isoflurane, or sevoflurane, using fresh or partially dehydrated Amsorb, Baralyme, and new and old formulations of sodalime. Anesthetic concentrations in the fresh (preabsorber), inspired (postabsorber), and end-tidal gas were measured, as were inspired CO and compound A concentrations and blood oxyhemoglobin and COHb concentrations. RESULTS: For desflurane and isoflurane, the order of inspired CO and COHb formation was dehydrated Baralyme >> soda-lime > Amsorb. For desflurane and Baralyme, peak CO was 9,700 +/- 5,100 parts per million (ppm), and the increase in COHb was 37 +/- 14%. CO and COHb increases were undetectable with Amsorb. Oxyhemoglobin desaturation occurred with desflurane and Baralyme but not Amsorb or sodalime. The gap between inspired and end-tidal desflurane and isoflurane did not differ between the various dehydrated absorbents. Neither fresh nor dehydrated Amsorb caused compound A formation from sevoflurane. In contrast, Baralyme and sodalime caused 20-40 ppm compound A. The gap between inspired and end-tidal sevoflurane did not differ between fresh absorbents, but was Amsorb < sodalime < Baralyme with dehydrated absorbents. CONCLUSION: Amsorb caused minimal if any CO formation, minimal compound A formation regardless of absorbent hydration, and the least amount of sevoflurane degradation. An absorbent like Amsorb, which does not contain strong base or cause anesthetic degradation and formation of toxic products, may have benefit with respect to patient safety, inhalation induction, and anesthetic consumption (cost).

Absorption↗

PubMed2002

Mechanisms underlying greater sensitivity of neonatal cardiac muscle to volatile anesthetics.

BACKGROUND: In neonatal heart, plasma membrane Na+-Ca2+ exchange (NCX) and Ca2+ influx channels play greater roles in intracellular Ca2+ concentration [Ca2+]i regulation compared with the sarcoplasmic reticulum (SR). In neonatal (aged 0-3 days) and adult (aged 84 days) rat cardiac myocytes, we determined the mechanisms underlying greater sensitivity of the neonatal myocardium to inhibition by volatile anesthetics. METHODS: The effects of 1 and 2 minimum alveolar concentration halothane and sevoflurane on Ca2+ influx during electrical stimulation in the presence or blockade of NCX and the Ca2+ channel agonist BayK8644 were examined. [Ca2+]i responses to caffeine were used to examine anesthetic effects on SR Ca2+ release (via ryanodine receptor channels) and reuptake (via SR Ca2+ adenosine triphosphatase). Ca2+ influx via NCX was examined during rapid activation in the presence of the reversible SR Ca2+ adenosine triphosphatase inhibitor cyclopiazonic acid and ryanodine to inhibit the SR. Efflux mode NCX was examined during activation by extracellular Na+ in the absence of SR reuptake. RESULTS: Intracellular Ca2+ concentration transients during electrical stimulation were inhibited to a greater extent in neonates by halothane (80%) and sevoflurane (50%). Potentiation of [Ca2+]i responses by BayK8644 (160 and 120% control in neonates and adults, respectively) was also blunted by anesthetics to a greater extent in neonates. [Ca2+]i responses to caffeine in neonates ( approximately 30% adult responses) were inhibited to a lesser extent compared with adults (35 vs. 60% by halothane). Both anesthetics inhibited Ca2+ reuptake at 2 minimum alveolar concentration, again to a greater extent in adults. Reduction in NCX-mediated influx was more pronounced in neonates (90%) compared with adults (65%) but was comparable between anesthetics. Both anesthetics also reduced NCX-mediated efflux to a greater extent in neonates. Potentiation of NCX-mediated Ca2+ efflux by extracellular Na+ and NCX-mediated Ca2+ influx by intracellular Na+ were both prevented by halothane, especially in neonates. CONCLUSIONS: These data indicate that greater myocardial depression in neonates induced by volatile anesthetics may be mediated by inhibition of NCX and Ca2+ influx channels rather than inhibition of SR Ca2+ release.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2006

Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein.

