RESUMO
High-altitude (HA, >2500 m) hypoxic exposure evokes several physiological processes that may be abetted by differential genetic distribution in sojourners, who are susceptible to various HA disorders, such as high-altitude pulmonary edema (HAPE). The genetic variants in hypoxia-sensing genes influence the transcriptional output; however the functional role has not been investigated in HAPE. This study explored the two hypoxia-sensing genes, prolyl hydroxylase domain protein 2 (EGLN1) and factor inhibiting HIF-1α (HIF1AN) in HA adaptation and maladaptation in three well-characterized groups: highland natives, HAPE-free controls and HAPE-patients. The two genes were sequenced and subsequently validated through genotyping of significant single nucleotide polymorphisms (SNPs), haplotyping and multifactor dimensionality reduction. Three EGLN1 SNPs rs1538664, rs479200 and rs480902 and their haplotypes emerged significant in HAPE. Blood gene expression and protein levels also differed significantly (P < 0.05) and correlated with clinical parameters and respective alleles. The RegulomeDB annotation exercises of the loci corroborated regulatory role. Allele-specific differential expression was evidenced by luciferase assay followed by electrophoretic mobility shift assay, liquid chromatography with tandem mass spectrometry and supershift assays, which confirmed allele-specific transcription factor (TF) binding of FUS RNA-binding protein (FUS) with rs1538664A, Rho GDP dissociation inhibitor 1 (ARHDGIA) with rs479200T and hypoxia upregulated protein 1 (HYOU1) with rs480902C. Docking simulation studies were in sync for the DNA-TF structural variations. There was strong networking among the TFs that revealed physiological consequences through relevant pathways. The two hydroxylases appear crucial in the regulation of hypoxia-inducible responses.
Assuntos
Doença da Altitude , Loci Gênicos , Hipertensão Pulmonar , Prolina Dioxigenases do Fator Induzível por Hipóxia , Oxigenases de Função Mista , Polimorfismo de Nucleotídeo Único , Edema Pulmonar , Proteínas Repressoras , Células A549 , Altitude , Doença da Altitude/enzimologia , Doença da Altitude/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/biossíntese , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Oxigenases de Função Mista/biossíntese , Oxigenases de Função Mista/genética , Edema Pulmonar/enzimologia , Edema Pulmonar/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Fatores de RiscoRESUMO
BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.
Assuntos
Proteínas Quinases Ativadas por AMP/sangue , Adaptação Fisiológica/fisiologia , Doença da Altitude/sangue , Eritrócitos/metabolismo , Receptor A2B de Adenosina/sangue , 2,3-Difosfoglicerato/sangue , 5'-Nucleotidase/sangue , 5'-Nucleotidase/deficiência , Lesão Pulmonar Aguda/fisiopatologia , Adenosina/sangue , Adulto , Doença da Altitude/enzimologia , Doença da Altitude/fisiopatologia , Animais , Bisfosfoglicerato Mutase/sangue , Ativação Enzimática , Proteínas Ligadas por GPI/sangue , Humanos , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/sangue , Fosforilação , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND: The failure of intestinal mucosal barrier may induce multiple organ dysfunction and systemic inflammatory response syndrome, but little work has been done on whether hypobaric hypoxia related to the failure of intestinal mucosal barrier. AIMS: To study the expression of hypoxia-inducible factor 1α (HIF-1α), inducible nitric oxide synthase (iNOS) and morphological changes of intestinal mucosa in albino rats at different altitude. METHODS: 30 male Wistar rats raised in plain for one month were randomly divided into 3 groups: Plain 500 m group (n=10), High-altitude (HA) 3842 m group (n=10) and HA4767 m group (n=10). Each group was delivered to different altitude area at the same shipping time and executed after 3 days' exposure to different altitude. Intestinal segments with the same location of all rats were removed for morphological analyses. Morphologic parameters (villous height, crypt depth, mucosal wall thickness and villous surface area) were measured by optical and scanning electron microscope. The expression of iNOS and HIF-1α were detected by immunohistochemistry. RESULTS: Morphological indexes in higher altitude groups were exacerbated obviously compared with those of lower altitude groups. While the expression of iNOS and HIF-1α in higher altitude groups were significantly increased than those of lower altitude groups. Linear correlation analysis showed that the expression of iNOS was positively correlated with that of HIF-1α. CONCLUSIONS: Hypobaric hypoxia increases the expression of HIF-1α and iNOS in intestinal mucosa, however exacerbates the mucous morphologic parameters with altitude increasing. HIF-1α may regulate the expression of iNOS and be involved in the damage of intestinal mucosa.
