RESUMEN
BACKGROUND: Verbal working memory (WM), which relies on intact functioning of frontostriatal circuits, has been suggested as a cognitive domain that is preferentially affected in HIV-1 infection. Although several studies have found WM impairments in HIV-1 infected patients, Baddeley's classic WM model has not been studied extensively in this population. METHODS: We used two cognitive neuropsychological approaches to examine verbal WM deficits in 18 HIV-1 seronegative, 16 HIV-1 asymptomatic, and 20 HIV-1 symptomatic patients. First, based on Baddeley's WM model of the Phonological Loop, we used the phonological similarity effect and the irrelevant speech effect to evaluate each individual's phonological store, and the word-length effect and the articulatory suppression effect to evaluate the articulatory control process. Secondly, an individual differences approach, which focuses on the capacity limitation of the WM system and potentially integrates the functions of Baddeley's Central Executive component with the Phonological Loop, was adopted. We evaluated each patient's simultaneous storage and processing of auditory material using the Verbal Memory Span test. RESULTS: The HIV-1 symptomatic individuals, but not the HIV-1 asymptomatic subjects, demonstrated impaired short-term storage of verbal material in the phonological store on Baddeley's measures. Although the HIV-1 asymptomatic and symptomatic subjects demonstrated intact rehearsal of speech-based material in the articulatory control process, both groups demonstrated impairment on the Verbal Memory Span test. CONCLUSIONS: These findings suggest that deficits in simultaneous short-term storage and processing occur during both early and later stages of HIV-1 infection.
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Seropositividad para VIH/psicología , Trastornos de la Memoria/diagnóstico , Conducta Verbal , Adulto , Antígenos CD4/inmunología , Comorbilidad , Femenino , Seropositividad para VIH/epidemiología , Seropositividad para VIH/inmunología , Humanos , Masculino , Trastornos de la Memoria/epidemiología , Pruebas Neuropsicológicas , Percepción del HablaRESUMEN
Problem-solving expertise has been associated with enhanced memory of domain-specific information. This enhanced memory is thought to play an important role in expert decisions. Meanwhile, research on psychodiagnostic decision making has found consistent limitations in experienced clinicians' ability to make optimal decisions. To what extent are these limitations associated with suboptimal memory processes? We compared memories of expert clinicians and novice graduate students for information learned while viewing a videotaped psychodiagnostic interview. Results of 3 tests suggest that expert clinicians exhibit enhanced memory that is flexible, selective, and accurate but with limitations that might contribute to poor decisions. Experts exhibited superior memory of personal criteria and disconfirmatory information. However, a framing manipulation induced performance in experts consistent with suboptimal decision making, and both groups needed exhaustive prompts for optimal memory search. Implications of these findings for expertise models are discussed.
Asunto(s)
Testimonio de Experto , Memoria , Trastornos Mentales/diagnóstico , Solución de Problemas , Competencia Profesional/estadística & datos numéricos , Escalas de Valoración Psiquiátrica , Adulto , Sesgo , Humanos , Grabación de Cinta de VideoRESUMEN
Transfer-appropriate processing (TAP), as applied to implicit memory, has tended to emphasize general forms of processing (e.g., perceptual or conceptual processing). In the present studies, the TAP principle was employed in a more specific manner in order to more precisely assess the relations between the processing engaged during first exposure and that engaged during second exposure to items. Thirteen experiments used a two-phase, cross-task design in which participants engaged in different combinations of seven specific intentional tasks between Phase 1 and Phase 2. Maximum repetition priming was found when tasks were the same in Phases 1 and 2. When Phase 1 and Phase 2 tasks differed, there were lesser, or no, repetition priming effects, depending on the particular combination of tasks. The results demonstrate the importance of the specific intentional processes engaged during repetition priming and the potential heuristic value of TAP, as a principle and methodology, for exploring the organization of memory and related process models.
