Stereoselective Loss of Righting Reflex in Rats by Isoflurane

2000 ◽  
Vol 93 (3) ◽  
pp. 837-843 ◽  
Author(s):  
Robert Dickinson ◽  
Ian White ◽  
William R. Lieb ◽  
Nicholas P. Franks
Keyword(s):  
Molecular Targets ◽  
Maximal Effect ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Response Curves ◽  
Loss Of Righting Reflex ◽  
Large Numbers ◽  
Righting Reflex ◽  
Volatile Agents

Background Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane. Methods Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane. Results The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers. Conclusions The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.

scholarly journals Involvement of Tuberomamillary Histaminergic Neurons in Isoflurane Anesthesia

2011 ◽  
Vol 115 (1) ◽  
pp. 36-43 ◽  
Author(s):  
Tao Luo ◽  
L. Stan Leung
Keyword(s):  
Critical Role ◽  
Cell Loss ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Isoflurane Anesthesia ◽  
Histaminergic Neurons ◽  
Loss Of Righting Reflex ◽  
Tuberomamillary Nucleus ◽  
Righting Reflex ◽  
H1 Receptor Antagonist

Background The brain histaminergic system plays a critical role in maintenance of arousal. Previous studies suggest that histaminergic neurotransmission might be a potential mediator of general anesthetic actions. However, it is not clear whether histaminergic tuberomamillary nucleus (TMN) is necessarily involved in the sedative/hypnotic effects of general anesthetics. Methods Male Long Evans rats underwent either TMN orexin-saporin/sham lesion or implantation of intracerebroventricular cannula 2 weeks before the experiment. The behavioral endpoint of loss of righting reflex was used to assess the hypnotic property of isoflurane, propofol, pentobarbital, and ketamine in animals. Histaminergic cell loss was assessed by adenosine deaminase expression in the TMN using immunohistochemistry. Results Rats with bilateral TMN orexin-saporin lesion induced an average 72% loss of histaminergic cells compared with sham-lesion rats. TMN orexin-saporin lesion or intracerebroventricular administration of triprolidine (an H1 receptor antagonist) decreased the 50% effective concentration for loss of righting reflex value and prolonged emergence time to isoflurane anesthesia. However, TMN orexin-saporin lesion had no significant effect on the anesthetic sensitivity to propofol, pentobarbital, and ketamine. Conclusions These findings suggest a role of the TMN histaminergic neurons in modulating isoflurane anesthesia and that the neural circuits for isoflurane-induced hypnosis may differ from those of γ-aminobutyric acid-mediated anesthetics and ketamine.

Heteromeric Nicotinic Inhibition by Isoflurane Does Not Mediate MAC or Loss of Righting Reflex

2002 ◽  
Vol 97 (4) ◽  
pp. 902-905 ◽  
Author(s):  
Pamela Flood ◽  
James M. Sonner ◽  
Diane Gong ◽  
Kristen M. Coates
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Genetically Engineered ◽  
Neuronal Nicotinic Acetylcholine Receptors ◽  
General Anesthetics ◽  
Nicotinic Acetylcholine ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Surgical Setting

Background Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in the mechanism of action of isoflurane as they are inhibited at subanesthetic concentrations. Despite clear evidence for nicotinic inhibition at relevant isoflurane concentrations, it is unclear what behavioral result ensues, if any. Methods The authors have modeled two behaviors common to all general anesthetics, immobility and hypnosis, as minimum alveolar concentration that prevents movement in response to a supramaximal stimulus (MAC) and loss of righting reflex (LORR). They have tested the ability of nicotinic pharmacologic modulators and congenital absence of most heteromeric nAChRs to affect concentration of isoflurane required for these behaviors. Results Neither mecamylamine, 5 mg/kg, nor chlorisondamine, 10 mg/kg, affected isoflurane MAC. Nicotine caused a small decrease in MAC. None of the above agents had any effect on the concentration of isoflurane required for LORR. Mice genetically engineered to lack the beta 2 nicotinic gene product were not different in MAC or LORR from controls. Conclusions Nicotinic antagonists do not cause MAC or LORR. Inhibition of nicotinic acetylcholine receptors by isoflurane is not likely related to its ability to provide immobility and hypnosis in a surgical setting. This is perhaps not surprising as the inhibition of nAChRs in vitro is complete at an isoflurane concentration equal to one half of MAC. Nicotinic inhibition may, however, be involved in anesthetic behaviors such as amnesia and analgesia, which occur at lower anesthetic concentrations.