BACKGROUND: Halothane inhibits airway smooth muscle contraction in part by inhibiting the functional coupling between muscarinic receptors and one of its cognate heterotrimeric G proteins, Galphaq. Based on previous studies indicating a more potent effect of halothane and sevoflurane on airway smooth muscle contraction compared with isoflurane, the current study hypothesized that at anesthetic concentrations of 2 minimum alveolar concentration (MAC) or less, halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange. METHODS: Galphaq guanosine nucleotide exchange was measured in crude membranes prepared from COS-7 cells transiently coexpressing the human M3 muscarinic receptor and human Galphaq. A radioactive, nonhydrolyzable analog of guanosine-5'-triphosphate, [35S]GTPgammaS, was used as a reporter for nucleotide exchange at Galphaq. RESULTS: Acetylcholine caused a concentration-dependent increase in Galphaq [35S]GTPgammaS-GDP exchange. Neither anesthetic affected constitutive Galphaq [35S]GTPgammaS-GDP exchange in the absence of acetylcholine. Conversely, each anesthetic caused a concentration-dependent and reversible inhibition of Galphaq [35S]GTPgammaS-GDP exchange when promoted by acetylcholine. At concentrations of 3 MAC or less, the effect of halothane and sevoflurane were significantly greater than that of isoflurane, with only a minimal inhibition by isoflurane observed at 2 MAC. CONCLUSION: The differential effects of volatile anesthetics on acetylcholine-promoted guanosine nucleotide exchange at Galphaq are consistent with the apparent more potent direct effect of halothane and sevoflurane compared with isoflurane on muscarinic receptor-mediated contraction of isolated airway smooth muscle. These differential effects also suggest a mode of anesthetic action that could be due to anesthetic-protein interactions and not simply anesthetic accumulation in the lipid membrane.

Acetylcholine↗

PubMed1984

Computer-controlled anesthetic delivery system.

We designed and tested a computer-controlled syringe pump for the administration of volatile anesthetics into a closed breathing circuit. The system consists of a small computer, a flip-flop circuit, and an automatic syringe pump. The computer was programmed to administer liquid anesthetics according to the square root of time model of anesthetic uptake. A simple electronic flip-flop circuit connected the computer to the syringe pump. Safeguards to prevent accidental anesthetic overdosage and algorithms to provide for dosage changes based on patient response were written into the program. After testing, the system was used to administer anesthetics to ten patients undergoing surgical procedures. The anesthetic uptake deviated from the square root of time model after approximately two hours. The system provided smooth and reliable administration of volatile anesthetics during closed circuit anesthesia.

Adult↗

PubMed2001

Topical anesthetics in children: agents and techniques that equally comfort patients, parents, and clinicians.

Topical anesthetics are increasingly important, as the number of outpatient surgeries for dermatologic problems in infants and children is steadily growing. This noninvasive modality of anesthetic delivery in conjunction with a reassuring environment may minimize the discomfort of otherwise painful procedures. Since the 1880s, when cocaine was first used as a topical ophthalmologic anesthetic, many ester-and amide-based local anesthetics have been developed for a variety of simple and complex procedures. The pediatric dermatologist's arsenal of topical anesthetic preparations is increasing with the development of novel vehicles of transdermal delivery and the use of anesthetics in combination. Eutectic mixture of local anesthetics is currently the most frequently prescribed topical agent, though the use of ELA-max, another lidocaine-containing preparation, is gaining momentum, especially in the neonatal population. Amethocaine, tetracaine, iontophoresis, and the S-caine patch, a product on the horizon for use in the pediatric population, also are included in this discussion.

Administration, Topical↗

PubMed1980

Use-dependent conduction block produced by volatile general anesthetic agents.