Asunto(s)
Atención , Toma de Decisiones , Práctica Psicológica , Semántica , Transferencia de Experiencia en Psicología , Aprendizaje Verbal , Adulto , Formación de Concepto , Femenino , Humanos , Masculino , PsicolingüísticaRESUMEN
Plasma membrane Ca2+-ATPase (PMCA), a regulator of intracellular calcium, is inhibited by volatile anesthetics and by xenon and nitrous oxide. Response of a cellular system to anesthetics, particularly to volatile agents, raises the question of non-specific, even toxic, side effects unrelated to anesthetic action. Compounds with chemical and physical properties similar to halogenated anesthetics, but which lack anesthetic effect, have been used to address this question. We have compared the effects of halothane and flurothyl, a non-anesthetic fluorinated ether, on PMCA Ca2+ transport across isolated brain synaptic plasma membranes (SPM). Flurothyl, at concentrations predicted by the Meyer-Overton curve to range from 0.4 to 2.6 MAC (minimum alveolar concentration), had no significant on PMCA activity. In contrast halothane, 1.3 MAC, reduced Ca2+ transport 30 to 40%. These findings provide further evidence for a specific effect of inhalation anesthetics on neuronal plasma membrane Ca2+-ATPase.
Asunto(s)
Anestésicos por Inhalación/farmacología , Encéfalo/enzimología , ATPasas Transportadoras de Calcio/efectos de los fármacos , Flurotilo/farmacología , Membranas Sinápticas/enzimología , Animales , Encéfalo/efectos de los fármacos , Calcio/metabolismo , Halotano/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Many inhalation anesthetics at clinically relevant concentrations inhibit plasma membrane Ca2+-adenosine triphosphatase (PMCA) ion pumping in brain synaptic membranes and in cultured cells of neural origin. In this study, the authors investigated the effect of inhalation anesthetics on cytosolic calcium homeostasis in cortical neurons maintained at physiologic and room temperatures and on cortical neurons and pheochromocytoma cells with antisense blockade of specific PMCA isoforms. METHODS: Using Ca2+-specific confocal microfluorimetry, the anesthetic effects on Ca2+ dynamics were examined in mouse embryonic cortical neurons in association with ligand-stimulated Ca2+ influx. Studies were done at 21 degrees C and 37 degrees C. Mouse embryonic cortical neurons with oligodeoxyribonucleotide blockade of PMCA2 expression and transfected rat pheochromocytoma cells with blocked expression of PMCA1 were also examined. RESULTS: Baseline and poststimulation peak cytosolic calcium concentrations ([Ca2+]i) were increased, and Ca2+ clearance was delayed in cells exposed at 37 degrees C, but not at 21 degrees C, to concentrations < or = 1 minimum alveolar concentration (MAC)-equivalent of halothane, isoflurane, and sevoflurane. Neurons exposed to xenon solutions < or = 0.4, 0.6, and 0.8 MAC showed dose-related perturbations of cytosolic Ca2+. Calcium dynamics were altered in neural cells with blocked PMCA isoform production, but at much lower halothane concentrations: 0.5 MAC for cortical neurons and 0.1 MAC for pheochromocytoma cells. CONCLUSIONS: By extruding Ca2+ through the plasma membrane, PMCA maintains resting neuronal [Ca2+]i at low levels and clears physiologic loads of Ca2+ after influx through calcium channels. Inhalation anesthetics perturb this process and thus may interfere with neurotransmitter release, altering interneuronal signaling.
Asunto(s)
Anestésicos por Inhalación/farmacología , ATPasas Transportadoras de Calcio/metabolismo , Calcio/metabolismo , Halotano/farmacología , Isoflurano/farmacología , Éteres Metílicos/farmacología , Neuronas/fisiología , Animales , Membrana Celular/metabolismo , Células Cultivadas , Electrofisiología , Transporte Iónico/efectos de los fármacos , Ratones , Neuronas/ultraestructura , Ratas , Sevoflurano , TemperaturaRESUMEN
Halothane inhibits neural plasma membrane Ca(2+)-ATPase, a pump that ejects Ca2+ from the cell after influx through voltage- or ligand-activated channels. Intracellular microelectrode recordings in mouse embryonic cortical and spinal cord neurons showed that halothane and eosin, a pump inhibitor, prolonged repolarization associated with spontaneous bursts of depolarization. These agents also prolonged the repolarization phases of electrically induced action potentials and of capsaicin-mediated Ca(2+)-dependent depolarization in mouse adult dorsal root ganglion neurons. In keeping with these findings, confocal microfluorimetry showed that halothane delayed clearance of intracellular Ca2+ accumulated by N-methyl-D-aspartate stimulation of single neurons.
