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PTSD is associated with disturbed hepatic morphology and metabolism. Neuronal mitochondrial dysfunction is considered a subcellular determinant of PTSD, but a link between hepatic mitochondrial dysfunction and hepatic damage in PTSD has not been demonstrated. Thus, the effects of experimental PTSD on the livers of high anxiety (HA) and low anxiety (LA) rats were compared, and mitochondrial determinants underlying the difference in their hepatic damage were investigated. Rats were exposed to predator stress for 10 days. Then, 14 days post-stress, the rats were evaluated with an elevated plus maze and assigned to HA and LA groups according to their anxiety index. Experimental PTSD caused dystrophic changes in hepatocytes of HA rats and hepatocellular damage evident by increased plasma ALT and AST activities. Mitochondrial dysfunction was evident as a predominance of small-size mitochondria in HA rats, which was positively correlated with anxiety index, activities of plasma transaminases, hepatic lipids, and negatively correlated with hepatic glycogen. In contrast, LA rats had a predominance of medium-sized mitochondria. Thus, we show links between mitochondrial dysfunction, hepatic damage, and heightened anxiety in PTSD rats. These results will provide a foundation for future research on the role of hepatic dysfunction in PTSD pathogenesis.
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Trastornos por Estrés Postraumático , Animales , Ratas , Trastornos de Ansiedad , Ansiedad/etiología , Hígado , MitocondriasRESUMEN
Susceptibility and resilience to post-traumatic stress disorder (PTSD) are recognized, but their mechanisms are not understood. Here, the hexobarbital sleep test (HST) was used to elucidate mechanisms of PTSD resilience or susceptibility. A HST was performed in rats 30 days prior to further experimentation. Based on the HST, the rats were divided into groups: (1) fast metabolizers (FM; sleep duration < 15 min); (2) slow metabolizers (SM; sleep duration ≥ 15 min). Then the SM and FM groups were subdivided into stressed (10 days predator scent, 15 days rest) and unstressed subgroups. Among stressed animals, only SMs developed experimental PTSD, and had higher plasma corticosterone (CORT) than stressed FMs. Thus, resilience or susceptibility to PTSD was consistent with changes in glucocorticoid metabolism. Stressed SMs had a pronounced decrease in hippocampal dopamine associated with increased expressions of catecholamine-O-methyl-transferase and DA transporter. In stressed SMs, a decrease in monoaminoxidase (MAO) A was associated with increased expressions of hippocampal MAO-A and MAO-B. BDNF gene expression was increased in stressed FMs and decreased in stressed SMs. These results demonstrate relationships between the microsomal oxidation phenotype, CORT concentration, and anxiety, and they help further the understanding of the role of the liver−brain axis during PTSD.
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Trastornos por Estrés Postraumático , Animales , Ratas , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/metabolismo , Dopamina/metabolismo , Hipocampo/metabolismo , Corticosterona , Hexobarbital , Modelos Animales de Enfermedad , Estrés Psicológico/metabolismoRESUMEN
Stress-induced conditions are associated with impaired cerebral blood flow (CBF) and increased risk of dementia and stroke. However, these conditions do not develop in resilient humans and animals. Here the effects of predator stress (PS, cat urine scent, ten days) on CBF and mechanisms of CBF regulation were compared in PS-susceptible (PSs) and PS-resilient (PSr) rats. Fourteen days post-stress, the rats were segregated into PSs and PSr groups based on a behavior-related anxiety index (AI). CBF and its endothelium-dependent changes were measured in the parietal cortex by laser Doppler flowmetry. The major findings are: (1) PS susceptibility was associated with reduced basal CBF and endothelial dysfunction. In PSr rats, the basal CBF was higher, and endothelial dysfunction was attenuated. (2) CBF was inversely correlated with the AI of PS-exposed rats. (3) Endothelial dysfunction was associated with a decrease in eNOS mRNA in PSs rats compared to the PSr and control rats. (4) Brain dopamine was reduced in PSs rats and increased in PSr rats. (5) Plasma corticosterone of PSs was reduced compared to PSr and control rats. (6) A hypercoagulation state was present in PSs rats but not in PSr rats. Thus, potential stress resilience mechanisms that are protective for CBF were identified.