The ability of tertiary amine local anesthetic, barbiturates, and several volatile general anesthetics to block conduction of the compound action potential was measured in the frog sciatic nerve. Action potentials from large myelinated fibers were monitored using a desheathed nerve preparation in a sucrose-gap chamber. Supramaximal stimuli were applied over a range of stimulus frequencies from 0.1 Hz to 500 Hz. All three anesthetic agents produced a phasic, frequency-dependent anesthetic block, which developed with repetitive stimulation and returned to a tonic level when the nerve remained a rest. Saxitoxin produced a frequency-independent block. The frequency-dependent conduction block produced by the teritary amine anesthetic and by the barbiturates were potentiated by elevated Ca2+ in the solution bathing the nerve, but Ca2+ changes did not modify the block produced by any of the volatile anesthetics, so the latter agents probably act by a different mechanism than local anesthetics or barbiturates.

Action Potentials↗

PubMed1988

Modulation of the benzodiazepine/gamma-aminobutyric acid receptor chloride channel complex by inhalation anesthetics.

Inhalation anesthetics, such as diethyl ether, halothane, and enflurane, increase 36Cl- uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent, picrotoxin-sensitive fashion. At concentrations consistent with those that stimulate 36Cl- uptake, inhalation anesthetics also inhibit the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to well-washed cortical membranes. Scatchard analysis of [35S]TBPS binding indicates that these agents reduce the apparent affinity of this radioligand and have little effect on the Bmax. The ability of inhalation anesthetics to directly stimulate 36Cl- uptake and inhibit [35S]TBPS binding is a property shared by nonvolatile anesthetics. Nonetheless, there are differences between nonvolatile agents (such as barbiturates and alcohols) and inhalation anesthetics, because the former compounds augment muscimol (a GABAmimetic) stimulated 36Cl- uptake, whereas the latter group (such as ether and enflurane) inhibit this effect. These findings demonstrate that therapeutically relevant concentrations of inhalation anesthetics perturb the benzodiazepine/gamma-aminobutyric acid receptor chloride channel complex, and suggest this oligomeric protein may be a common mediator of some aspects of anesthetic action.

Anesthesia, Inhalation↗

PubMed1993

The defibrillation threshold: a comparison of anesthetics and measurement methods.

In 18 open-chested mongrel dogs (18.0 +/- 1.7 kg) we compared three anesthetics and three methods for measuring the defibrillation threshold. Six animals were anesthetized with pentobarbital (30 mg/kg) and maintained with a pentobarbital infusion (4 mg/kg per hour). All other animals were anesthetized with sodium brevital (10 mg/kg) and maintained with either halothane gas (1.5%, N = 6) or isoflurane gas (1.8%, N = 6). In each dog, we measured the energy required for 50% successful defibrillation (E50) with: (A) a 3 reversal--up/down method; (B) a 15 shock--up/down method; and (C) a percent success method. Anesthetics and methods were selected in a balanced random order. Ventricular fibrillation was induced with 50 Hz electrical pacing. After 15 seconds, monophasic truncated exponential shocks were delivered by way of a spring-patch electrode configuration. The animal was rescued (if needed) and fibrillation/defibrillation episodes were repeated at 3 minute intervals. After each determination of the E50, the E50 was delivered in ten successive defibrillation trials to determine its actual success rate. We found no significant difference in E50 among anesthetics; a significant difference (P < 0.05) in E50 between method C (9.7 +/- 2.6 joules) and method B (8.2 +/- 1.6 joules); no significant difference among anesthetics or methods for the actual success rate of the E50 (45 +/- 21% successful); and method A required significantly fewer fibrillation episodes and number of shocks and less cumulative energy than the other methods. We concluded that the anesthetics tested had little effect on E50 but that the method used to determine E50 could have an effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed2003

Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5).

