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PubMed1981

Permeability of axon membranes to local anesthetics.

The permeability of the neutral form of tertiary amine local anesthetics across squid axon membranes was studied by utilizing three different experimental methods: (1) narcotic action of axon excitability was measured by monitoring the time derivative of action potential and the results were analyzed in terms of a diffusion reaction equation of local anesthetics to obtain their permeabilities; (2) the influx of local anesthetic into the axon was measured by use of the radioisotope tracer technique; and (3) the desorption rates of the neutral form of local anesthetics from lipid monolayers were measured and the desorption rate was correlated with permeability. The relative permeabilities obtained for procaine, lidocaine and tetracaine by the above three methods were comparable. The order of relative permeabilities was procaine greater than lidocaine greater than tetracaine, and had an inverse correlation with the partition coefficients of anesthetics at oil/water phases. Some discussion concerning the concept of permeability is made when the partition coefficient of a permeant molecule is high.

Action Potentials↗

PubMed1990

A solid-solution theory of anesthetic interaction with lipid membranes: temperature span of the main phase transition.

Anesthetics (or any other small additives) depress the temperature of the main phase transition of phospholipid bilayers. Certain anesthetics widen the temperature span of the transition, whereas others do not. The widening in a first-order phase transition is intriguing. In this report, the effects of additive molecules on the temperature and its span were explained by the solid-solution theory. By assuming coexistence of the liquid-crystal and solid-gel phases of lipid membranes at phase transition, the phase boundary is determined from the distribution of anesthetic molecules between the liquid-crystal membrane versus water and between the solid-gel membrane versus water. The theory shows that when the lipid concentration is large or when the lipid solubility of the drug is large, the width of the transition temperature increases, and vice versa. Highly lipid-soluble molecules, such as long-chain alkanols and volatile anesthetics, increase the width of the transition temperature when the lipid:water ratio is large, whereas highly water-soluble molecules, such as methanol and ethanol, do not. The aqueous phase serves as the reservoir for anesthetics. Depletion of the additive molecules from the aqueous phase is the cause of the widening. When the reservoir capacity is large, the temperature width does not increase. The theory also predicts asymmetry of the specific heat profile at the transition.

Anesthetics↗

PubMed1995

Electrokinetic charge of the anesthetic-induced bR480 and bR380 spectral forms of bacteriorhodopsin.

The translational and rotational electrokinetics of the anesthetic-induced spectral transitions bR568-->bR480-->bR380 of bacteriorhodopsin have been investigated. Formation of the bR480 form is associated with an increase of the purple membrane negative electrokinetic charge, while the transformation of bR480 into bR380 is accompanied by a decrease of the membrane negative charge as compared to that of the 480 nm-absorbing form. Removal of anesthetics leads to the back transitions bR480-->bR568 and (in part) bR380-->bR568; however, the electrokinetic charge of the native membranes is not restored. A strong decrease in the electric polarizability and the appearance of a slow polarizability component are also observed in anesthetic-treated membranes. Comparison with the electrokinetic behaviour of partially delipidated membranes and with that of liposomes composed of purple membrane total lipids suggests that: (i) anesthetic molecules partition mainly at the protein/lipid interface inducing irreversible rearrangement of the boundary lipid layer, and (ii) different mode(s) or site(s) of interaction are responsible for the spectral and surface charge effects. The data are compatible with the hypothesis of anesthetics acting through partial dehydration of the membrane surface.

Anesthetics↗

PubMed1995

Spermidine attenuation of volatile anesthetic inhibition of glutamate-stimulated [3H](5D,10S)-(+)-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding to N-methyl-D-aspartate (NMDA) receptors in rat brain.

The influence of spermidine, a polyamine agonist, on volatile anesthetic inhibition of N-methyl-D-aspartate (NMDA) receptor activation, as indicated by glutamate stimulation of [3H]MK-801 ([3H](5D,10S)-(+)-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine) binding, was studied in rat brain. Spermidine reserved the inhibition caused by four volatile anesthetics (enflurane, halothane, methoxyflurane and chloroform) at the same concentrations (EC50 approximately 3 microM) at which it potentiated glutamate opening of the NMDA ion channel. The anesthetics had no effect on the direct stimulation of channel opening by spermidine, which occurred at concentrations of spermidine greater than 30 microM in the absence of receptor agonist. In these actions, spermidine closely resembled the allosteric co-agonist glycine. The present results suggest that anesthetic action on NMDA receptors involves a set of sites on the channel complex that is distinct from the recognition sites for glutamate, glycine, and channel blockers, and are consistent with the idea that blockade of NMDA receptors contributes to the development of the anesthetic state.

