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1.
J Neurosci ; 43(28): 5204-5220, 2023 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-37328291

RESUMO

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 Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane.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.


Assuntos
Ritmo Gama , Halotano , Masculino , Feminino , Animais , Retina/fisiologia , Corpos Geniculados/fisiologia , Visão Ocular , Estimulação Luminosa/métodos
2.
J Biol Chem ; 299(8): 104992, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37392848

RESUMO

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.


Assuntos
Halotano , Resposta ao Choque Térmico , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta , Hipertermia Maligna , Animais , Camundongos , Cálcio/metabolismo , Halotano/farmacologia , Resposta ao Choque Térmico/genética , Hipertermia Maligna/genética , Hipertermia Maligna/metabolismo , Hipertermia Maligna/patologia , Músculo Esquelético/metabolismo , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética
3.
Hepatology ; 78(1): 45-57, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36632993

RESUMO

BACKGROUND AND AIM: Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury. APPROACH AND RESULTS: Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury. CONCLUSION: We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Halotano , Hepatócitos , Receptores Depuradores , Receptores Depuradores/metabolismo , Animais , Camundongos , Acetaminofen/toxicidade , Halotano/toxicidade , Fígado/efeitos dos fármacos , Inflamação , Hepatócitos/metabolismo , Homeostase
4.
Paediatr Anaesth ; 34(7): 592-596, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38231007

RESUMO

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.


Assuntos
Anestésicos Inalatórios , Halotano , Humanos , Halotano/farmacologia , Lactente , Recém-Nascido , Criança , Pré-Escolar , Miocárdio/metabolismo , História do Século XX , Hipotensão/induzido quimicamente , Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Parada Cardíaca/induzido quimicamente , Pediatria/métodos , Anestesia Pediátrica
5.
Int J Mol Sci ; 25(6)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38542460

RESUMO

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.


Assuntos
Hipertermia Maligna , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/metabolismo , Halotano/farmacologia , Halotano/metabolismo , Fosforilação Oxidativa , Cálcio/metabolismo , Músculo Esquelético/metabolismo , Suscetibilidade a Doenças/metabolismo , Biópsia , Expressão Gênica , Contração Muscular , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas de Transporte/metabolismo
6.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731919

RESUMO

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.


Assuntos
Anestesia Geral , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Humanos , Mioglobina/química , Ácido Clorídrico/química , Fumaça/efeitos adversos , Anestésicos Inalatórios/química , Hemoglobinas/química , Hemoglobinas/metabolismo , Halotano/química , Sítios de Ligação
7.
Anesthesiology ; 138(2): 209-215, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36629464

RESUMO

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.


Assuntos
Anestesia , Succinilcolina , Animais , Cães , Succinilcolina/farmacologia , Fasciculação , Halotano/farmacologia , Músculos/inervação
8.
Anesthesiology ; 139(1): 63-76, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37027798

RESUMO

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.


Assuntos
Anestésicos Inalatórios , Isoflurano , Canais de Potássio de Domínios Poros em Tandem , Animais , Camundongos , Isoflurano/farmacologia , Halotano/farmacologia , Anestésicos Inalatórios/farmacologia , Camundongos Knockout , Canais de Potássio de Domínios Poros em Tandem/genética , Complexo I de Transporte de Elétrons/genética
9.
Br J Anaesth ; 131(1): 5-8, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37198032

RESUMO

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.


Assuntos
Anestesia , Hipertermia Maligna , Humanos , Hipertermia Maligna/etiologia , Hipertermia Maligna/genética , Halotano , Cafeína , Biópsia
10.
Br J Anaesth ; 131(1): 47-55, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36792386

RESUMO

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.