Asunto(s)
Anestésicos por Inhalación/farmacología , Calcio/metabolismo , Halotano/farmacología , Neuronas/efectos de los fármacos , Animales , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Capsaicina/farmacología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/enzimología , Corteza Cerebral/citología , Electrofisiología , Eosina Amarillenta-(YS)/farmacología , Técnica del Anticuerpo Fluorescente Indirecta , Colorantes Fluorescentes/farmacología , Ganglios Espinales/citología , Activación del Canal Iónico/fisiología , Ratones , Microelectrodos , Neuronas/enzimología , Médula Espinal/citología , Tetrodotoxina/farmacologíaRESUMEN
BACKGROUND: Halothane can be reductively metabolized to free radical intermediates that may initiate lipid peroxidation. Hypoxia and phenobarbital pretreatment in Sprague-Dawley rats increases reductive metabolism of halothane. F(2)-isoprostanes, a novel measure of lipid peroxidation in vivo, were used to quantify halothane-induced lipid peroxidation in rats. METHODS: Rats were exposed to 1% halothane or 14% O(2) for 2 h. Pretreatments included phenobarbital, isoniazid, or vehicle. Rats also were exposed to halothane, enflurane, and desflurane at 21% O(2). Lipid peroxidation was assessed by mass spectrometric quantification of F(2)-isoprostanes. RESULTS: Exposure of phenobarbital-pretreated rats to 1% halothane at 21% O(2) for 2 h caused liver and plasma F(2)-isoprostane concentrations to increase fivefold compared to nonhalothane control rats. This halothane-induced increase was enhanced by 14% O(2), but hypoxia alone had no significant effect. Alanine aminotransferase activity at 24 h was significantly increased only in the 1% halothane/14% O(2) group. The effect of cytochrome P450 enzyme induction on halothane-induced F(2)-isoprostane production and liver injury was determined by comparing the effects of isoniazid and phenobarbital pretreatment with no pretreatment under hypoxic conditions. Halothane caused 4- and 11-fold increases in plasma and liver F(2)-isoprostanes, respectively, in non-pretreated rats, whereas isoniazid pretreatment had no effect. Phenobarbital pretreatment potentiated halothane-induced lipid peroxidation with 9- and 20-fold increases in plasma and liver F(2)-isoprostanes, respectively. Alanine aminotransferase activity was increased only in this group. At ambient oxygen concentrations, halothane but not enflurane or desflurane, caused F(2)-isoprostanes to increase. CONCLUSIONS: Specific halothane-induced lipid peroxidation was demonstrated in Sprague-Dawley rats using quantification of F(2)-isoprostanes and was increased by hypoxia and phenobarbital pretreatment, but not isoniazid pretreatment.
Asunto(s)
Anestésicos por Inhalación/farmacología , Dinoprost/biosíntesis , Halotano/farmacología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Animales , Isoniazida/farmacología , Masculino , Fenobarbital/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Aging is associated with a decrease in anesthetic requirements. Animal models of aging manifest alteration of brain Ca2+ homeostasis and increased methyltransferase I (PLMTI) activity. In this study we evaluated concurrently anesthetic requirements and brain plasma membrane Ca(2+)-ATPase (PMCA) and PLMTI activities in young and aged rats. Halothane, desflurane, isoflurane and xenon MEDs (lowest partial pressures that suppress a pain response) were measured in 2 and 25 month old, male Fisher-344 rats. Halothane MED was also measured in 2 and 30 month old F344/BNF1 rats, a strain that undergoes aging with less debilitation. PMCA pumping and PLMTI activities were measured in synaptic plasma membranes (SPM) prepared from the cortex and diencephalon-mesencephalon (DM). For aged Fisher-344 rats, MEDs for halothane, desflurane, isoflurane and xenon were reduced to 81%, 82%, 67% and 86%, respectively, of young controls; PMCA activity was diminished to 91% in cortical SPM and 82% in DM SPM; and cortical and DM PLMTI activities were increased to 131% and 114% of young control. For F344/BNF1 rats, MED for halothane was reduced to 87%, PMCA activity was diminished to 90% in cortical SPM and 72% DM SPM, and PLMTI activity was increased to 133% in cortical SPM and 112% in DM SPM. The strong association between age and reduced anesthetic requirements for inhalational agents on the one hand and altered PMCA and PLMTI activity on the other lends support to the underlying hypothesis that PMCA and PLMTI may be involved in the production of the anesthetic state.