Anesthetics, Inhalation↗

PubMed1981

Opiate and digitalis receptor assays distinguish between neuroexcitant and inactive organochlorines and between anesthetics and convulsants.

Specific binding of [3H]naloxone to rat brain tissue in vitro was inhibited by the excitant organochlorinated insecticides (OCI), by ether (E) and octanol (OCT), and by the convulsant indoklon (IND) and its anesthetic isomer, isoindoklon (ISO). In the presence of 100 mM NaCl the inhibition of naloxone binding by E, OCT and ISO was greatly potentiated, whereas that by OCI and IND was attenuated. KCl (100 mM) was equally effective as NaCl on the action of anesthetics, but the effect of the excitant drugs was, in contrast to NaCl, unaffected by KCl. Specific binding of [3H]ouabain in the absence of Na, was depressed by anesthetics and enhanced by neuroexcitants. In the presence of NaCl, which by itself inhibits ouabain binding to brain, both anesthetics and excitants enhanced ouabain binding. DDE, a non-insecticidal analog of DDT, and the dimethyl derivative of the OCI, lindane, were inactive in the receptor assays. These observations point to a unique isolated system which responds consistently to anesthetic agents as a class and, in a different way, to neuroexcitant compounds.

Anesthetics↗

PubMed1988

Anesthetic effects on 5-hydroxytryptamine uptake by rat brain synaptosomes.

As a neurotransmitter involved in modulating central nervous system nociception and awareness, 5-hydroxytryptamine (5-HT) may play an important role in the clinical sequelae of certain anesthetic compounds. Anesthetic agents are known to affect peripheral, non-neuronal 5-HT uptake but little is known about their effects on 5-HT metabolism in the central nervous system. The effects of several anesthetic compounds on 5-HT uptake were examined in synaptosomes isolated from rat brain cortex. Inhibition of this uptake process was observed by exposure to clinically relevant concentrations of the volatile anesthetics halothane, isoflurane, and enflurane. The non-volatile agent, ketamine also inhibited uptake while the narcotic fentanyl had an effect only at the highest concentrations tested. Non-volatile agents which had neither a consistent nor significant effect on synaptosomal 5-HT uptake included pentobarbital, sufentanil, and etomidate. These alterations of 5-HT metabolism could represent a mechanism that contributes to anesthetic action.

Anesthetics↗

PubMed1994

A ketamine mixture anesthetic inhibits neuroendocrine and behavioral consequences of cocaine administration.

Cocaine is known to affect different brain systems, particularly those associated with arousal, motor and motivational functions. In order to identify a possible neurochemical link among these systems, we investigated the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and dissociative anesthetic, ketamine (as a mixture with the sedatives acepromazine and xylazine) on the secretion of pituitary adrenocorticotropin hormone (ACTH) and on the development of behavioral sensitization induced by cocaine. Pretreatment with the ketamine anesthetic mixture (1.6 ml/kg; s.c.) completely blocked the stimulation of ACTH by cocaine (5 mg/kg, i.v.; administered 30 min after the ketamine mixture) without interfering with ACTH secretion induced by exogenous corticotropin-releasing factor (CRF; 5 micrograms/kg; i.v.) or interleukin-1 beta (IL-1 beta; 100 ng/kg; i.v.). Administration of the ketamine mixture prior to each of five repeated cocaine injections (15 mg/kg; i.p.) also completely reversed the behavioral sensitization observed in saline-treated control animals. Administration of the anesthetic mixture did not appear to impair the dopamine (DA) re-uptake blocking properties of cocaine in the nucleus accumbens since substantial increases in extracellular DA were observed in the presence of the ketamine mixture. In addition to the present results, no behavioral sensitization was also observed in rats anesthetized with a different general anesthetic (pentobarbital, 50 mg/kg) under similar conditions to that of the ketamine mixture. Taken together, these results are in accordance with the hypothesis that stimulation of excitatory amino acid receptor function may be just one of the mechanisms whereby cocaine exerts its effects on neuroendocrine and behavioral activating systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1985

Effects of anesthetic and anticonvulsant drugs on calcium-dependent efflux of potassium from human erythrocytes.