Blockade of voltage-gated sodium (Na+) channels by local anesthetics represents the main mechanism for inhibition of impulse propagation. Local anesthetic-induced potassium (K+) channel inhibition is also known to influence transmission of sensory impulses and to potentiate inhibition. K+ channels involved in this mechanism may belong to the emerging family of background tandem pore domain K+ channels (2P K+ channels). To determine more precisely the effects of local anesthetics on members of this ion channel family, we heterologously expressed the 2P K+ channels TASK-2 (KCNK5), TASK-1 (KCNK3), and chimeric TASK-1/TASK-2 channels in oocytes of Xenopus laevis. TASK-2 cDNA-transfected HEK 293 cells were used for single-channel recordings. Local anesthetic inhibition of TASK-2 was dose-dependent, agent-specific, and stereoselective. The IC50 values for R-(+)-bupivacaine and S-(-)-bupivacaine were 17 and 43 micro M and for R-(+)-ropivacaine and S-(-)-ropivacaine, 85 and 236 micro M. Lidocaine (1 mM) inhibited TASK-2 currents by 55 +/- 4%, whereas its quaternary positively charged analog N-ethyl lidocaine (QX314) had no effect. Bupivacaine (100 micro M) decreased channel open probability from 20.8 +/- 1.6% to 5.6 +/- 2.2%. Local anesthetics [300 micro M R-(+)-bupivacaine] caused significantly greater depolarization of the resting membrane potential of TASK-2-expressing oocytes compared with water-injected control oocytes (15.8 +/- 2.5 mV versus 0.1 +/- 0.05 mV; p < 0.001). Chimeric TASK-1/TASK-2 2P K+ channel subunits that retained pH sensitivity demonstrated that the carboxy domain of TASK-2 mediates the greater local anesthetic sensitivity of TASK-2. These results show that clinically achievable concentrations of local anesthetics inhibit background K+ channel function and may thereby enhance conduction blockade.

Amides↗

PubMed2004

Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels.

Voltage-gated Na(+) channels (Na(+) channels) mediate the rising phase of action potentials in neurons and excitable cells. Nine subtypes of the alpha subunit (Na(v)1.1-Na(v)1.9) have been shown to form functional Na(+) channels to date. Recently, anesthetic concentrations of volatile anesthetics and ethanol were reported to inhibit Na(+) channel functions, but it is not known whether all subtypes are inhibited by anesthetics. To investigate possible subtype-specific effects of anesthetics on Na(+) channels, mRNA of Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.8 alpha subunit-encoded genes were injected individually or together with a beta subunit mRNA into Xenopus oocytes. Na(+) currents were recorded using the two-electrode voltage-clamp technique. Isoflurane, at clinically relevant concentrations, inhibited the currents produced by Na(v)1.2, Na(v)1.4, and Na(v)1.6 by approximately 10% at the holding potential of -90 mV and by approximately 30% at -60 mV, but it did not affect the Na(v)1.8-mediated current. An anesthetic fluorocyclobutane (1-chloro-1,2,2-trifluorocyclobutane) also inhibited the Na(v)1.2 channel, whereas the nonanesthetic fluorocyclobutane (1,2-dichlorohexafluorocyclobutane) had no effect. The perfluorinated heptanol [CF(3)(CF(2))(5)CH(2)OH], which produces anesthesia, inhibited the Na(v)1.2 channel like other alcohols tested (ethanol, heptanol, and CF(3)CH(2)OH), even though this compound does not affect GABA, glycine, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, or kainate receptors. In contrast, most intravenous anesthetics did not have significant effects on the Na(v)1.2 channel at clinically relevant concentrations although urethane inhibited. These results show that isoflurane inhibits the Na(+) channel functions except Na(v)1.8 in a voltage-dependent manner. These findings indicate that the Na(+) channel is a neuronal target for anesthetic action.

Alcohols↗

PubMed2004

Volatile anesthetics inhibit calcitonin gene-related peptide receptor-mediated responses in pithed rats and human neuroblastoma cells.

