Abnormal heart rate variability and atrial fibrillation after aortic surgery / Variabilidade anormal da frequência cardíaca e fibrilação atrial após cirurgia aórtica

Introduction: Complete denervation of transplanted heart exerts protective effect against postoperative atrial fibrillation; various degrees of autonomic denervation appear also after transection of ascending aorta during surgery for aortic aneurysm. Objective: This study aimed to evaluate if the level of cardiac denervation obtained by resection of ascending aorta could exert any effect on postoperative atrial fibrillation incidence. Methods: We retrospectively analysed the clinical records of 67 patients submitted to graft replacement of ascending aorta (group A) and 132 with aortic valve replacement (group B); all episodes of postoperative atrial fibrillation occurred during the 1-month follow-up have been reported. Heart Rate Variability parameters were obtained from a 24-h Holter recording; clinical, echocardiographic and treatment data were also evaluated. Results: Overall, 45% of patients (group A 43%, group B 46%) presented at least one episode of postoperative atrial fibrillation. Older age (but not gender, abnormal glucose tolerance, ejection fraction, left atrial diameter) was correlated with incidence of postoperative atrial fibrillation. Only among a subgroup of patients with aortic transection and signs of greater autonomic derangement (heart rate variability parameters below the median and mean heart rate over the 75th percentile), possibly indicating more profound autonomic denervation, a lower incidence of postoperative atrial fibrillation was observed (22% vs. 54%). Conclusion: Transection of ascending aorta for repair of an aortic aneurysm did not confer any significant protective effect from postoperative atrial fibrillation in comparison to patients with intact ascending aorta. It could be speculated that a limited and heterogeneous cardiac denervation was produced by the intervention, creating an eletrophysiological substrate for the high incidence of postoperative atrial fibrillation observed. .

Introdução: Denervação completa do coração transplantado exerce efeito protetor contra a fibrilação atrial no pós-operatório; vários graus de denervação autonômica aparecem também após a transecção da aorta ascendente durante a cirurgia de aneurisma da aorta. Objetivo: Este estudo teve como objetivo avaliar se o nível de denervação cardíaca obtida por ressecção da aorta ascendente poderia exercer algum efeito sobre a incidência de fibrilação atrial no pós-operatório. Métodos: Foram analisados retrospectivamente os prontuários de 67 pacientes submetidos a enxerto de substituição de aorta torácica (grupo A) e 132 com a substituição da valva aórtica (grupo B). Foram relatados todos os episódios de fibrilação atrial pós-operatória ocorridos durante 1 mês de seguimento. Parâmetros de variabilidade da frequência cardíaca foram obtidos a partir de 24 h de gravação do Holter; dados clínicos, ecocardiográficos e de tratamento também foram avaliados. Resultados: No geral, 45% dos pacientes (grupo A 43%, grupo B 46%) apresentaram pelo menos um episódio de fibrilação atrial no pós-operatório. Idade mais avançada (mas não gênero, tolerância à glicose anormal, fração de ejeção, diâmetro do átrio esquerdo) foi correlacionada com a incidência de fibrilação atrial pós-operatória. Apenas em um subgrupo de pacientes com transecção aórtica e sinais de maior desarranjo autonômico (parâmetros de variabilidade da frequência cardíaca abaixo da mediana e a média de frequência cardíaca acima do percentil 75), indicando possivelmente denervação autonômica mais profunda, foi observada menor incidência de fibrilação atrial pós-operatória (22% vs. 54%). Conclusão: Transecção da aorta ascendente para correção de um aneurisma da aorta não confere qualquer efeito protetor significativo de fibrilação atrial no pós-operatório em comparação com pacientes com aorta ascendente intacta. Pode-se especular que uma denervação cardíaca limitada e heterogênea foi produzida pela ...

Advances in research of ketamine addiction mechanism / 法医学杂志

Ketamine is a phencyclidine derivative acting primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) excitatory glutamate receptors. As a common intravenous anaesthetic in clinic, it is also increasingly abused because of its hallucination and addiction effects. Based on the pharmacological and toxicologic characteristics of ketamine and the acknowledged addiction mechanism of other abused drugs, this article reviews the possible addiction mechanism of the ketamine in the aspects of its enhanced effects and reward systems, the anatomic structures, the related receptors and the individual differences.