Anesthetic (halothane, enflurane, isoflurane, chloroform, diethyl ether, pentobarbital, phenyclidine) and anticonvulsant (ethosuximide, phenytoin, phenobarbital, sodium valproate, carbamazepine, delta 9-tetrahydrocannabinol) drugs were investigated for their effects on the calcium-dependent efflux of 86Rb (used as a marker for potassium) from resealed human red blood cells. Most anesthetic agents produced biphasic effects, having stimulatory actions at low (anesthetic) concentrations and inhibitory actions at higher (toxic) concentrations. The drug concentrations required to increase calcium-dependent 86Rb efflux were closely correlated with plasma concentrations required for anesthesia in vivo. Two anticonvulsant agents (phenytoin and phenobarbital) inhibited the efflux process in a concentration-dependent manner, while all other tested anticonvulsants were without significant effects. Neither the anesthetic nor the anticonvulsant substances significantly altered the calcium-independent release of 86Rb. The possibility that general anesthetic and anticonvulsant drugs act on calcium-dependent potassium conductance in the central nervous system, and the therapeutic importance of such actions, is discussed.

Anesthetics↗

PubMed1986

Properties of a local anesthetic receptor in rat brain.

Saturable binding of local anesthetics in rat brain homogenates was demonstrated using (14C)-lidocaine and (3H)-bupivacaine. Saturation analyses revealed a single class of binding sites for lidocaine and bupivacaine. A series of drugs with local anesthetic properties inhibited this binding, while drugs without local anesthetic activity did not affect the specific binding. Specific binding of lidocaine and bupivacaine was maximal from pH 8 to 10; the pH versus binding profile was similar to that reported for local anesthetic blocking of peripheral nerve conduction. These characteristics suggest that binding of local anesthetics to this or similar sites mediates their pharmacological activity.

Anesthetics, Local↗

PubMed1996

Effects of inhalation anesthetics of Kainate-induced glutamate release from cerebellar granule cells.

The mechanisms of inhalation anesthesia may include inhibiting non NMDA excitatory amino acid neurotransmission. This possibility was addressed by measuring the effect of three anesthetics at clinically relevant concentration on kainate-induced glutamate release from cerebellar granule cells. Cerebellar granule cells were obtained from 8-day-old SD rats and maintained in vitro for 9-14 days. Medium glutamate concentrations were measured by HPLC after 90 minutes incubation with kainate or NMDA. Inhalation anesthetics were introduced by holding the cells under a continuous flow of air/anesthetic mixtures. All anesthetics tested did not effect NMDA-induced glutamate release. Halothane (1 MAC), isoflurane (1 MAC) inhibited kainate-induced glutamate release from the cultured cells whereas enflurane (1 MAC) had no effect on kainate-induced glutamate release. The difference between enflurane and the other anesthetics tested suggests that anesthesia is dependent on more than one process and the extent at which each function is perturbed is dependent on the specific anesthetic used. Halothane inhibition of kainate-induced glutamate release was not reversible by increasing kainate concentration, indicating halothane does not directly compete with kainate at its receptor.

Anesthetics, Inhalation↗

PubMed1995

The effects of four general anesthetics on intracellular [Ca2+] in cultured rat hippocampal neurons.

It has been suggested that general anesthesia might arise as a consequence of increased cytoplasmic free ionized calcium concentration ([Ca2+]i). The effect of increased [Ca2+]i might be to activate K+ channels or to modulate other ion channels important for the control of excitability, such as the GABAA receptor. A direct test of this hypothesis has not been reported. Microfluorimetry with the calcium-sensitive dye fura-2 was used to study the effects of four anesthetic agents on the regulation of intracellular free Ca2+ in hippocampal neurons cultured from the embryonic rat hippocampus. Basal intracellular free ionized calcium concentration [Ca2+]i in the neurons was 50-100 nM. Depolarization of the neurons with 50 mM K+ resulted in the elevation of [Ca2+]i to 200-800 nM, with subsequent recovery of [Ca2+]i over several minutes. The volatile anesthetics halothane, enflurane and isoflurane did not alter basal [Ca2+]i, even above clinically relevant concentrations; however, they did inhibit elevation of [Ca2+]i by high K+ stimulation. The intravenous anesthetic methohexital caused small increases in basal [Ca2+]i at concentrations > or = 50 microM; methohexital (5-50 microM) also inhibited elevations of [Ca2+]i induced by high K+. The evidence presented here suggests that the anesthetics studied do not produce their actions via sustained or transient increases in [Ca2+]i. However, all of the anesthetics studied appear to possess inhibitory effects on hippocampal voltage-dependent Ca2+ channels, in addition to their previously described effects at GABAA receptors.

Anesthetics↗

PubMed1986

Anesthetics and anticoagulants used in the preparation of rat platelet-rich-plasma alter rat platelet aggregation.