Calcitonin gene-related peptide (CGRP) has a potent vasodilatory effect that is mediated by specific receptors predominantly coupled to the activation of adenylate cyclase. The effects of volatile anesthetics on CGRP-induced vasodilation are unclear. We studied the effects of sevoflurane and isoflurane on CGRP-induced vasodilation in pithed rats and CGRP receptor-mediated responses in SK-N-MC cells, which are used as a model system to study the CGRP receptor and its downstream pathways. Male Wistar rats were pithed by inserting a stainless steel rod into the spinal cord. Mean arterial pressure (MAP) and cardiac output were maintained at approximately 100 mmHg and 50 ml.min(-1), respectively, with continuous infusion of noradrenaline. After 30 min of inhalation of anesthetics, CGRP (0.1, 0.3, 1.0, and 3.0 microg/kg) was administered intravenously. In SK-N-MC cells, CGRP-, forskolin-, or cholera toxin-induced cAMP production was measured with or without anesthetics using radioimmunoassays. CGRP receptor binding density and affinity for the agonist were determined with (2-[125I]iodohystidyl10) CGRP with or without the anesthetics. Sevoflurane (4%) and isoflurane (2%) significantly inhibited the decrease in MAP and systemic vascular resistance. Furthermore, both anesthetics significantly inhibited CGRP- but not forskolin-induced cAMP production. Sevoflurane (4%) and isoflurane (4%) significantly inhibited cholera toxin-induced cAMP production. Both anesthetics did not affect ligand binding. These data suggest that sevoflurane and isoflurane inhibit CGRP-induced vasodilation at the site between the CGRP receptor and adenylate cyclase activation. The inhibitory site of volatile anesthetics on the CGRP receptor-mediated response involves Gs protein.

Anesthetics, Inhalation↗

PubMed2005

Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear.

Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA(A)-Rs that harbor the alpha1 subunit. To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.

Administration, Inhalation↗

PubMed2000

A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor beta(2) subunit affects allosteric sensitivity to GABA and anesthetics.

Site-directed mutagenesis of the gamma-aminobutyric acid type A (GABA(A)) receptor beta(2) subunit has demonstrated that conversion of a conserved glycine residue located at the entrance to the first transmembrane domain into the homologous rho(1) residue phenylalanine alters the modulating effects of four different i.v. anesthetics: pentobarbital, alphaxalone, etomidate, and propofol. Using the baculovirus expression system in Spodoptera frugiperda 9 cells, anesthetic-induced enhancement of [(3)H]muscimol and [(3)H]flunitrazepam binding in receptors containing the beta(2)(G219F) point mutation displayed a significantly reduced efficacy in modulation by all four i.v. anesthetics tested. Furthermore, GABA(A) receptors containing the alpha(1)(G223F) point mutation also significantly decreased the maximal effect of etomidate- and propofol-induced enhancement of ligand binding. Conversely, the homologous point mutation in rho(1) receptors (F261G) changed the i.v. anesthetic-insensitive receptor to confer anesthetic modulation of [(3)H]muscimol binding. Consistent with the binding, functional analysis of pentobarbital-enhanced GABA currents recorded with whole-cell patch clamp demonstrated the beta(2)(G219F) subunit mutation eliminated the potentiating effect of the anesthetic. Similarly, propofol-enhanced GABA currents were potentiated less in alpha(1)beta(2)(G219F)gamma(2) receptors than in alpha(1)beta(2)gamma(2) receptors. Although ligand binding displayed comparable K(D) values for muscimol among wild-type, alpha(1)beta(2)gamma(2), and mutant receptors, patch-clamp recordings showed that alpha(1)beta(2)(G219F)gamma(2) receptors had a significantly more potent response to GABA than did alpha(1)beta(2)gamma(2) or alpha(1)(G223F)beta(2)gamma(2). The alpha(1)beta(2)(G219F)gamma(2) receptors also were more sensitive to direct channel activation by pentobarbital and propofol in the absence of GABA. These results suggest that the first transmembrane glycine residue on the beta(2) subunit may be important for conformational or allosteric interactions of channel gating by both GABA and anesthetics.

Allosteric Regulation↗

PubMed2004

Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane.