Assuntos
Hipertermia Maligna , Humanos , Hipertermia Maligna/diagnóstico , Halotano/farmacologia , Cálcio , Fibras Musculares Esqueléticas , Suscetibilidade a Doenças/complicações , Cafeína/farmacologia , Contração Muscular
11.
Anesth Analg ; 136(3): 569-577, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36201369

RESUMO

BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994-2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%-35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%-19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%-90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5-28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene ( RYR1 ) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3-30.9; P = .013). Dantrolene median dose was 50 (25-400) and 200 (25-400) mg·day -1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipertermia Maligna , Rabdomiólise , Humanos , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/tratamento farmacológico , Dantroleno , Estudos Retrospectivos , Mialgia/tratamento farmacológico , Halotano/efeitos adversos , Fadiga/complicações , Rabdomiólise/induzido quimicamente , Rabdomiólise/diagnóstico , Rabdomiólise/complicações
12.
Heart Surg Forum ; 26(6): E905-E916, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38178332

RESUMO

OBJECTIVES: Prolongation of cardiac repolarization, especially the heart rate-corrected QT (QTc) interval, is associated with life-threatening dysrhythmias. This study aimed to identify the anesthetic with the lowest risk of prolonging cardiac repolarization and provide guidance for anesthesia management in patients with cardiac diseases or long QT syndrome. METHODS: Randomized controlled trials (RCTs) comparing the effects of anesthetics on cardiac repolarization indices were searched for in multiple databases. The primary outcome was QTc; and the secondary outcomes were other repolarization indices. A network meta-analysis was conducted using a frequentist approach and registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022304970). RESULTS: Thirteen RCTs investigating 953 adults with normal QTc interval and without cardiovascular diseases were included. Direct meta-analyses found that propofol had less influence than sevoflurane (95% confidence interval (CI): 16.10, 33.54) and desflurane (95% CI: 4.85, 35.36), and sevoflurane had less influence than desflurane (95% CI: 6.96, 19.39) on QTc prolongation. Network analysis found that propofol had less influence than sevoflurane (95% CI: 17.78, 29.63), halothane (95% CI: 11.29, 41.24), desflurane (95% CI: 23.79, 39.88), and isoflurane (95% CI: 20.11, 46.10), and sevoflurane had less influence than desflurane (95% CI: 0.43, 15.82) on QTc prolongation. The rank order of cumulative ranking curve analysis was propofol (100%), sevoflurane (63.8%), halothane (49.5%), desflurane (21.1%), and isoflurane (15.6%). The direct meta-analysis found that propofol had less influence than sevoflurane on QT prolongation (95% CI: 23.12, 57.86). Other secondary outcomes showed no conclusive findings. CONCLUSIONS: This meta-analysis found that propofol had a minimal effect on QTc prolongation, followed by sevoflurane and desflurane in adults with normal QTc interval and without cardiovascular diseases. Propofol is the best anesthetic for adult patients with long QT syndrome or cardiac diseases, but still needs more robust evidence.


Assuntos
Anestésicos Inalatórios , Doenças Cardiovasculares , Isoflurano , Síndrome do QT Longo , Éteres Metílicos , Propofol , Adulto , Humanos , Sevoflurano , Propofol/efeitos adversos , Desflurano , Halotano , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto
13.
Toxicol Ind Health ; 39(2): 67-80, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36602468

RESUMO

Although both can cause DNA damage, the combined impact of volatile anesthetics halothane/sevoflurane/isoflurane and radiotherapeutic exposure on sensitive brain cells in vivo has not been previously analyzed. Healthy Swiss albino male mice (240 in total, 48 groups) were exposed to either halothane/sevoflurane/isoflurane therapeutic doses alone (2 h); 1 or 2 gray of gamma radiation alone; or combined exposure. Frontal lobe brain samples from five animals were taken immediately and 2, 6, and 24 h after exposure. DNA damage and cellular repair index were analyzed using the alkaline comet assay and the tail intensity parameter. Elevated tail intensity levels for sevoflurane/halothane were the highest at 6 h and returned to baseline within 24 h for sevoflurane, but not for halothane, while isoflurane treatment caused lower tail intensity than control values. Combined exposure demonstrated a slightly halothane/sevoflurane protective and isoflurane protective effect, which was stronger for 2 than for 1 gray. Cellular repair indices and tail intensity histograms indicated different modes of action in DNA damage creation. Isoflurane/sevoflurane/halothane preconditioning demonstrated protective effects in sensitive brain cells in vivo. Owing to the constant increases in the combined use of radiotherapy and volatile anesthetics, further studies should explore the mechanisms behind these effects, including longer and multiple exposure treatments and in vivo brain tumor models.