Aggregation of platelets in heparin- and citrate-anticoagulated platelet-rich-plasma (PRP) from rats anesthetized with methoxyflurane (M), diethyl ether (E), acepromazine/ketamine (A/K), or sodium pentobarbital (P) is described, as are platelet counts. Platelet counts were highest in heparin- or citrate-PRP from E and A/K anesthetized rats. Collagen and arachidonic acid (AA) induced aggregation in heparin-PRP only, and ADP induced greater aggregation in heparin-PRP than in citrate-PRP. Differences between citrate-PRP and heparin-PRP are probably due to citrate inhibition of platelet aggregation, since addition of citrate to heparin-PRP decreased aggregation, while addition of heparin to citrate-PRP did not alter aggregation. Aggregation of hirudin-PRP was slightly less than heparin-PRP. Anesthetics affected rat platelet aggregation: the rank order of the maximal extent of ADP-induced aggregation in citrate-PRP was M greater than E = A/K greater than P, and that for AA and collagen in heparin-PRP was E = A/K greater than M = P. The correlation between the effect of the anesthetics and activation of the sympathoadrenal system is discussed. It appeared that of the commonly used anticoagulants and anesthetics, heparin and methoxyflurane had the least influence on rat platelet aggregation.

Anesthetics↗

PubMed1990

Local anesthetics: stimulation of incorporation of inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes.

Various local anesthetics enhanced the incorporation of [3H]inositol into phosphoinositides in guinea pig cerebral cortical synaptoneurosomes. Dibucaine, QX-572 and dimethisoquin showed maximum stimulation at 100 microM, tetracaine and diphenhydramine at 300 microM, and QX-314 at 1 mM, while quinacrine, lidocaine and cocaine showed no or only slight stimulation. There was no correlation between local anesthetic activity, estimated by inhibition of the 22Na+ flux elicited by the sodium channel activator batrachotoxin, and the potency for stimulation of inositol incorporation. A quaternary, relatively weak, local anesthetic, QX-572, was the most potent agent in stimulation of inositol incorporation, while the next most potent agent was dibucaine, a tertiary, very potent, local anesthetic. Dibucaine did not affect the uptake of [3H]inositol by synaptoneurosomes. The incorporation of [3H]inositol into phosphoinositides was increased in calcium-free buffer. The presence of dibucaine resulted in further stimulation of [3H]inositol incorporation in calcium-free buffer. Although dibucaine and QX-572 markedly stimulated incorporation of [3H]inositol into phosphoinositides, only QX-572 significantly enhanced the incorporation of 32PO4(3-) into phosphoinositides. The results suggest that certain local anesthetics enhance a pathway involving an exchange reaction between inositol and the phosphoinositol ester bond of phosphatidylinositol, but do not markedly affect the de novo pathway of phosphoinositide synthesis.

Anesthetics, Local↗

PubMed1982

Effects of small nonpolar molecules on membrane compressibility and permeability. A theoretical study of the effects of anesthetic gases.

We explore from a theoretical perspective the effects of small nonpolar molecules, such as anesthetic gases, on membrane compressibility and permeability. As a model system we expand a previously proposed generalization of Nagle's model for biomembrane phase transitions. In this model anesthetic gases alter membrane compressibility, causing profound changes in membrane permeability. Anesthetics either increase or decrease membrane permeability, depending on whether the membrane lipid is originally in the solid or melted state, or in a two-phase region. These changes are reversed by high pressure, in agreement with experimental results. Anesthetic-induced changes in compressibility are predicted to inhibit fusion of phospholipid vesicles to each other and to planar bilayers, and thus might be expected to inhibit the fusion of presynaptic vesicles with the presynaptic nerve membrane. This work provides a detailed molecular theory for many of the effects of anesthetic gases on both synapse and axon, and provides a coherent framework for understanding diverse experimental results.

Anesthesia↗

PubMed1980

Effects of local anesthetics on guanyl nucleotide modulation of the catecholamine-sensitive adenylate cyclase system and on beta-adrenergic receptors.

