ABSTRACT
Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.
Subject(s)
Anesthetics, Inhalation , Halothane , Heart Rate , Morphine , Animals , Dogs , Morphine/administration & dosage , Heart Rate/drug effects , Anesthetics, Inhalation/administration & dosage , Anesthetics, Inhalation/pharmacokinetics , Male , Toxicokinetics , Dose-Response Relationship, Drug , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Blood Pressure/drug effects , Electrocardiography/drug effects , Female , Infusions, Intravenous , Vasodilation/drug effects , Electrophysiological Phenomena/drug effectsABSTRACT
Smoke intoxication is a central event in mass burn incidents, and toxic smoke acts at different levels of the body, blocking breathing and oxygenation. The majority of these patients require early induction of anesthesia to preserve vital functions. We studied the influence of hemoglobin (HMG) and myoglobin (MGB) blockade by hydrochloric acid (HCl) in an interaction model with gaseous anesthetics using molecular docking techniques. In the next part of the study, molecular dynamics (MD) simulations were performed on the top-scoring ligand-receptor complexes to investigate the stability of the ligand-receptor complexes and the interactions between ligands and receptors in more detail. Through docking analysis, we observed that hemoglobin creates more stable complexes with anesthetic gases than myoglobin. Intoxication with gaseous hydrochloric acid produces conformational and binding energy changes of anesthetic gases to the substrate (both the pathway and the binding site), the most significant being recorded in the case of desflurane and sevoflurane, while for halothane and isoflurane, they remain unchanged. According to our theoretical model, the selection of anesthetic agents for patients affected by fire smoke containing hydrochloric acid is critical to ensure optimal anesthetic effects. In this regard, our model suggests that halothane and isoflurane are the most suitable choices for predicting the anesthetic effects in such patients when compared to sevoflurane and desflurane.
Subject(s)
Anesthesia, General , Molecular Docking Simulation , Molecular Dynamics Simulation , Humans , Myoglobin/chemistry , Hydrochloric Acid/chemistry , Smoke/adverse effects , Anesthetics, Inhalation/chemistry , Hemoglobins/chemistry , Hemoglobins/metabolism , Halothane/chemistry , Binding SitesABSTRACT
Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, n = 8) and non-susceptible controls (MHN, n = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: n = 36; MHS: n = 36) validated the reduced expression of ATP5MD and COQ6 in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in SDHB and UQCC3 expression, and a difference in ATP5MD expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHSh (n = 4); trigger to both in vitro halothane and caffeine exposure, MHShc (n = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.
Subject(s)
Malignant Hyperthermia , Humans , Malignant Hyperthermia/genetics , Malignant Hyperthermia/metabolism , Halothane/pharmacology , Halothane/metabolism , Oxidative Phosphorylation , Calcium/metabolism , Muscle, Skeletal/metabolism , Disease Susceptibility/metabolism , Biopsy , Gene Expression , Muscle Contraction , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Carrier Proteins/metabolismABSTRACT
Previous results show that halothane gas anaesthesia has a suppressive effect on the visually evoked single-cell activities in the feline caudate nucleus (CN). In this study, we asked whether the low-frequency neuronal signals, the local field potentials (LFP) are also suppressed in the CN of anaesthetized animals.To answer this question, we compared the LFPs recorded from the CN of two halothane-anaesthetized (1.0%), paralyzed, and two awake, behaving cats during static and dynamic visual stimulation. The behaving animals were trained to perform a visual fixation task.Our results denoted a lower proportion of significant power changes to visual stimulation in the CN of the anesthetized cats in each frequency range (from delta to beta) of the LFPs, except gamma. These differences in power changes were more obvious in static visual stimulation, but still, remarkable differences were found in dynamic stimulation, too. The largest differences were found in the alpha and beta frequency bands for static stimulation. Concerning dynamic stimulation, the differences were the biggest in the theta, alpha and beta bands.Similar to the single-cell activities, remarkable differences were found between the visually evoked LFP changes in the CN of the anaesthetized, paralyzed and awake, behaving cats. The halothane gas anaesthesia and the immobilization suppressed the significant LFP power alterations in the CN to both static and dynamic stimulation. These results suggest the priority of the application of behaving animals even in the analysis of the visually evoked low-frequency electric signals, the LFPs recorded from the CN.