scholarly journals Dementia Enhances Inhibitory Actions of General Anesthetics in Hippocampal Synaptic Transmission

2011 ◽  
Vol 2011 ◽  
pp. 1-5
Author(s):  
Masana Yamada ◽  
Rika Sasaki ◽  
Koki Hirota ◽  
Mitsuaki Yamazaki
Keyword(s):  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Gaba Release ◽  
Recurrent Inhibition ◽  
General Anesthetics ◽  
Presynaptic Terminals ◽  
Loss Of Righting Reflex ◽  
Healthy Control

In order to investigate whether dementia modifies the anesthetic actions in the central nervous systems, we have studied effects of general anesthetics on the hippocampal synaptic transmission using the dementia model mice. Preliminary in vivo experiments revealed that time of loss of righting reflex following sevoflurane inhalation was more shortened in dementia mice than in healthy control mice. Field population spikes of hippocampal CA1 pyramidal neurons were elicited in vitro using orthodromic stimulation of Schaffer collateral commissural fibers (test pulse). The recurrent inhibition was enhanced with the second stimulating electrode placed in alveus hippocampi (prepulse) to activate recurrent inhibition of CA1. The prepulses were applied as train stimuli to activate release and then deplete γ-amino-butyric acid (GABA) at presynaptic terminals of inhibitory interneurons. Sevoflurane and thiopental had greater actions on inhibitory synaptic transmission in dementia model mice than in control mice. The pre-pulse train protocol revealed that the anesthetic-induced GABA discharge was more enhanced in dementia mice than in control mice. Dementia enhances the actions of general anesthetics due to the increase in GABA release from presynaptic terminals.

Halothane-induced synaptic depression at both in vivo and in vitro reconstructed synapses between identified Lymnaea neurons

1995 ◽  
Vol 74 (6) ◽  
pp. 2604-2613 ◽  
Author(s):  
G. E. Spencer ◽  
N. I. Syed ◽  
K. Lukowiak ◽  
W. Winlow
Keyword(s):  
Synaptic Transmission ◽  
Lymnaea Stagnalis ◽  
Cell Types ◽  
Inhibitory Synapses ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Presynaptic Neuron ◽  
Novel Approach

1. In the present study we tested the ability of the general anesthetic, halothane, to affect synaptic transmission at in vivo and in vitro reconstructed peptidergic synapses between identified neurons of Lymnaea stagnalis. 2. An identified respiratory interneuron, visceral dorsal 4 (VD4), innervates a number of postsynaptic cells in the central ring ganglia of Lymnaea. Because VD4 has previously been shown to exhibit immunoreactivity for FMRFamide-related peptides, it was hypothesized that these peptides may be utilized by VD4 during synaptic transmission. In the intact, isolated CNS of Lymnaea, we have identified novel connections between VD4 and the pedal A (PeA) cells. We demonstrate that VD4 makes inhibitory connections with the PeA neurons, in particular PeA4, and that these synaptic responses are mimicked by exogenous application of FMRFamide. 3. The synaptic transmission between VD4 and the PeA cells in an intact, isolated CNS preparation was completely blocked in 2%, but not 1% halothanc. Interestingly, the postsynaptic responses (PeA) to exogenous FMRFamide were maintained in the presence of both 1 and 2% halothane. 4. To determine the specificity of the observed responses and to determine the precise synaptic site of anesthetic action, we reconstructed the VD4/PeA synapses in vitro. After isolation from their respective ganglia, both cell types extended processes and established neuritic contact. We demonstrated that not only did the presynaptic neuron reestablish the appropriate inhibitory synapses with the PeA neurons, but that the PeA cells also maintained their responsiveness to exogenous FMRFamide. 5. Superfusion of the in vitro synaptically connected VD4 and PeA cells with 2% halothane completely abolished the synaptic transmission between these cells. However, even higher concentrations of 4% halothane failed to block the responsiveness of the PeA neurons to exogenous FMRFamide. Moreover, both 1 and 2% halothane enhanced the duration of the postsynaptic response to exogenously applied FMRFamide. These data suggest that the halothane-induced depression of synaptic transmission most likely occurred at the presynaptic level. 6. This study provides the first direct evidence that peptidergic transmission in the nervous system may also be susceptible to the actions of general anesthetics. In addition, we utilized a novel approach of in vitro reconstructed synapses for studying the effects of general anesthetics on monosynaptic transmission in the absence of other synaptic influences.