Tetracaine and other local anesthetics exert multiple actions on the catecholamine-sensitive adenylate cyclase system of frog erythrocyte membranes. Tetracaine (0.2--20 mM) reduces the responsiveness of adenylate cyclase to (a) guanyl-5'-yl-imidodiphosphate and (b) isoproterenol in the presence of GTP or guanyl-5'-yl-imidodiphosphate. Local anesthetics did not affect (a) basal enzyme activity, and (b) enzyme responsiveness to NaF. Tetracaine inhibited stimulation of adenylate cyclase by guanyl-5'-yl-imidodiphosphate over the whole range of nucleotide concentrations. By contrast, inhibition by tetracaine of isoproterenol activity in the presence of GTP was significant only if GTP concentrations exceeded 10(-7) M. Tetracaine also competitively inhibited binding of both the antagonist [3H]dihydroalprenolol and the agonist [3H]hydroxybenzylisoproterenol to beta-adrenergic receptors. However, it was twice as potent in inhibiting [3H]hydroxybenzylisoproterenol as [3H]dihydroalprenolol binding. The greater potency for inhibition of agonist binding was due to the ability of the anesthetics to promote dissociation of the high-affinity nucleotide sensitive state of the beta-adrenergic receptor induced by agonists. Other local anesthetics mimicked the effects of tetracaine on adenylatecyclase and in dissociating high-affinity agonist-receptor complexes. The other of potency for both processes was dibucaine greater than tetracaine greater than bupivacaine greater than lidocaine which agrees with their relative potencies as local anesthetics. By contrast, a different order of potency was observed for competitive inhibition of [3H]dihydroalprenolol binding: dibucaine greater than tetracaine greater than greater than lidocaine greater than bupivacaine.

Adenylyl Cyclases↗

PubMed1994

Local anesthetics as adjuvant analgesics.

Local anesthetics administered to block nerve conduction for surgical anesthesia and to provide analgesia in management of acute pain have become a standard of anesthesiology practice. These drugs have had an important role in the multimodality management of chronic pain as well, and this role is expanding since the revival of systemic administration. Local anesthetics are analgesics, albeit not in the traditional clinical and pharmacologic sense. Evidence suggests that intravenous administration is an effective treatment in chronic neuropathic pain syndromes. There is also evidence that intravenous local anesthetics can relieve acute pain. Furthermore, the novel idea that acute procedural and postprocedural pain control with local anesthetics could prevent the development of chronic pain syndromes, including chronic neuropathic pain syndromes, adds another important potential dimension to the role of local anesthetics in pain management.

Adjuvants, Pharmaceutic↗

PubMed1990

Comparison of anesthetic techniques in patients undergoing heart valve replacement.

A prospective study of 324 adult patients undergoing operations requiring cardiopulmonary bypass for heart valve replacement was undertaken to determine the effect of anesthetic technique on outcome. Patients received one of three primary techniques: fentanyl (40-100 micrograms/kg), sufentanil (4-8 micrograms/kg), or diazepam (0.4-1 mg/kg) with ketamine (3-6 mg/kg). Supplemental inhalation anesthesia with enflurane, halothane, or isoflurane was used in 43.8% of cases. Patients in these anesthetic groupings had similar perioperative demographic and risk classifications. Although there were differences in the requirements for vasopressors postoperatively among the intravenous anesthetic agents, neither mortality rates, length of ICU stay, nor incidence of postoperative heart failure showed the advantage of any intravenous or inhalational agent. There were also no significant differences in the incidences of serious pulmonary, renal, or neurologic morbidity among primary anesthetic techniques nor among supplemental inhalation agents. Multivariate discriminant analysis of these data suggests that many factors are significantly more important than anesthetic technique as determinants of outcome after heart valve replacement.

Analysis of Variance↗

PubMed1988

Physical status score and trends in anesthetic complications.

Since deaths due to anesthesia have now become rare, emphasis in quality assurance of anesthetic care must focus on morbidity rather than only on mortality. To facilitate comparisons of outcomes, data from a large anesthesia follow-up program (N = 112,000 anesthetics) were used to evaluate the usefulness of the American Society of Anesthesiologists' Physical Status score (PS) as an independent predictor of nonfatal adverse anesthetic complications. For each patient, the anesthesiologist filled out a form containing information about the patient, the anesthetic, the operative procedure, and outcomes in the operating and recovery rooms. Postoperative complications were assessed by a designated anesthesia follow-up nurse. We calculated the PS-specific complication rate by dividing the number of complications to patients in each PS category by the number of anesthetics given to patients in the same category. We found that PS-specific complication rates increased with increasing PS scores for most complications sought. For intraoperative and recovery room complications, the PS-specific rates increased from 1978-80 and 1981-83 as compared to 1975-77. However, there was no increase over time in the rate of postoperative major complications. After adjusting for patient, anesthesia, and surgery-related variables by multiple logistic regression, the relative odds of having an intraoperative or postoperative major complication were increased for patients classified PS2, PS3 and PS4 & 5 as compared to PS1. However, those in higher PS categories were less likely to have a recovery room complication than PS1 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