Asunto(s)
Envejecimiento/metabolismo , Anestésicos/farmacología , Encéfalo/efectos de los fármacos , ATPasas Transportadoras de Calcio/metabolismo , Metiltransferasas/metabolismo , Anestésicos/administración & dosificación , Animales , Encéfalo/enzimología , Calcio/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Masculino , Fosfatidil-N-Metiletanolamina N-Metiltransferasa , Fosfatidiletanolamina N-Metiltransferasa , Ratas , Ratas Endogámicas F344RESUMEN
A wide spectrum of structurally disparate inhalational anesthetics reduce brain synaptic plasma membrane Ca(2+)-ATPase (PMCA) activity, whereas phospholipid methyltransferase I (PLMTI) is enhanced by anesthetics. Several rat models with incidental or disease-induced reduction of PMCA and enhancement of PLMTI activities manifest increased sensitivity to inhalational anesthetics. Because insulin is known to stimulate PMCA, anesthetic requirements in hyperinsulinemic obese Zucker rats (fa/fa) and in normoinsulinemic lean Zucker heterozygotes (fa/+) were examined, and brain synaptic PMCA and PLMTI activities were determined in both genotypes. Significantly higher partial pressures of halothane, enflurane, isoflurane, and desflurane were required to inhibit the pain response in obese rats compared to lean Zucker rats. Dose dependent stimulation of PMCA pumping was observed in synaptic membranes from both types, but insulin concentrations in extracts of diencephalon-mesencephalon, cerebellum, and medulla (but not cortex) were higher in obese than in lean Zucker rats. Microdialysis of three subcortical regions showed marked increases in insulin levels with halothane exposure in obese rats, compared to lean controls. These observations in an anesthetic resistant rat model lend further support to the hypothesis that the calcium pump plays a functional role in production of the anesthetic state.
Asunto(s)
Anestésicos por Inhalación/administración & dosificación , ATPasas Transportadoras de Calcio/metabolismo , Insulina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Membrana Celular/metabolismo , Activación Enzimática , Ratas , Ratas ZuckerRESUMEN
The role of substance P (SP) in cholesterol-induced anaphylactoid reaction was investigated in 13 Landrace pigs. Pigs were anesthetized with sodium thiopental and ventilation was controlled with 70% nitrous oxide in oxygen. A Swan-Ganz catheter and a carotid arterial line were placed to monitor the hemodynamic data. Group 1 pigs (control group, n = 5) each received 20 ml of intravenous (IV) colloid infusion solution (Haemaccel) and group 2 pigs (cholesterol group, n = 8) each received an IV injection of pure cholesterol emulsion (12 mg/kg) in 20 ml of Haemaccel. Blood samples for SP and histamine (H) levels were taken just before and for 10 min following the placebo, Haemaccel, and cholesterol injections. Urine samples were also collected just before and at 60 min following the injections for methyl histamine (MH) levels. Group 2 pigs (cholesterol) developed an anaphylactoid reaction as indicated by marked and significant hemodynamic changes. None of the group 1 (placebo) pigs developed an anaphylactoid reaction. Significant increases in blood SP and H levels (P < 0.05), and urine MH levels (P < 0.05) were seen in cholesterol-treated pigs (group 2), whereas no significant changes were seen in control pigs (group 1). Our results suggest that SP is involved in the cholesterol-induced anaphylactoid reaction in pigs.
Asunto(s)
Colesterol/farmacología , Sustancia P/metabolismo , Anafilaxia , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Histamina/sangre , Histamina/metabolismo , Metilhistaminas/metabolismo , Metilhistaminas/orina , Sustancia P/sangre , Porcinos/metabolismo , Resistencia VascularRESUMEN
We have recently reported that plasma membrane Ca(2+)-ATPase (PMCA) pumping activity in rat brain synaptic plasma membranes (SPM) was reduced by in vitro or prior in vivo exposure to inhalation anesthetics (IA). In addition, rats with streptozocin-induced diabetes were found to have diminished brain synaptic PMCA pumping and a decrease in the partial pressures of several IA required to prevent movement in response to stimulation, defined as the minimum effective dose or MED. Diminished PMCA activity in erythrocytes of spontaneously hypertensive rats (SHR) has been noted. Because PMCA is ubiquitous, it seemed possible that PMCA pumping might be decreased in the brain of SHR and perhaps associated with decreased IA requirement. Eighteen SHR and 18 control, normotensive Wistar-Kyoto rats (WKY) were studied. PMCA activity was assessed by measurement of Ca2+ uptake into synaptic plasma membrane vesicles prepared from cerebrum and diencephalon-mesencephalon (D-M) in WKY and SHR. Ca2+ pumping was significantly less in SHR than in WKY, 85% of control in the cerebrum and 90% in the D-M (p < 0.01). The MEDs for halothane, isoflurane and desflurane were also lower in SHR than in WKY, 91%, 90% and 89%, respectively, of control (p < 0.05). Thus, an animal model of primary hypertension (SHR) manifested diminished brain synaptic PMCA activity and reduced MED for several volatile anesthetics. These findings provide further evidence for a role for PMCA in anesthetic action.