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Encéfalo , Circulación Cerebrovascular , Humanos , Animales , Ratas , Flujometría por Láser-Doppler , Dopamina/farmacología , Corticosterona/farmacologíaRESUMEN
We investigated the presence of a molecular pathway from hepatic 11-ßHSD-1 to brain MAO-A in the dynamics of plasma corticosterone involvement in anxiety development. During 14 days following repeated exposure of rats to predator scent stress for 10 days, the following variables were measured: hepatic 11-ßHSD-1 and brain MAO-A activities, brain norepinephrine, plasma corticosterone concentrations, and anxiety, as reflected by performance on an elevated plus maze. Anxiety briefly decreased and then increased after stress exposure. This behavioral response correlated inversely with plasma corticosterone and with brain MAO-A activity. A mathematical model described the dynamics of the biochemical variables and predicted the factor(s) responsible for the development and dynamics of anxiety. In the model, hepatic 11-ßHSD-1 was considered a key factor in defining the dynamics of plasma corticosterone. In turn, plasma corticosterone and oxidation of brain ketodienes and conjugated trienes determined the dynamics of brain MAO-A activity, and MAO-A activity determined the dynamics of brain norepinephrine. Finally, plasma corticosterone was modeled as the determinant of anxiety. Solution of the model equations demonstrated that plasma corticosterone is mainly determined by the activity of hepatic 11-ßHSD-1 and, most importantly, that corticosterone plays a critical role in the dynamics of anxiety following repeated stress.
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11-beta-Hidroxiesteroide Deshidrogenasas , Ansiedad , Corticosterona , Monoaminooxidasa , Estrés Psicológico , 11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Ansiedad/metabolismo , Conducta Animal/fisiología , Encéfalo/metabolismo , Corticosterona/sangre , Monoaminooxidasa/metabolismo , Norepinefrina/metabolismo , Ratas , Estrés Psicológico/metabolismoRESUMEN
BACKGROUND: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. METHODS: Rats were exposed to PSS for ten days. Thirty days later, the rats' anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. RESULTS: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. CONCLUSION: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.
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Glándulas Suprarrenales/fisiopatología , Corticosterona/metabolismo , Trastornos por Estrés Postraumático/patología , Estrés Psicológico/complicaciones , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Animales , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Corticosterona/análogos & derivados , Corticosterona/sangre , Desoxicorticosterona/sangre , Desoxicorticosterona/metabolismo , Modelos Animales de Enfermedad , Fenotipo , Ratas , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/metabolismo , Zona Fascicular/metabolismo , Zona Fascicular/patología , Zona Fascicular/fisiopatologíaRESUMEN
Traumatic stress causes posttraumatic stress disorder (PTSD). PTSD is associated with cardiovascular diseases and risk of sudden cardiac death in some subjects. We compared effects of predator stress (PS, cat urine scent, 10 days) on mechanisms of cardiac injury and protection in experimental PTSD-vulnerable (PTSD) and -resistant (PTSDr) rats. Fourteen days post-stress, rats were evaluated with an elevated plus-maze test, and assigned to PTSD and PTSDr groups according to an anxiety index calculated from the test results. Cardiac injury was evaluated by: 1) exercise tolerance; 2) ECG; 3) myocardial histomorphology; 4) oxidative stress; 5) pro- and anti-inflammatory cytokines. Myocardial heat shock protein 70 (HSP70) was also measured. Experimental PTSD developed in 40% of rats exposed to PS. Exercise tolerance of PTSD rats was 25% less than control rats and 21% less than PTSDr rats. ECG QRS, QT, and OTc intervals were significantly longer in PTSD rats than in control and PTSDr rats. Only cardiomyocytes of PTSD rats had histomorphological signs of metabolic and hypoxic injury and impaired contractility. Oxidative stress markers were higher in PTSD than in PTSDr rats. Pro-inflammatory IL-6 was higher in PTSD rats than in control and PTSDr rats, and anti-inflammatory IL-4 was lower in PTSD than in control and PTSDr rats. Myocardial HSP70 was lower in PTSD rats than in PTSDr and control rats. Our conclusion was that rats with PTSD developed multiple signs of cardiac injury. PTSDr rats were resistant also to cardiac injury. Factors that limit cardiac damage in PS rats include reduced inflammation and oxidative stress and increased protective HSP70.NEW & NOTEWORTHY For the first time, rats exposed to stress were segregated into experimental PTSD (ePTSD)-susceptible and ePTSD-resistant rats. Cardiac injury, ECG changes, and impaired exercise tolerance were more pronounced in ePTSD-susceptible rats. Resistance to ePTSD was associated with decreased inflammation and oxidative stress and with increased protective heat shock protein 70. Results may help identify individuals at high risk of PTSD and also provide a foundation for developing preventive and therapeutic means to restrict PTSD-associated cardiac morbidity.