Assuntos
Anestésicos Inalatórios , Isoflurano , Éteres Metílicos , Camundongos , Animais , Sevoflurano/farmacologia , Isoflurano/farmacologia , Anestésicos Inalatórios/farmacologia , Halotano/farmacologia , Éteres Metílicos/farmacologia , Raios gama/efeitos adversos , Encéfalo
14.
Int J Mol Sci ; 24(3)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36768163

RESUMO

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.


Assuntos
Anestésicos Inalatórios , Anestésicos , Isoflurano , Animais , Drosophila melanogaster/genética , Halotano/farmacologia , Anestésicos Inalatórios/farmacologia , Éter , Elétrons , Isoflurano/farmacologia , Mutação , Drosophila , Éteres , Complexo I de Transporte de Elétrons/genética , Etil-Éteres , Mamíferos
15.
Anesthesiology ; 136(5): 823-826, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35180293

RESUMO

Effect of Nitrous Oxide and of Narcotic Premedication on the Alveolar Concentration Required for Anesthesia. By , Eger EI II. Anesthesiology 1964; 25:302-6. Hyperthermia during Anesthesia. By Saidman LJ, Havard ES, Eger EI II. JAMA 1964; 190:1029-32. The minimum alveolar concentration (MAC) of an inhaled anesthetic preventing movement in response to a surgical incision as a measure of equipotency was "invented" in 1964 at the University of California, San Francisco. The principal advantage of MAC is that it allows the pharmacologic effects of inhaled anesthetics to be compared against each other at a similar anesthetic depth. Thus, if the hemodynamic effect (hypotension, decreased cardiac output) of anesthetic "A" is greater than that of anesthetic "B," the anesthesiologist may elect to use "A" in patients with myocardial dysfunction. A rare side effect of a volatile anesthetic is that in some patients, malignant hyperthermia may occur with or without succinylcholine use. This phenomenon was detected in a patient in whom halothane MAC was being measured. The availability of the Severinghaus blood gas device allowed for the first ever measurement of the metabolic and respiratory acidemia that accompanies malignant hyperthermia.


Assuntos
Anestésicos Inalatórios , Isoflurano , Hipertermia Maligna , Anestésicos Inalatórios/farmacologia , Halotano/farmacologia , Hemodinâmica , Humanos , Isoflurano/farmacologia , Óxido Nitroso
16.
J Pharmacol Sci ; 148(4): 343-350, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35300808

RESUMO

Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.


Assuntos
Halotano , Síndrome do QT Longo , Animais , Arritmias Cardíacas/induzido quimicamente , Cães , Halotano/efeitos adversos , Ventrículos do Coração , Humanos , Síndrome do QT Longo/induzido quimicamente , Memantina/efeitos adversos
17.
J Pharmacol Sci ; 150(3): 154-162, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36184120

RESUMO

Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4). Effects of imatinib on each phase of isovolumetric contraction, ejection, isovolumetric relaxation and filling were studied, whereas its electrophysiological effects on early and late repolarization were analyzed by measuring J-Tpeak and Tpeak-Tend, respectively. The low and high doses of imatinib provided peak plasma concentrations of 3.23 and 17.39 µg/mL, reflecting clinically-relevant and supratherapeutic concentrations, respectively. Neither lethal ventricular tachyarrhythmia nor cardiohemodynamic collapse was observed. Imatinib decreased amplitude of peak -dP/dt, indicating suppression of isovolumetric relaxation, whereas no significant change was detected in the other phases. Imatinib prolonged QTc and J-Tpeakc without altering Tpeak-Tend, indicating increase of net inward current, which leads to intracellular Ca2+ overload. Thus, imatinib suppressed ventricular active relaxation and early repolarization, which may suggest the association of mitochondrial dysfunction-associated inhibition of ATP production. Since those findings were also reported for dasatinib, sunitinib and lapatinib, they could be common cardiac phenotype of tyrosine kinase inhibitors in vivo.