Asunto(s)
Anestésicos por Inhalación/farmacología , Encéfalo/enzimología , ATPasas Transportadoras de Calcio/metabolismo , Hipertensión/enzimología , Membranas Sinápticas/enzimología , Animales , Presión Sanguínea , Encéfalo/efectos de los fármacos , Calcio/metabolismo , Membrana Celular/enzimología , Desflurano , Halotano/farmacología , Isoflurano/análogos & derivados , Isoflurano/farmacología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Membranas Sinápticas/efectos de los fármacosRESUMEN
We have recently reported that streptozocin (STZ)-induced diabetes in rats was associated with i) reduced Ca2+ pumping by rat brain synaptic plasma membrane Ca(2+)-ATPase (PMCA) and ii) a substantial reduction in the partial pressures of halothane and xenon required to prevent movement in response to stimulation (minimum effective dose or MED). MED for both agents correlated well with the degree of hemoglobin glycation and with PMCA activity. We now report that MEDs for isoflurane, enflurane, and desflurane were also substantially reduced in STZ-diabetic rats, compared with placebo-injected controls. In addition, we examined the effect of insulin treatment, begun 2 weeks after induction of diabetes and continued for 3 more weeks, on isoflurane MED and on brain synaptic PMCA and phospholipid-N-methyltransferase I (PLMT I), another enzyme altered by inhalation anesthetics (IA). Partial treatment of diabetes, as indicated by decreased glycated hemoglobin (GHb) compared to untreated diabetic rats, was associated with an isoflurane MED of 1.05 vol%, intermediate between a control mean of 1.57 vol% and an untreated diabetic mean of 0.82 vol% (p < 0.01), with a trend toward normalization of both PMCA and PLMT I activity. We also examined isoflurane MED and PMCA activity in the cerebrum and diencephalon-mesencephalon (D-M) of control and diabetic rats 2 and 12 weeks after induction of diabetes. Isoflurane MED was substantially reduced in diabetic rats from both treatment periods. Cerebral and D-M PMCA activities were each reduced to about 90% of control values 2 weeks after STZ induction. At 12 weeks, cerebral PMCA pumping in SPM from diabetic rats did not differ from control values, but PMCA pumping in SPM from the D-M was reduced to about 85% of control levels. Good correlation (r = 0.89, p < 0.01) was found between isoflurane MED and GHb in all treatment groups. These findings provide further evidence for an important role for PMCA in IA action. They also suggest that anesthetic effects on the calcium pump at specific anatomic sites may be of major importance in producing anesthesia.
Asunto(s)
Anestésicos por Inhalación , Encéfalo/enzimología , ATPasas Transportadoras de Calcio/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Insulina/farmacología , Fosfolípidos/metabolismo , Sinapsis/enzimología , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Membrana Celular/enzimología , Membrana Celular/metabolismo , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Diabetes Mellitus Experimental/fisiopatología , Diencéfalo/enzimología , Diencéfalo/metabolismo , Diencéfalo/ultraestructura , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Mesencéfalo/enzimología , Mesencéfalo/metabolismo , Mesencéfalo/ultraestructura , Metilación , Ratas , Ratas Sprague-DawleyRESUMEN
Halothane and isoflurane increase the rate of phospholipid methylation (PLM) in rat brain synaptosomal membranes, a process linked to the coupling of neuronal excitation to neurotransmitter release. In contrast, synaptic plasma membrane (SPM) Ca2+ ATPase (PMCA) pumping is reduced by exposure to halothane, isoflurane, xenon and nitrous oxide (N2O). To examine further the relationship between PLM, PMCA and anesthetic action, we investigated the effect of clinically relevant concentrations of two less potent anesthetic gases, N2O and xenon, on PLM in SPM. Biochemical assays were performed on SPM exposed to 1.3 MAC of N2O (2 atm), 1.3 MAC of xenon (1.23 atm) or an equivalent pressure of helium for control. N2O or xenon exposure increased PLM to 115% or 113%, respectively, of helium control (p < 0.02). Similar exposures to N2O or xenon depressed PMCA activity to 78% and 85% of control (p < 0.05). Observations that PLM and PMCA are both altered by a wide variety of inhalation anesthetic agents at clinically relevant partial pressures lend support to a possible involvement and interaction of these processes in anesthetic action.