COMPUTERIZED PLATELET AGGREGOMETRY

1987 ◽  
Author(s):  
T Szabados ◽  
F Hermán ◽  
G Kollányi ◽  
P Hadházy ◽  
K Magyar
Keyword(s):  
Dose Response ◽  
In Vitro Tests ◽  
Response Curves ◽  
Dual Channel ◽  
Large Numbers ◽  
Platelet Aggregometry ◽  
Enormous Amount ◽  
Dose Response Curves ◽  
The Individual

One of the commonly used in vitro tests for assessing platelet function is a photodensitometric assay first established by Born. However the collection and analysis of aggregation data are tedious and time consuming. The single- and dual-channel aggregometers have limited utility for the analysis of large numbers of plasma samples in clinical laboratories or in studies on the mode of action of drugs.We now report on a multichannel platelet aggregome-ter system consisting of an IBM XT personal computer and three microprocessor-controlled 4 channel aggregometers. The system collects, displays and analyzes 12 different aggregation curves simultaneously, and - like other computerized systems - (1) significantly increa ses the efficiency and ease in performing the experiment, analyzing and presenting the data; (2) provides systematic storage and rapid retrieval of the data;(3) saves an enormous amount of time; (4) because of multichannel capability eliminates the effects of time-related changes in PRP on the dose-response curves.However our system has some advantages over the computerized aggregometer systems used so far: (1) since the aggregometers contain built in microprocessors they can be utilized to measure and analyse platelet aggregation without being coupled to a computer; (2) a special program helps to check the validity of the calculated parameters under visual control; (3) the individual points of the dose-response curves can be checked at any time during the experiment.

scholarly journals Effect of insulin on glucose metabolism in adipocytes from virgin and late-pregnant rats

1984 ◽  
Vol 224 (2) ◽  
pp. 685-688 ◽  
Author(s):  
A Leturque ◽  
M Guerre-Millo ◽  
M Lavau ◽  
J Girard
Keyword(s):  
Glucose Metabolism ◽  
High Sensitivity ◽  
Late Pregnancy ◽  
Maximal Response ◽  
Maximal Effect ◽  
Insulin Stimulation ◽  
Response Curves ◽  
Pregnant Rats

Under basal conditions (zero insulin), paraovarian adipocytes from 19-day-pregnant rats exhibited the same rates of [U-14C]glucose conversion into CO2 and total lipids as did those from age-matched virgin rats. The dose-response curves for insulin stimulation of glucose metabolism were similar in both groups: maximal response (+100% over basal values) and high sensitivity (half-maximal effect at 0.05 nM-insulin). The present results suggest that the insulin resistance in vivo that occurs during late pregnancy may involve circulating factors lost in vitro.

Identification of a Novel Secreted Metabolite Cyclo(Phenylalanyl-Prolyl) from Batrachochytrium Dendrobatidis and its effect on Galleria Mellonella.

2021 ◽  
Author(s):  
Amanda Michelle Starr ◽  
Masoud Zabet-Moghaddam ◽  
Michael San Francisco
Keyword(s):  
Batrachochytrium Dendrobatidis ◽  
Galleria Mellonella ◽  
Ultra Performance Liquid Chromatography ◽  
Liquid Chromatography Mass Spectrometry ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Fragmentation Patterns ◽  
Eventual Death ◽  
Wax Moth

Abstract The fungus, Batrachochytrium dendrobatidis, is the causative agent of chytridiomycosis and a leading cause of global decline in amphibian populations . The first stages of chytridiomycosis include: inflammation, hyperkeratosis, lethargy, loss of righting reflex, and disruption of internal electrolyte levels leading to eventual death of the host. Previous work indicates that B. dendrobatidis can produce immunomodulatory compounds and other secreted molecules that regulate the growth of the fungus. In this study, filtrates of the fungus grown in media and water were subjected to ultra performance liquid chromatography-mass spectrometry and analyzed using Compound Discoverer 3.0. Identification of cyclo(phenylalanyl-prolyl), chitobiose, and S-adenosylmethionine were verified by their retention times and fragmentation patterns from B. dendrobatidis supernatants. Previous studies have analyzed the effects of B. dendrobatidis on amphibian models, in vitro, or in cell culture. We studied the effects of live B. dendrobatidis cells, spent culture filtrates containing secreted metabolites, and cyclo(pheylalanyl-prolyl) on wax moth larvae ( Galleria mellonella) . Concentrated filtrates caused melanization within 24 hours, while live B. dendrobatidis caused melanization within 48 hours. Our results indicate B. dendrobatidis produces secreted metabolites previously unreported. These findings provide another alternative for the use of a non-amphibian model system to study pathogenicity traits in this fungus.