Subject(s)
Caudate Nucleus , Wakefulness , Cats , Animals , Caudate Nucleus/physiology , Wakefulness/physiology , Halothane , Photic Stimulation/methods , Neurons/physiologyABSTRACT
Introduced in the late 1950s, halothane became the anesthetic of choice for inhalational induction of children for over 40 years. Halothane enjoyed a generally favorable safety record during its time, but its cardiac contractility depressant effect-well tolerated by most age groups-was profoundly heightened in neonates and infants, leading to increased incidences of hypotension and cardiac arrest. The neonatal myocardium is immature and is characterized by poor ventricular compliance, poor contractility due to fewer contractile elements, immature sympathetic innervation with decreased norepinephrine stores, and immature mechanisms for storage and exchange of calcium in the sarcoplasmic reticulum. In vitro studies of myocardial contractility of mammalian fetal and adult myocardium demonstrated that the fetal heart was twice as sensitive to halothane as the adult. Clinical studies demonstrated that most neonates and infants less than 6 months of age experienced hypotension during halothane induction of anesthesia and significantly (p < .01) greater decreases in blood pressure than older children at equipotent concentrations of halothane. Intraoperative cardiac arrest during the halothane era occurred over twice as frequently in neonates aged less than 1 month than in infants aged 1-12 months and nearly 10 times more frequently than children 1-5 years of age. Halothane was associated with 66% of intraoperative drug-related cardiac arrests in children. The halothane era began to close in the late 1990s with the introduction of sevoflurane, which had a more favorable hemodynamic profile. Shortly thereafter, halothane was completely displaced from pediatric anesthesia practice in North America.
Subject(s)
Anesthetics, Inhalation , Halothane , Humans , Halothane/pharmacology , Infant , Infant, Newborn , Child , Child, Preschool , Myocardium/metabolism , History, 20th Century , Hypotension/chemically induced , Heart/drug effects , Myocardial Contraction/drug effects , Heart Arrest/chemically induced , Pediatrics/methods , Pediatric AnesthesiaSubject(s)
Malignant Hyperthermia , Animals , Mice , Malignant Hyperthermia/genetics , Calcium , HalothaneABSTRACT
Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.
Subject(s)
Halothane , Proton Pump Inhibitors , Dogs , Animals , Proton Pump Inhibitors/toxicity , Rabeprazole , Omeprazole/toxicity , Lansoprazole/toxicityABSTRACT
Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.
Subject(s)
Halothane , Heat-Shock Response , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits , Malignant Hyperthermia , Animals , Mice , Calcium/metabolism , Halothane/pharmacology , Heat-Shock Response/genetics , Malignant Hyperthermia/genetics , Malignant Hyperthermia/metabolism , Malignant Hyperthermia/pathology , Muscle, Skeletal/metabolism , Mutation , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/geneticsABSTRACT
Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies conducted under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multielectrode recordings of spiking activity in the retina and the LGN of both male and female cats, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were nonoscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent on halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision.SIGNIFICANCE STATEMENT Gamma rhythms have been proposed to be a robust encoding mechanism critical for visual processing. In the retinogeniculate system of the cat, many studies have shown gamma oscillations associated with responses to static stimuli. Here, we extend these observations to dynamic stimuli. An unexpected finding was that retinal gamma responses strongly depend on halothane concentration levels and are absent in the awake cat. These results weaken the notion that gamma in the retina is relevant for vision. Notably, retinal gamma shares many of the properties of cortical gamma. In this respect, oscillations induced by halothane in the retina may serve as a valuable preparation, although artificial, for studying oscillatory dynamics.