Asunto(s)
Encéfalo/efectos de los fármacos , Óxido Nitroso/farmacología , Fosfolípidos/metabolismo , Membranas Sinápticas/efectos de los fármacos , Xenón/farmacología , Animales , Encéfalo/metabolismo , Masculino , Metilación , Ratas , Ratas Sprague-Dawley , Membranas Sinápticas/metabolismoRESUMEN
BACKGROUND: Perturbation of neuronal calcium homeostasis may alter neurotransmission in the brain, a phenomenon postulated to characterize the anesthetic state. Because of the central role of plasma membrane Ca(2+)-ATPase (PMCA) in maintaining Ca2+ homeostasis, the authors examined the effect of several inhalational anesthetics on PMCA function in synaptic plasma membranes (SPM) prepared from rat brain. METHODS: Ca(2+)-ATPase pumping activity was assessed by measurement of ATP-dependent uptake of Ca2+ by SPM vesicles. ATPase hydrolytic activity was assessed by spectrophotometric measurement of inorganic phosphate (Pi) released from ATP. For studies of anesthetic effects on PMCA activity, Ca2+ uptake or Pi release was measured in SPM exposed to halothane, isoflurane, xenon, and nitrous oxide at partial pressures ranging from 0 to 1.6 MAC equivalents. Halothane and isoflurane exposures were carried out under a gassing hood. For xenon and nitrous oxide exposures, samples were incubated in a pressure chamber at total pressures sufficient to provide anesthetizing partial pressures for each agent. RESULTS: Dose-related inhibition of Ca(2+)-ATPase pumping activity was observed in SPM exposed to increasing concentrations of halothane and isoflurane, confirmed by ANOVA and multiple comparison testing (P < 0.05). Concentrations of halothane and isoflurane equivalent to one minimum effective dose (MED) depressed PMCA pumping approximately 30%. Xenon and nitrous oxide also inhibited Ca2+ uptake by SPM vesicles. At partial pressures of these two gases equivalent to 1.3 MAC, PMCA was inhibited approximately 20%. Hydrolysis of ATP by SPM fractions was also inhibited in a dose-related fashion. An additive effect occurred when 1 vol% of halothane was added to xenon or nitrous oxide at partial pressures equivalent to 0-1.6 MAC for the latter two agents. CONCLUSIONS: Plasma membranes Ca(2+)-ATPase is significantly inhibited, in a dose-related manner, by clinically relevant partial pressures of halothane, isoflurane, xenon, and nitrous oxide. Furthermore, these anesthetics inhibit PMCA activity in accordance with their known potencies, and an additive effect was observed. How inhalational anesthetics inhibit the PMCA pump is not known at this time. It is noteworthy that the only shared characteristic of this group of agents of widely different structure is anesthetic action. The relevance of this dual commonality, anesthetic action and PMCA inhibition, to actual production of the anesthetic state remains to be determined.