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Trastornos por Estrés Postraumático , Animales , Ansiedad , Inflamación/metabolismo , Miocardio/metabolismo , Estrés Oxidativo , RatasRESUMEN
Hexobarbital sleep test (HST) was performed in male Wistar rats (hexobarbital 60 mg/kg, i.p.) 30 days prior to stress exposure. Based on the duration of hexobarbital-induced sleep, rats were divided into two groups, animals with high intensity (fast metabolizers (FM), sleep duration <15 min) or low intensity of hexobarbital metabolism (slow metabolizers (SM), sleep duration ≥15 min). The SM and FM groups were then divided into two subgroups: unstressed and stressed groups. The stressed subgroups were exposed to predator scent stress for 10 days followed by 15 days of rest. SM and FM rats from the unstressed group exhibited different behavioral and endocrinological patterns. SM showed greater anxiety and higher corticosterone levels. In stressed animals, anxiety-like posttraumatic stress disorder (PTSD) behavior was aggravated only in SM. Corticosterone levels in the stressed FM, PTSD-resistant rats, were lower than in unstressed SM. Thus, HST was able to predict the susceptibility or resistance to experimental PTSD, which was consistent with the changes in glucocorticoid metabolism.
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Hexobarbital/farmacología , Hipnóticos y Sedantes/farmacología , Sueño/efectos de los fármacos , Trastornos por Estrés Postraumático/psicología , Animales , Corticosterona/sangre , Susceptibilidad a Enfermedades , Masculino , Ratas , Ratas Wistar , Trastornos por Estrés Postraumático/fisiopatologíaRESUMEN
BACKGROUND: Repeated exposure to predator scent stress (PSS) has been used as an animal model of complex post-traumatic stress disorder (CPTSD). The aim of the current study was to assess brain monoamines and their primary metabolites concentrations in male Wistar rats (16 control, 19 exposed to chronic PSS). METHODS: Rats were exposed to PSS for ten days. Fourteen days later, the rats' anxiety index (AI) was assessed with an elevated plus maze test; based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone levels were measured by radioimmunoassay. Brain monoamines and their metabolites were measured using high-performance liquid chromatography with electrochemical detector. RESULTS: PSS exposure led to a significant increase in average rats' AI and a reduction in plasma corticosterone levels. Medullar catecholamines and hippocampal and neocortical norepinephrine levels were increased, and pontine norepinephrine and cerebellar dopamine decreased in PSS-exposed rats. Cerebellar norepinephrine levels were increased, and midbrain, hippocampal, and neocortical 5-HT and hypothalamic and hippocampal dopamine levels-decreased in high-, but not in low-anxiety rats. The decrease in hippocampal dopamine levels was accompanied by an increase of DOPAC levels, suggesting and abnormal metabolism of this transmitter. CONCLUSION: Reductions in 5-HT and dopamine in mid- and forebrain brain areas are associated with stress susceptibility in rodents and perhaps also with PTSD vulnerability in humans. Dopamine and 5-HT metabolism and its modulation by glucocorticoids appear to play a role in stress susceptibility and in CPTSD.
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Ansiedad/metabolismo , Encéfalo/metabolismo , Corticosterona/sangre , Dopamina/metabolismo , Norepinefrina/metabolismo , Serotonina/sangre , Trastornos por Estrés Postraumático/metabolismo , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Masculino , Fenotipo , Ratas , Ratas Wistar , Trastornos por Estrés Postraumático/etiología , Estrés Psicológico/complicacionesRESUMEN
Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC's ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC's reduction of oxidative stress.