Subject(s)
Gamma Rhythm , Halothane , Male , Female , Animals , Retina/physiology , Geniculate Bodies/physiology , Vision, Ocular , Photic Stimulation/methodsABSTRACT
The molecular mechanisms of susceptibility to malignant hyperthermia are complex. The malignant hyperthermia susceptibility phenotype should be reserved for patients who have a personal or family history consistent with malignant hyperthermia under anaesthesia and are subsequently demonstrated through diagnostic testing to be at risk.
Subject(s)
Anesthesia , Malignant Hyperthermia , Humans , Malignant Hyperthermia/etiology , Malignant Hyperthermia/genetics , Halothane , Caffeine , BiopsyABSTRACT
As the number of radiotherapy and radiology diagnostic procedures increases from year to year, so does the use of general volatile anaesthesia (VA). Although considered safe, VA exposure can cause different adverse effects and, in combination with ionising radiation (IR), can also cause synergistic effects. However, little is known about DNA damage incurred by this combination at doses applied in a single radiotherapy treatment. To learn more about it, we assessed DNA damage and repair response in the liver tissue of Swiss albino male mice following exposure to isoflurane (I), sevoflurane (S), or halothane (H) alone or in combination with 1 or 2 Gy irradiation using the comet assay. Samples were taken immediately (0 h) and 2, 6, and 24 h after exposure. Compared to control, the highest DNA damage was found in mice receiving halothane alone or in combination with 1 or 2 Gy IR treatments. Sevoflurane and isoflurane displayed protective effects against 1 Gy IR, while with 2 Gy IR the first adverse effects appeared at 24 h post-exposure. Although VA effects depend on liver metabolism, the detection of unrepaired DNA damage 24 h after combined exposure with 2 Gy IR indicates that we need to look further into the combined effects of VA and IR on genome stability and include a longer time frame than 24 h for single exposure as well as repeated exposure as a more realistic scenario in radiotherapy treatment.
Subject(s)
Anesthetics, Inhalation , Isoflurane , Animals , Mice , Sevoflurane/pharmacology , Halothane/toxicity , DNA Damage , Anesthetics, Inhalation/toxicity , LiverABSTRACT
BACKGROUND: A variety of molecular targets for volatile anesthetics have been suggested, including the anesthetic-sensitive potassium leak channel, TREK-1. Knockout of TREK-1 is reported to render mice resistant to volatile anesthetics, making TREK-1 channels compelling targets for anesthetic action. Spinal cord slices from mice, either wild type or an anesthetic- hypersensitive mutant, Ndufs4, display an isoflurane-induced outward potassium leak that correlates with their minimum alveolar concentrations and is blocked by norfluoxetine. The hypothesis was that TREK-1 channels conveyed this current and contribute to the anesthetic hypersensitivity of Ndufs4. The results led to evaluation of a second TREK channel, TREK-2, in control of anesthetic sensitivity. METHODS: The anesthetic sensitivities of mice carrying knockout alleles of Trek-1 and Trek-2, the double knockout Trek-1;Trek-2, and Ndufs4;Trek-1 were measured. Neurons from spinal cord slices from each mutant were patch clamped to characterize isoflurane-sensitive currents. Norfluoxetine was used to identify TREK-dependent currents. RESULTS: The mean values for minimum alveolar concentrations (± SD) between wild type and two Trek-1 knockout alleles in mice (P values, Trek-1 compared to wild type) were compared. For wild type, minimum alveolar concentration of halothane was 1.30% (0.10), and minimum alveolar concentration of isoflurane was 1.40% (0.11); for Trek-1tm1Lex, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.387), and minimum alveolar concentration of isoflurane was 1.38% (0.09; P = 0.268); and for Trek-1tm1Lzd, minimum alveolar concentration of halothane was 1.27% (0.11; P = 0.482), and minimum alveolar concentration of isoflurane was 1.41% (0.12; P = 0.188). Neither allele was resistant for loss of righting reflex. The EC50 values of Ndufs4;Trek-1tm1Lex did not differ from Ndufs4 (for Ndufs4, EC50 of halothane, 0.65% [0.05]; EC50 of isoflurane, 0.63% [0.05]; and for Ndufs4;Trek-1tm1Lex, EC50 of halothane, 0.58% [0.07; P = 0.004]; and EC50 of isoflurane, 0.61% [0.06; P = 0.442]). Loss of TREK-2 did not alter anesthetic sensitivity in a wild-type or Trek-1 genetic background. Loss of TREK-1, TREK-2, or both did not alter the isoflurane-induced currents in wild-type cells but did cause them to be norfluoxetine insensitive. CONCLUSIONS: Loss of TREK channels did not alter anesthetic sensitivity in mice, nor did it eliminate isoflurane-induced transmembrane currents. However, the isoflurane-induced currents are norfluoxetine-resistant in Trek mutants, indicating that other channels may function in this role when TREK channels are deleted.