Phencyclidine, excitatory amino acids, psychiatry and drug abuse: Historical perspectives on clinical-laboratory interactions

1997 ◽  
Vol 9 (2) ◽  
pp. 87-88
Author(s):  
S.R. Zukin
Keyword(s):  
Clinical Observation ◽  
Clinical Laboratory ◽  
Psychiatric Inpatient ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Emergency Rooms ◽  
New Era ◽  
New Class ◽  
Historical Perspectives ◽  
Large Numbers

Some 40 years ago phencyclidine (PCP) was developed as the prototype of a proposed new class of ‘dissociative’ general anesthetics, so called because it induced a marked dissociation from the environment without complete loss of consciousness. In the earliest clinical trials of PCP anesthesia, it was observed that as many as half the subjects experienced severe psychotic reactions during and beyond emergence. This striking clinical observation at once marked the failure of PCP as a suitable general anesthetic, and the beginning of a remarkable new era in basic and clinical neuroscience which can serve as an example of the interaction between clinical observation and basic science. At once, clinical researchers turned their focus upon the characterization of the PCP-induced psychosis, and recognized striking similarities between PCP-induced symptoms and signs and both the negative and positive symptoms of schizophrenia, proposing the PCP psychosis as a new model of that illness. Several years later PCP suddenly emerged as a major drug of abuse, with the result that emergency rooms and psychiatric inpatient units were observing and treating large numbers of these patients, in many of whom a diagnosis of schizophrenia could not be ruled out until toxicological analyses were performed. This natural experiment yielded a huge amount of additional data, and contributed a strong public-health based impetus to research into the nature and treatment of PCP intoxication.

Uniform characterization of potentiation in simple and complex situations when agents bind to different molecular sites

1995 ◽  
Vol 73 (11) ◽  
pp. 1574-1581 ◽  
Author(s):  
G. Pöch ◽  
P. Köck ◽  
R. J. Reiffenstein ◽  
S. N. Pancheva
Keyword(s):  
Dose Response ◽  
Fixed Dose ◽  
Response Curves ◽  
Complex Situation ◽  
Cytopathic Effects ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Infected Cells ◽  
Dose Response Curves ◽  
Independent Effects

There is general agreement about potentiation in dose–response studies, characterized by a left shift of the dose–response curve of A by a fixed dose of B when B is causing no effect by itself (simple situation). When B causes an effect similar to A (complex situation) by binding to different molecular sites, we propose an analogous analysis. This approach is based on comparison of experimental effects of A and B in combination with theoretical, independent effects, representing an effect of A that is not affected by B. We argue here that comparison of experimental effects with those of dose-additive (additive) combinations is inappropriate. Theoretical considerations and several practical examples show that the magnitude of effects due to additive combinations widely varies with the slope of dose–response curves of A. Consequently, it is also shown that one and the same theoretical effect may appear overadditive, additive, or underadditive. These situations are demonstrated by the experimental examples: inhibition of cytopathic effects in virus-infected cells, loss of righting reflex in mice, and smooth muscle relaxant effects of organic solvents.Key words: dose–response curves, ED50, slope, independent effects, enhancement.

scholarly journals Methoxycarbonyl-etomidate

2009 ◽  
Vol 111 (2) ◽  
pp. 240-249 ◽  
Author(s):  
Joseph F. Cotten ◽  
S Shaukat Husain ◽  
Stuart A. Forman ◽  
Keith W. Miller ◽  
Elizabeth W. Kelly ◽  
...  
Keyword(s):  
Half Life ◽  
Human Liver ◽  
Type A ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Loss Of Righting Reflex ◽  
Acid Type ◽  
Righting Reflex ◽  
S9 Fraction

Background Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration. Conclusions MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.

Sign in / Sign up

Export Citation Format

Share Document