Assuntos
Halotano , Inibidores de Proteínas Quinases , Trifosfato de Adenosina , Animais , Biomarcadores , Dasatinibe , Cães , Halotano/farmacologia , Mesilato de Imatinib/farmacologia , Lapatinib , Inibidores de Proteínas Quinases/efeitos adversos , Sunitinibe
18.
Heart Vessels ; 37(10): 1808-1815, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35426504

RESUMO

Elevation of the head and expiratory negative airway pressure (ENAP) ventilation can both significantly alter cardiovascular hemodynamics. The impact of head-up tilt (HUT) position on mechanically regulated ENAP ventilation-induced hemodynamics was assessed in microminipigs under halothane anesthesia (n = 4) in the absence and presence of adrenergic blockade. Supine ENAP ventilation increased cardiac output, but decreased mean right atrial, systolic pulmonary arterial, and mean left atrial pressures without significantly altering heart rate or aortic pressure. With HUT, the magnitude of ENAP ventilation-induced reduction in right and left atrial pressures was attenuated. HUT minimally altered ENAP ventilation-induced increase in cardiac output and reduction in pulmonary arterial systolic pressure. In addition, with up to 10 cm of HUT there was a significant increase in mean right atrial pressure with and without the ENAP ventilation, whereas HUT did not alter the other hemodynamic variables irrespective of ENAP ventilation. These observations suggest that head elevation augments venous return from the brain irrespective of the ENAP ventilation. Additional studies with pharmacological adrenergic blockade revealed that ENAP ventilation-induced increases in cardiac output and decreases in pulmonary systolic pressure were minimally altered by sympathetic nerve activity, irrespective of the head position. However, the observed ENAP ventilation-induced decreases in right and left atrial pressures were largely dependent upon adrenergic activity. These experimental findings may provide insight into future clinical application of HUT and ENAP for patients with head injury and hypotension.


Assuntos
Halotano , Hipertensão Pulmonar , Adrenérgicos , Pressão Sanguínea/fisiologia , Halotano/farmacologia , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Humanos
19.
Int J Mol Sci ; 23(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36012286

RESUMO

Cell-cell communication via gap junction channels is known to be inhibited by the anesthetics heptanol, halothane and isoflurane; however, despite numerous studies, the mechanism of gap junction channel gating by anesthetics is still poorly understood. In the early nineties, we reported that gating by anesthetics is strongly potentiated by caffeine and theophylline and inhibited by 4-Aminopyridine. Neither Ca2+ channel blockers nor 3-isobutyl-1-methylxanthine (IBMX), forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester or H7 had significant effects on gating by anesthetics. In our publication, we concluded that neither cytosolic Ca2+i nor pHi were involved, and suggested a direct effect of anesthetics on gap junction channel proteins. However, while a direct effect cannot be excluded, based on the potentiating effect of caffeine and theophylline added to anesthetics and data published over the past three decades, we are now reconsidering our earlier interpretation and propose an alternative hypothesis that uncoupling by heptanol, halothane and isoflurane may actually result from a rise in cytosolic Ca2+ concentration ([Ca2+]i) and consequential activation of calmodulin linked to gap junction proteins.


Assuntos
Anestésicos Inalatórios , Anestésicos , Isoflurano , Anestésicos/farmacologia , Anestésicos Inalatórios/farmacologia , Cafeína/metabolismo , Cafeína/farmacologia , Cálcio/metabolismo , Calmodulina/metabolismo , Comunicação Celular , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Halotano/metabolismo , Halotano/farmacologia , Heptanol/metabolismo , Canais Iônicos/metabolismo , Isoflurano/farmacologia , Teofilina/farmacologia
20.
J Perianesth Nurs ; 37(4): 435-444, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35414440

RESUMO

Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with RYR1, CACNA1S, or STAC3 mutations. And these genetic abnormalities often cause the imperfection of calcium release channels of skeletal muscle. The incidence of MH among different racial groups across the world ranges from approximately 1:5,000-1:250,000, but there is no national statistic MH incidence in China. It is not clear whether there are racial or regional differences in the incidence, but patients under 18 years old may be more affected. MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, "5C principles" were summarized as an algorithm to guide clinicians.


Assuntos
Hipertermia Maligna , Adolescente , Cafeína , China , Halotano , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/terapia , Mutação
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