Assuntos
Doença da Altitude/enzimologia , Altitude , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Íleo/enzimologia , Mucosa Intestinal/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Doença da Altitude/patologia , Animais , Modelos Animais de Doenças , Íleo/ultraestrutura , Mucosa Intestinal/ultraestrutura , Modelos Lineares , Masculino , Microscopia Eletrônica de Varredura , Permeabilidade , Ratos Wistar , Fatores de Tempo , Regulação para CimaRESUMO
INTRODUCTION: Our prior publication suggested that elevated serum concentrations of low-density lipoprotein (LDL) was protective against the development of acute mountain sickness (AMS) while an inflammatory response was contributory to its development. The use of 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors ("statins") may be of interest to those traveling to altitude-these medications will lower serum LDL concentrations, but are also reported to have anti-inflammatory properties. METHODS: Prior to flying from sea level to the South Pole (â¼10,498.7 ft or 3200 m) during the austral summer months of 2005-2006 and 2006-2007, the 248 subjects provided informed consent. Questionnaires related to AMS symptoms, acetazolamide use, personal history, and anthropometrics were paired with results from blood samples. Statin use was reported by six subjects who were matched for age, sex, altitude of residence, and acetazolamide use with seven subjects not using a statin. RESULTS: No significant differences were identified in any of the matched variables between the groups. No statin users reported symptoms of AMS while 57% of participants not using a statin did report AMS symptoms (P = 0.03). No significant difference was noted between LDL levels in the statin group (108.3 ± 61.0) as compared to the group not taking statins (104.6 ± 22.1) (P = 0.88). DISCUSSION: Our previous results suggested that elevated LDL was protective while an inflammatory response was contributory with respect to AMS development. The present results suggest that statin use may provide protection against AMS symptoms, possibly through an anti-inflammatory property, despite its lipid-lowering capacity. Harrison MF, Johnson BD. Statin use and the development of acute mountain sickness.
Assuntos
Medicina Aeroespacial , Doença da Altitude/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipoproteínas LDL/sangue , Adulto , Doença da Altitude/sangue , Doença da Altitude/enzimologia , Feminino , Hormônios/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/sangue , Inquéritos e QuestionáriosRESUMO
The effects of exposure to acute and chronic high altitude hypoxia on the activity and expression of CYP2E1 and CYP3A1 were examined in rats. Rats were divided into low altitude (LA, 400 m), acute moderate altitude hypoxia (AMH, 2800 m), chronic moderate altitude hypoxia (CMH, 2800 m), acute high altitude hypoxia (AHH, 4300 m), and chronic high altitude hypoxia groups (CHH, 4300 m). Probe drugs were administrated orally to all five groups. Then the serum concentration of probe drug and its metabolite was determined by RP-HPLC. The activity of CYP2E1 and CYP3A1 was evaluated using the ratio of the metabolite to chlorzoxazone and testosterone, respectively. ELISA and real-time PCR were used to analyze the protein and mRNA expression of CYP2E1 and CYP3A1 in liver microsomes, respectively. Chronic high altitude hypoxia caused significant decreases in the activity and protein and mRNA expression of rat CYP2E1 and CYP3A1 in vivo. Acute high altitude hypoxia was not found to change the activity, protein or mRNA expression of rat CYP2E1 or CYP3A1. This study showed significant changes in the activity and protein and mRNA expression of CYP2E1 or CYP3A1 in rats after exposure to chronic high altitude hypoxia.