Asunto(s)
Encéfalo/efectos de los fármacos , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Halotano/farmacología , Isoflurano/farmacología , Óxido Nitroso/farmacología , Xenón/farmacología , Animales , Encéfalo/enzimología , Calcio/metabolismo , ATPasas Transportadoras de Calcio/fisiología , Hidrólisis , Técnicas In Vitro , Masculino , Fosfatos/metabolismo , Ratas , Ratas Sprague-Dawley , Membranas Sinápticas/efectos de los fármacos , Membranas Sinápticas/metabolismoRESUMEN
BACKGROUND: The authors recently showed that plasma membrane Ca(2+)-ATPase (PMCA) activity in cerebral synaptic plasma membrane (SPM) is diminished in a dose-related fashion during exposure in vitro to halothane, isoflurane, xenon, and nitrous oxide at clinically relevant partial pressures. They have now extended their work to in vivo studies, examining PMCA pumping in SPM obtained from control rats decapitated without anesthetic exposure, from rats decapitated during halothane anesthesia, and from rats decapitated after recovery from halothane anesthesia. METHODS: Three treatment groups were studied: 1) C, control rats that were decapitated without anesthetic exposure, 2) A, anesthetized rats exposed to 1 minimum effective dose (MED) for 20 min and then decapitated, and 3) R, rats exposed to 1 MED for 20 min and then decapitated after recovery from anesthesia, defined as beginning to groom. Plasma membrane Ca(2+)-ATPase pumping and Ca(2+)-dependent ATPase hydrolytic activity, as well as sodium-calcium exchanger activity and Na+-K+-ATPase hydrolytic activity, were assessed in cerebral SPM. In addition, halothane effect on smooth endoplasmic reticulum Ca(2+)-ATPase (SERCA) was examined. RESULTS: Plasma membrane Ca(2+)-ATPase transport of Ca2+ into SPM vesicles from anesthetized rats was reduced to 71% of control (P < 0.01) compared with 113% of control for the recovered group (NS). No depression by halothane of SERCA activity, sodium-calcium exchanger, or Na+-K+-ATPase activity was noted among the CAR treatment groups. CONCLUSIONS: Plasma membrane Ca(2+)-ATPase is selectively and stably inhibited in cerebral SPM from rats killed while anesthetized with halothane, compared with rats killed without anesthesia or after recovery from anesthesia. The studies described in this report, in conjunction with previously reported inhibition of PMCA activity in vitro by a wide range of anesthetic agents, indicate a relationship between inhibition of PMCA and action of inhalational anesthetics.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/enzimología , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Halotano/farmacología , Membranas Sinápticas/efectos de los fármacos , Animales , Cámaras de Exposición Atmosférica , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Transporte Iónico , Masculino , Ratas , Ratas Sprague-Dawley , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Membranas Sinápticas/enzimologíaRESUMEN
We have compared the effect of two inhalational anesthetics, halothane and xenon, on Ca(2+)-ATPase (PMCA) pumping activity in plasma membrane vesicles prepared from cultured rat C6 glioma cells. Halothane, at concentrations ranging from 0.5 to 1.75 vol% (equivalent to 0.5 to 1.6 MAC), significantly inhibited Ca2+ uptake (transport) by plasma membrane vesicles in a dose-related fashion. Xenon, at partial pressures ranging from 0.5 to 1.5 atm (equivalent to 0.5 to 1.6 MAC), similarly inhibited PMCA pumping activity. Additive effects on suppression of PMCA pump activity were observed when C6 cell plasma membrane vesicles were exposed to increasing partial pressures of xenon in the presence of halothane (1 vol%). Halothane also inhibited PMCA pumping in cells from two other lines of neural origin, B104 (rat neuroblastoma) and PC12 (rat pheochromocytoma). Studies described in this report support the thesis that PMCA in cells of neural origin is inhibited by quite different inhalational anesthetics at clinically relevant concentrations.
Asunto(s)
ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Membrana Celular/enzimología , Glioma/enzimología , Halotano/farmacología , Xenón/farmacología , Animales , Relación Dosis-Respuesta a Droga , Halotano/administración & dosificación , Neuroblastoma/enzimología , Células PC12/enzimología , Ratas , Células Tumorales Cultivadas , Xenón/administración & dosificaciónRESUMEN
To determine the effects of total hepatectomy and inhibition of plasma cholinesterase activity on cocaine metabolism, we measured plasma concentrations of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, by high-performance liquid chromatography in three groups of male pigs. Pigs were anesthetized with sodium thiopental and lungs were ventilated with nitrous oxide in oxygen. A right carotid arterial cannula and an internal jugular venous catheter were then inserted for the administration of cocaine and for blood sampling. A Swan-Ganz catheter was inserted through the right internal jugular vein. Group 1 pigs underwent sham operation; group 2 and 3 pigs underwent hepatectomy and portocaval shunt. In addition, group 3 pigs were treated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor. After this preparation, pigs were given 4 mg/kg cocaine intravenously over 2 minutes. After cocaine injection, 4 ml blood was collected