Subject(s)
Anesthetics, Inhalation , Isoflurane , Potassium Channels, Tandem Pore Domain , Animals , Mice , Isoflurane/pharmacology , Halothane/pharmacology , Anesthetics, Inhalation/pharmacology , Mice, Knockout , Potassium Channels, Tandem Pore Domain/genetics , Electron Transport Complex I/geneticsABSTRACT
Abstract Introduction Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. Objective To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. Methods We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). Results Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). Conclusions Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Young Adult , Contracture/diagnosis , Disease Susceptibility/diagnosis , Malignant Hyperthermia/diagnosis , Brazil , Caffeine , Muscle, Skeletal , Muscle Weakness , Halothane , Muscle ContractionABSTRACT
Abstract Background Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered by halogenated anesthesia agents/succinylcholine and characterized by hypermetabolism crisis during anesthesia, but also by day-to-day symptoms, such as exercise intolerance, that may alert the health professional. Objective The study aimed to analyze the incidence of fatigue in MH susceptible patients and the variables that can impact perception of fatigue, such as the level of routine physical activity and depression. Methods A cross-sectional observational study was carried out with three groups - 22 patients susceptible to MH (positive in vitro muscle contracture test), 13 non-susceptible to MH (negative in vitro muscle contracture test) and 22 controls (no history of MH). Groups were assessed by a demographic/clinical questionnaire, a fatigue severity scale (intensity, specific situations, psychological consequences, rest/sleep response), and the Beck depression scale. Subgroups were re-assessed with the Baecke habitual physical exercise questionnaire (occupational physical activity, leisure physical exercise, leisure/locomotion physical activity). Results There were no significant differences among the three groups regarding fatigue intensity, fatigue related to specific situations, psychological consequences of fatigue, fatigue response to resting/sleeping, depression, number of active/sedentary participants, and the mean time and characteristics of habitual physical activity. Nevertheless, unlike the control sub-group, the physically active MH-susceptible subgroup had a higher fatigue response to resting/sleeping than the sedentary MH susceptible subgroup (respectively, 5.9 ± 1.9 vs. 3.9 ± 2, t-test unpaired, p< 0.05). Conclusion We did not detect subjective fatigue in MH susceptible patients, although we reported protracted recovery after physical activity, which may alert us to further investigation requirements.
Subject(s)
Humans , Contracture , Malignant Hyperthermia/diagnosis , Malignant Hyperthermia/epidemiology , Exercise , Cross-Sectional Studies , Depression , Disease Susceptibility/diagnosis , HalothaneABSTRACT
The induction of ischemic stroke in the experimental model requires general anesthesia. One of the factors that can be effective in the size of ischemic brain lesions and neurological outcomes is the type of anesthesia. So, the current study was designed to compare the impacts of the most important and widely used anesthetics including halothane, isoflurane, and chloral hydrate on the transient middle cerebral artery occlusion (MCAO) outcomes. Adult Male Sprague-Dawley rats were randomly divided into three groups as follows: (1) MCAO + halothane group, (2) MCAO + isoflurane group, and (3) MCAO + chloral hydrate group. After 24 h, the mortality rate, infarct size, tissue swelling, neurological function, hemodynamic, and arterial blood gas parameters were assessed. Our finding showed that 60 min MCAO rats anesthetized with chloral hydrate significantly increased mortality rate, infarct size, tissue swelling, and neurological deficits compared with halothane and isoflurane anesthetics after 24 h of MCAO. Also, chloral hydrate caused a significant decrease in mean arterial pressure and arterial pO2 compared to halothane and isoflurane anesthetics. On the basis of the current data, we concluded that chloral hydrate increased cerebral infarct volume and neurological outcomes and reduced hemodynamic and metabolic parameters compared with halothane and isoflurane-anesthetized rats temporal MCAO.