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Estrés Oxidativo , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/terapia , Alanina Transaminasa/metabolismo , Animales , Ansiedad/inducido químicamente , Ansiedad/fisiopatología , Aspartato Aminotransferasas/metabolismo , Escala de Evaluación de la Conducta , Encéfalo/metabolismo , Gatos , Corteza Cerebral/enzimología , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Glucógeno/metabolismo , Hipoxia , Hígado/enzimología , Hígado/metabolismo , Masculino , Aprendizaje por Laberinto , Monoaminooxidasa/metabolismo , Miocardio/citología , Miocardio/metabolismo , Miocardio/patología , Norepinefrina/metabolismo , Odorantes , Ratas , Ratas Wistar , Trastornos por Estrés Postraumático/enzimología , Trastornos por Estrés Postraumático/metabolismo , Orina/químicaRESUMEN
The aim of this study was to investigate the effect of chronic predator scent stress (PSS) on monoamine levels in rat thalamus and hypothalamus. Rats were exposed to the PSS (sand containing cat urine) for ten minutes daily for ten days. Control animals were exposed to the sand containing clean water. Fifteen days later, rats' behavior and thalamic and hypothalamic levels of monoamines were analyzed. PSS rats had elevated anxiety, increased thalamic serotonin and decreased hypothalamic dopamine concentrations. This decrease in hypothalamic dopamine may explain, at least in part, lowered corticosterone levels observed in PSS animals in our previous studies.
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Dopamina , Hipotálamo , Odorantes , Serotonina , Tálamo , Animales , Corticosterona , Hipotálamo/fisiología , Conducta Predatoria , Ratas , Serotonina/metabolismo , Estrés Psicológico , Tálamo/fisiologíaRESUMEN
The original version of this article unfortunately contained a mistake in the co-author name.
RESUMEN
Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.
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Enfermedades de las Glándulas Suprarrenales/terapia , Hipoxia/metabolismo , Hipoxia/psicología , Condicionamiento Físico Animal/fisiología , Trastornos por Estrés Postraumático/terapia , Corteza Suprarrenal/fisiopatología , Enfermedades de las Glándulas Suprarrenales/etiología , Enfermedades de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/patología , Altitud , Animales , Ansiedad/psicología , Corticosterona/sangre , Reacción Cataléptica de Congelación , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/patología , Trastornos por Estrés Postraumático/psicologíaRESUMEN
The calibrated application of limited-duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion and, in many cases, improve contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease and produced robust, persistent, antihypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on ß-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that use protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC clearly merits further evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions.
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Enfermedades Cardiovasculares/terapia , Precondicionamiento Isquémico Miocárdico/métodos , Acondicionamiento Físico Humano/métodos , Animales , Enfermedades Cardiovasculares/prevención & control , HumanosRESUMEN
Posttraumatic stress disorder (PTSD) is associated with myocardial injury, but changes in coronary regulatory mechanisms in PTSD have not been investigated. This study evaluated the effect of PTSD-inducing stress on coronary tone and its regulation by nitric oxide (NO) and voltage-gated K+ channels. PTSD was induced by exposing rats to predator stress, 15 min daily for 10 days, followed by 14 stress-free days. Presence of PTSD was confirmed by the elevated plus-maze test. Coronary tone was evaluated from changes in coronary perfusion pressure of Langendorff isolated hearts. Predator stress induced significant decreases in coronary tone of isolated hearts and in blood pressure of intact rats. L-NAME, a non-selective NO synthase (NOS) inhibitor, but not S-MT, a selective iNOS inhibitor, and increased coronary tone of control rats. In PTSD rats, both L-NAME and S-MT increased coronary tone. Therefore, the stress-induced coronary vasodilation resulted from NO overproduction by both iNOS and eNOS. NOS induction was apparently due to systemic inflammation as evidenced by increased serum interleukin-1ß and C-reactive protein in PTSD rats. Decreased corticosterone in PTSD rats may have contributed to inflammation and its effect on coronary tone. PTSD was also associated with voltage-gated K+ channel dysfunction, which would have also reduced coronary tone.