into heparinized test tubes containing 2.5% sodium fluoride for determination of cocaine and its metabolites at 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. We also measured hemodynamic responses after cocaine administration, including heart rate and rhythm, cardiac output, and arterial blood pressure. Data were analyzed by analysis of variance. Blood levels of cocaine and its metabolites were significantly different among the three groups (p < 0.05 by analysis of variance). Our results show that total hepatectomy was associated with a marked slowing of cocaine metabolism, absence of norcocaine, and increased benzoylecgonine levels when compared with the baseline values in the control pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Colinesterasas/sangre , Cocaína/metabolismo , Cocaína/farmacología , Hígado/fisiología , Animales , Inhibidores de la Colinesterasa/farmacología , Cocaína/análogos & derivados , Cocaína/sangre , Hemodinámica/efectos de los fármacos , Hepatectomía , Masculino , Concentración Osmolar , Porcinos , Tetraisopropilpirofosfamida/farmacologíaRESUMEN
We investigated whether alcohol pretreatment would affect the disposition and metabolic pattern of intravenously (i.v.) administered cocaine in pigs. Six pigs (Group A) received alcohol (1 g/kg/day) and six pigs (control; Group D) received an equal volume of isocaloric dextrose 44% in water for 10 days via an intragastric tube. On day 11, arterial samples were taken for five hours following an intravenous administration of cocaine hydrochloride (4 mg/kg). Plasma concentrations of cocaine and its major metabolites were analyzed by HPLC method. Significant decrease in plasma half-life (10 +/- 1.2 vs. 18.7 +/- 1.4 min), and significant increases in apparent volume of distribution (73 +/- 6 vs. 51 +/- 31) and clearance (5.37 +/- 0.6 vs. 1.82 +/- 0.1 l/min) were seen in alcohol pretreated pigs as compared with control pigs (P < 0.05). Significant increases in plasma concentrations of benzoylecgonine (P < 0.05), and insignificant differences in ecgonine methyl ester and norcocaine levels were seen between the two groups. Neither ecgonine nor cocaethylene was detected in the blood samples. Our data show that alcohol administration for ten days accelerated the elimination of i.v. administered cocaine and altered its metabolic pattern in pigs.
Asunto(s)
Cocaína/farmacocinética , Etanol/farmacología , Animales , Biotransformación , Cocaína/administración & dosificación , Etanol/farmacocinética , Infusiones Intravenosas , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , PorcinosRESUMEN
Recent evidence suggests that chronic hyperglycemia may inhibit plasma membrane Ca(2+)-ATPase (PMCA) in cells from several tissues. Inhalational anesthetics (IA) can inhibit brain synaptic PMCA activity. We proposed that diabetic rats may manifest chronic inhibition of brain synaptic PMCA and thus provide a model for testing the hypothesis that synaptic PMCA plays a key role in IA pharmacodynamics. Ca2+ pumping activity of PMCA was measured in cerebral synaptic plasma membrane (SPM) vesicles prepared from rats with streptozocin (STZ)-induced diabetes and from control, normoglycemic rats. Dose requirements for halothane and xenon were estimated in treated and untreated rats. Brain PMCA activity in hyperglycemic rats was depressed by about 8.4%, compared to controls. In vitro glycation also caused a significant decrease in PMCA pumping activity. Halothane requirement for STZ-hyperglycemic rats was dramatically reduced to about 65% of control. Xenon requirement was also significantly reduced, to 88% of control. Correlation of IA dose with percent glycated hemoglobin for each rat revealed a strong association between reduced requirements for halothane or xenon and increased protein glycation. These results indicate that inhibition of brain synaptic PMCA in chronically hyperglycemic rats is associated with a significant reduction in IA requirement.
Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Encéfalo/enzimología , ATPasas Transportadoras de Calcio/metabolismo , Diabetes Mellitus Experimental/enzimología , Membranas Sinápticas/enzimología , Animales , Glucemia/metabolismo , Halotano/administración & dosificación , Masculino , Ratas , Ratas Sprague-Dawley , Xenón/administración & dosificaciónRESUMEN
In a series of studies, generation effects were obtained under encoding conditions designed to induce incongruous, unrelated item generation. Experiments 1 and 2, using free- and cued-recall measures, respectively, provided evidence that this unrelated generation effect was due to response-specific processing. Experiment 3 demonstrated a lack of relation between free recall and indices of clustering. A preliminary protocol study suggested that Ss generate multiple items in their search for appropriate unrelated responses. In Experiments 4 and 5, conditions designed to produce more extensive multiple generations demonstrated enhanced free recall. These results supported a multiple-cue account of facilitated recall for incongruous item generation. The multiple-cue perspective is consistent with traditional conceptualizations of memory, such as the principle of congruity, and contemporary distinctions between cue-target relational and item-specific processing.