Nitrous oxide, xenon, and cyclopropane are anesthetic gases that have a distinct pharmacological profile. Whereas the molecular basis for their anesthetic actions remains unclear, they behave very differently to most other general anesthetics in that they have little or no effect on GABAA receptors, yet strongly inhibit the N-methyl-d-aspartate subtype of glutamate receptors. Here we show that certain members of the two-pore-domain K+ channel superfamily may represent an important new target for these gaseous anesthetics. TREK-1 is markedly activated by clinically relevant concentrations of nitrous oxide, xenon, and cyclopropane. In contrast, TASK-3, a member of this family that is very sensitive to volatile anesthetics, such as halothane, is insensitive to the anesthetic gases. We demonstrate that the C-terminal cytoplasmic domain is not an absolute requirement for the actions of the gases, although it clearly plays an important modulatory role. Finally, we show that Glu306, an amino acid that has previously been found to be important in the modulation of TREK-1 by arachidonic acid, membrane stretch and internal pH, is critical for the activating effects of the anesthetic gases.

Anesthetics, Inhalation↗

PubMed1992

Area postrema stimulation induces differential renal hemodynamics with two anesthetics.

The effect of area postrema stimulation (APS) on blood pressure, renal blood flow (RBF), and renal vascular resistance was compared in urethan-anesthetized and pentobarbital sodium-anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) increased in a frequency-dependent manner during APS in both urethan- and pentobarbital-anesthetized rats. Although no significant differences occurred in the maximum percent change in MAP between groups, marked differences occurred in RBF and calculated renal vascular resistance (RVR) changes. In urethan-anesthetized rats, RBF and MAP increased during APS, but RVR did not change. In contrast, APS significantly decreased RBF (-26.5 +/- 1.9%) while increasing RVR (+99.4 +/- 11.4%) in pentobarbital-anesthetized rats. The increase in RVR in the pentobarbital-anesthetized group during APS was eliminated by prior ganglionic blockade. It was concluded that the anesthetic agent employed can significantly alter the degree to which APS can activate renal vasomotion in the rat.

Anesthetics↗

PubMed1981

Pharmacology of local anesthetic agents.

Local anesthetic agents may be classified according to their intrinsic anesthetic potency and duration of activity. Procaine and chloroprocaine are relatively weak, short-acting drugs. Lidocaine, mepivacaine, and prilocaine represent agents of intermediate potency and duration of action. Tetracaine, bupivacaine, and etidocaine are highly potent, long-acting agents. The toxicity of local anesthetic drugs is usually due to inadvertent rapid intravascular injection or extravascular administration of an excessive amount. Intravascular toxicity is correlated with intrinsic anesthetic potency, whereas toxicity following extravascular injections is a function of physiological disposition characteristics of the various agents, such as rate of vascular absorption, rate of tissue redistribution, and rate of metabolism. The central nervous system is most susceptible to the toxic effects of local anesthetic agents. Signs and symptoms of CNS excitation followed by depression are the most common manifestations of local anesthetic toxicity. Cardiovascular depression may also occur following administration of excessive doses of local anesthetic agents or following high spinal or epidural anesthesia.

Anesthetics, Local↗

PubMed1981

Current concepts of the mechanism of action of local anesthetics.

Recent experiments are reviewed to present a current view of the mechanisms of conduction block by local anesthetics. Local anesthetics block the sodium channels whose opening causes the rising phase of the action potential. Both charged and neutral forms of local anesthetics are able to block channels. Charged anesthetics interfere with a "gating" mechanism after gaining access to a "receptor" site in the aqueous pore of the channel from the axoplasmic surface of the membrane. This site is only available to charged compounds when the gate of the channel is open. In contrast, uncharged compounds (including the free base form of local anesthetics) appear to reach the site through the membrane's lipid interior, bypassing the channel "gates." Anesthetics blocking the gate of the channel can either enhance or inhibit the normal inactivation mechanism of the sodium channel, depending on the particular anesthetic.

Action Potentials↗