Subject(s)
Anesthetics , Brain Ischemia , Isoflurane , Rats , Male , Animals , Halothane/pharmacology , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/pathology , Isoflurane/pharmacology , Rats, Sprague-Dawley , Chloral Hydrate/pharmacology , HemodynamicsABSTRACT
BACKGROUND: Most patients with malignant hyperthermia susceptibility diagnosed by the in vitro caffeine-halothane contracture test (CHCT) develop excessive force in response to halothane but not caffeine (halothane-hypersensitive). Hallmarks of halothane-hypersensitive patients include high incidence of musculoskeletal symptoms at rest and abnormal calcium events in muscle. By measuring sensitivity to halothane of myotubes and extending clinical observations and cell-level studies to a large group of patients, we reach new insights into the pathological mechanism of malignant hyperthermia susceptibility. METHODS: Patients with malignant hyperthermia susceptibility were classified into subgroups HH and HS (positive to halothane only and positive to both caffeine and halothane). The effects on [Ca2+]cyto of halothane concentrations between 0.5 and 3 % were measured in myotubes and compared with CHCT responses of muscle. A clinical index that summarises patient symptoms was determined for 67 patients, together with a calcium index summarising resting [Ca2+]cyto and spontaneous and electrically evoked Ca2+ events in their primary myotubes. RESULTS: Halothane-hypersensitive myotubes showed a higher response to halothane 0.5% than the caffeine-halothane hypersensitive myotubes (P<0.001), but a lower response to higher concentrations, comparable with that used in the CHCT (P=0.055). The HH group had a higher calcium index (P<0.001), but their clinical index was not significantly elevated vs the HS. Principal component analysis identified electrically evoked Ca2+ spikes and resting [Ca2+]cyto as the strongest variables for separation of subgroups. CONCLUSIONS: Enhanced sensitivity to depolarisation and to halothane appear to be the primary, mutually reinforcing and phenotype-defining defects of halothane-hypersensitive patients with malignant hyperthermia susceptibility.
Subject(s)
Malignant Hyperthermia , Humans , Malignant Hyperthermia/diagnosis , Halothane/pharmacology , Calcium , Muscle Fibers, Skeletal , Disease Susceptibility/complications , Caffeine/pharmacology , Muscle ContractionABSTRACT
The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The ND-2360114 and mt:ND2del1 lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. ND-2360114 flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i) ND-2360114 and mt:ND2del1 were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.
Subject(s)
Anesthetics, Inhalation , Anesthetics , Isoflurane , Animals , Drosophila melanogaster/genetics , Halothane/pharmacology , Anesthetics, Inhalation/pharmacology , Ether , Electrons , Isoflurane/pharmacology , Mutation , Drosophila , Ethers , Electron Transport Complex I/genetics , Ethyl Ethers , MammalsABSTRACT
The objective of this study was to determine if ractopamine (RAC) impacts postmortem muscle metabolism and subsequent pork quality in Halothane (HAL) and Rendement Napole (RN) mutant pigs. All RAC fed pigs had increased (P < 0.04) L* values. HAL and RN mutants muscle had lower (P < 0.01) pH values but RAC feeding had no effect. RN mutants had higher and lower (P < 0.05) muscle pH and temperatures, respectfully at 15 min and RN mutant pigs had greater (P < 0.0001) glycogen initially but lactate levels similar to wild type (WT) pigs at 24 h. RAC lowered (P < 0.05) glycogen in RN mutants but not in HAL mutated or WT pig muscle. These data show RAC feeding changes postmortem energy metabolism but does not change pH and pork quality hallmark of two major pig gene mutations and supports our contention that ultimate meat quality traits and their biochemical drivers may be more complex than originally reasoned.