A reviewing for abusing of ketamine / 法医学杂志

Ketamine is a noncompetitive NMDA receptor antagonist and comes into being a new problem of drug abuse. It can cause a certain extent of hallucination, which makes ketamine be abused in the casinos. The paper reviews the pharmacological and toxicology characteristic of Ketamine, the possible physiological mechanism and the methods for detecting Ketamine abuse.

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 microliter of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.

Infusions of AP5 into the basolateral amygdala impair the formation, but not the expression, of step-down inhibitory avoidance

We evaluated the effects of infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) on the formation and expression of memory for inhibitory avoidance. Adult male Wistar rats (215-300 g) were implanted under thionembutal anesthesia (30 mg/kg, ip) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Bilateral infusions of AP5 (5.0 µg) were given 10 min prior to training, immediately after training, or 10 min prior to testing in a step-down inhibitory avoidance task (0.3 mA footshock, 24-h interval between training and the retention test session). Both pre- and post-training infusions of AP5 blocked retention test performance. When given prior to the test, AP5 did not affect retention. AP5 did not affect training performance, and a control experiment showed that the impairing effects were not due to alterations in footshock sensitivity. The results suggest that NMDA receptor activation in the BLA is involved in the formation, but not the expression, of memory for inhibitory avoidance in rats. However, the results do not necessarily imply that the role of NMDA receptors in the BLA is to mediate long-term storage of fear-motivated memory within the amygdala.

Role of nitric oxide on insulin induced seizures in mice.

The role of nitric oxide (NO) on acute hypoglycemia-induced seizures in mice was investigated using insulin as the hypoglycemic agent. The NO precursor L-arginine in the doses of 150, 500 and 750 mg/kg exhibited a dose-dependent protective effect against seizures induced by 8 mu/kg insulin. The NO synthase inhibitor (L-NMMA) at the doses of 50 and 100 mg/kg potentiated the subconvulsive doses of insulin (2 mu/kg). The onset, duration, number of seizures and the mortality were noted in a 2 hr study period. The results of this study suggest than NO plays an important protective role in acute hypoglycemia induced seizures which are known to occur through the activation of NMDA receptors.

Cognitive dysfunction induced by phenytoin and valproate in rats: effect of nitric oxide.

Phenytoin (PHT) and Valproate (VPA) are known to induce cognitive dysfunction, in terms of long term memory loss. Nitric oxide (NO) on the other hand is said to help in long term potentiation and hence enhance memory. The effects of nitric oxide donor L-arginine (L-Arg) and nitric oxide synthase inhibitor N-W-L-Nitroarginine (L-NOARG) were studied on the cognitive dysfunction, induced by PHT and VPA in normal healthy rats, using the step-through passive avoidance test (PAT). It was observed that combining L-Arg with PHT significantly enhanced long term memory while, combining PHT with L-NOARG decreased it, as compared to PHT alone. When combined with VPA, L-Arg and L-NOARG increased the retention latency as compared to PVA alone but this was not statistically significant. We conclude that the No donor L-Arg is able to increase the difference in LTE in acquisition and retention trials with both PHT and VPA, but with VPA the increase is not statistically significant.

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-µl infusion containing 5.0 µg of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean Ý SEM number of conditioned responses (CRs) during retention test session was 16.47 Ý 1.78 in the vehicle group and 9.93 Ý 1.59 in the AP5 group; P<0.05). Post-training infusion of AP5 did not affect retention (mean Ý SEM number of conditioned responses during retention test session was 18.46 Ý 1.94 in the vehicle group and 20.42 Ý 2.38 in the AP5 group; P>0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory