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Presión Sanguínea/fisiología , Vasos Coronarios/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicología , Animales , Presión Sanguínea/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Corticosterona/metabolismo , Preparación de Corazón Aislado/métodos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , RatasRESUMEN
It has been shown in our previous study that monoamine oxidase (MAO) activity in different brain regions are correlated with a microsomal oxidation phenotype. The data obtained in this study, using the microsomal oxidation inhibitor SKF525, and using animals with different duration of hexobarbital sleep, has shown that increased intensity of microsomal oxidation might be associated with increased MAO activity. Since the rats with short hexobarbital sleep time had higher content of hepatic microsomal cytochrome P450 than did rats with long hexobarbital sleep time. In addition, the rats with higher hepatic content of CYP450 had higher activities of MAO-A and MAO-B. Moreover, the microsomal oxidation inhibitor SKF-525 reduced brain and liver activities of MAOA and MAO-B. Consequently, MAO activities in a brain and a liver depend on the microsomal oxidation process.
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Encéfalo/enzimología , Hígado/enzimología , Microsomas/metabolismo , Monoaminooxidasa/metabolismo , Sueño/fisiología , Animales , Activación Enzimática , Regulación Enzimológica de la Expresión Génica/fisiología , Masculino , Especificidad de Órganos , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
BACKGROUND: Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either ß1-adrenergic or δ-opioid receptors (δ-OR) suggests autonomic and/or opioidergic adaptations. PURPOSE: To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence. METHODS: Mongrel dogs completed 20d IHT, non-hypoxic sham training, or IHT with the δ-OR antagonist naltrindole (200µg/kgsc). The vagolytic effect of the δ-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in δ-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers. RESULTS: IHT enhanced vagal bradycardia vs. sham dogs (P<0.05), and blunted the δ2-OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals (P<0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers (P<0.05) suggesting an increase in parasympathetic arborization. IHT reduced select δ-OR labeled fibers in both the atria and sinoatrial node (P<0.05) consistent with moderation of the vagolytic δ2-OR signaling described above. Furthermore, blockade of δ-OR signaling with naltrindole during IHT increased the protein content of δ-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle (P<0.05). SUMMARY: IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems.
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Atrios Cardíacos/metabolismo , Hipoxia/tratamiento farmacológico , Plasticidad Neuronal , Receptores Opioides delta/metabolismo , Animales , Perros , Encefalina Metionina/farmacología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Microdiálisis/métodos , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Plasticidad Neuronal/efectos de los fármacos , Norepinefrina/metabolismo , Norepinefrina/farmacología , Nodo Sinoatrial/efectos de los fármacos , Nervio Vago/fisiopatologíaRESUMEN
Glucocorticoids (GCs) are used to treat numerous diseases, but their use in limited by adverse side effects. One such effect is occasional increased anxiety. Since the intensity of hepatic microsomal oxidation has been shown to alter responses to GC, we examined the possibility that rats with lower rates of hepatic GC metabolism would have increased anxiety. We hypothesized that the resulting, excessive GC would stimulate brain monoamine oxidase A (MAO-A), which would reduce brain serotonin, and thereby increase anxiety. Hepatic microsomal oxidative intensity was evaluated by the hexobarbital sleep time (HST) test. Results showed that rats with lower rates of hepatic GC metabolism had elevated brain MAO-A activity, reduced brain serotonin, and more anxiety than rats with higher rates of hepatic GC metabolism. We suggest that the HST test, as an integrative test of microsomal oxidation status, should be useful for predicting individual sensitivity to GC and to other drugs metabolized by the hepatic microsomal oxidation system.
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Ansiedad/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Glucocorticoides/farmacocinética , Microsomas Hepáticos/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Hexobarbital , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Monoaminooxidasa/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Trastornos Cerebrovasculares/prevención & control , Disfunción Cognitiva/prevención & control , Hipoxia , Animales , HumanosRESUMEN
Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 µg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 ± 0.3 to 0.7 ± 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 ± 5 % and arrhythmia score 3.7 ± 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.