N-methyl-D-aspartate receptors, nitric oxide, and ethanol tolerance

Several experimental models have been used to study tolerance to ethanol. The development of tolerance to the motor incoordinating effect of a single administration of ethanol occurs within 8-24 h after the effect of the first dose has disappeared. This form of tolerance is designated rapid tolerance and seems to involve functional rather than pharmacokinetic mechanisms. Like chronic tolerance, rapid tolerance has been shown to be infiuenced by processes related to learning and memory. It is known that N-methyl-D-aspartate (NMDA) receptor systems are involved in the expression and maintenance of one form of long-term potentiation (LTP), a synaptic adaptive process which has been suggested to be the cellular basis of memory or associative memory. Considering the similarities between learning and tolerance, the effects of NMDA agonists and antagonists on tolerance to ethanol were investigated. Our studies demonstrated that NMDA antagonists that impair learning, such as dizocilpine or ketamine, inhibit tolerance, while NMDA agonists that improve learning, such as D-cycloserine, increase tolerance. Moreover, the nitric oxide synthase inhibitor L-nitroarginine blocks tolerance to the effects of ethanol. Taken together, these data confirm the involvement of the NMDA system in ethanol tolerance and emphasize the participation of leaming in this phenomenon.

Role of the amygdala, hippocampus and entorhinal cortex in memory consolidation and expression

1. Experiments using localized microinfusions of specific agonists and antagonists of neurotransmitter receptors have shown that the amygdala, hippocampus, medial septum and entorhinal cortex are involved in memory consolidation, storage and expression. The data are consistent with observations derived from lesion studies suggesting a role for these structures in memory processes, but permit many additional conclusions concerning the mechanisms involved and their timing. 2. Memories are initially processed by glutamatergic N-methyl-D-aspartate (NMDA) receptors in amygdala, hippocampus and medial septum, which are sensitive to amino-phosphono valerate (AP5). Memory of inhibitory avoidance is processed by the three structures; memory of habituation to a novel environment is processed only by the hippocampus. At the time of consolidation, immediately after training, gamma-aminobutyrate type A (GABA-A) receptors, modulated by endogenous benzodiazepines, play an inhibitory role, and cholinergic muscarinic and beta-noradrenergic transmission play a modulatory role. 3. From 90 to 180 min after training, memories are blocked by cyano-nitro-quinoxalinedione (CNQX) given into the amygdala, septum and hippocampus. CNQX blocks non-NMDA glutamatergic receptors. Also between 90 and 180 min after training, memory of the habituation and inhibitory avoidance tasks is blocked by the infusion of AP5 or of the GABA-A agonist, muscimol, into the entorhinal cortex. This late post-training intervention of the entorhinal cortex is essential for the integration of successively acquired memories, and occurs in response to the simultaneous activation of CNQX-sensitive synapses in amygdala and hippocampus. 4. The expression of memory is blocked by the infusion of CNQX, at the time of testing, into the amygdala and hippocampus (inhibitory avoidance), into the hippocampus but not the amygdala (habituation), or into the entorhinal cortex (for the two tasks). Since consolidation is blocked by AP5 infused into these structures (see above), the data agree with the hypothesis that memories are mediated by (or actually consist of) long-term potentiation (LTP) in these areas of the brain. LTP induction is blocked by AP5 and LTP expression is blocked by CNQX. It is possible that, at the time of memory expression, the entorhinal cortex is an output of the amygdala and hippocampus

GABA/BZ-and NMDA-receptor interaction in digoxin-induced convulsions in rats.

Digoxin (7.5 micrograms icv) induced 'pop-corn' type of convulsions and 100% mortality. The GABA-ergic agents produced varying degree of protection against digoxin-induced neurotoxicity. Diazepam (4 mg/kg) offered significant protection whereas pentobarbital (5 mg/kg) and baclofen (5 mg/kg) markedly reduced per cent mortality, but ethanol (2 g/kg), progabide (50 mg/kg) and muscimol (0.5 mg/kg) as well as GABA (50 mg/kg) could not offer significant protection in doses used. GABA-ergic agonists; GABA, baclofen, diazepam and pentobarbital when administered along with MK-801 (0.5 mg/kg) a non-competitive NMDA antagonist, a potentiation of anticonvulsant action of MK-801 was observed. MK-801 showed potent anticonvulsant profile in dose range (0.25-1 mg/kg) studied. A synergistic influence of Mg2+ and K+ ions on NMDA receptor antagonism was also observed. A role of GABA-ergic facilitation and NMDA antagonism as a potential anticonvulsant approach in digoxin-induced convulsions in rats has been suggested.