Assuntos
Doença da Altitude/enzimologia , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , RNA Mensageiro/metabolismo , Doença Aguda , Altitude , Animais , Clorzoxazona/sangue , Doença Crônica , Feminino , Expressão Gênica , Masculino , Microssomos Hepáticos/enzimologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testosterona/sangueRESUMO
BACKGROUND: High altitude pulmonary edema (HAPE) is a potentially deadly disease associated with exposure to altitudes greater than 3000 m. Individuals who have previously experienced HAPE are at a significantly higher risk of recurrence, suggesting an underlying genetic component to HAPE pathogenesis. In a previous nuclear genomic study of individual variation in susceptibility to HAPE, the endothelial nitric oxide synthase (eNOS) gene G894T polymorphism was identified as being associated with HAPE. However, another study found no association. Because of the low incidence of HAPE, sample sizes in current reports have been relatively limited. In this study, the association between the eNOS G894T polymorphism and HAPE was assessed through a meta-analysis of published data. METHODS: The literature was searched in PubMed, Web of Science, and Embase for papers published before July 15, 2011. A fixed-effects model and a random-effects model were applied (Revman 5.0) on the basis of heterogeneity, and study quality was assessed in duplicate. RESULTS: Five studies with 360 HAPE patients and 469 control subjects were analyzed. There were no significant differences between carriers of the eNOS 894G and 894T polymorphism alleles in terms of the risk of developing HAPE. CONCLUSIONS: The eNOS 894G and 894T polymorphism alleles are not associated with HAPE incidence.
Assuntos
Alelos , Doença da Altitude/enzimologia , Doença da Altitude/genética , Altitude , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , HumanosRESUMO
Alpinists who challenge Mt. Everest need adaptation to hypoxia before the attack of Mt. Everest. Although this adaptation is important for the success of climbing Mt. Everest, the molecular mechanism on the adaptation to hypoxia is not well understood. In order to clarify this mechanism, we investigated hypoxia-induced gene expressions specific for top alpinists using microarray analyses. We report here that heme oxygenase-1 (HO-1) is significantly higher in the blood of top alpinist compared with non-alpinists. Although HO-1 expression of non-alpinists is also up-regulated in response to hypoxia, HO-1 level of the top alpinists are constitutively higher than that of non-alpinists. Serial examinations of HO-1 in one top alpinist revealed that the higher expression of HO-1 is maintained in high-level several months after the attack of top mountains. Taken together with the biochemical function of HO-1 that catalyzes heme into CO and bilirubin, HO-1 expression may improve the circulation and compensate with oxidative tissue damages induced by hypoxia. These data also suggest that peripheral blood has the memory on hypoxia independent of antigens by maintaining the high-level of HO-1 expression in top alpinists, which merits the rapid adaptation to hypoxia for 8000m climbing.
Assuntos
Altitude , Atletas , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/sangue , Montanhismo/fisiologia , Oxigênio/metabolismo , Doença da Altitude/sangue , Doença da Altitude/diagnóstico , Doença da Altitude/enzimologia , Doença da Altitude/genética , Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Studies on different populations have suggested variability in individual susceptibility to altitude sickness depending on genetic makeup. The renin-angiotensin-aldosterone system (RAAS) pathway plays a key role in regulation of vascular tone and circulatory homeostasis. The present study was undertaken to investigate the possible association of the RAAS in the development of high-altitude pulmonary edema (HAPE) in lowlanders exposed to high altitude. Three categories of subjects were selected: individuals who developed HAPE on acute induction to high altitude (HAPE); individuals tolerant to high-altitude exposure who showed no symptoms of HAPE (resistant controls; rCON); and natives of high altitude (HAN). Genetic variants in the genes of the RAAS such as renin (REN), angiotensin (AGT), angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2) and angiotensin II receptor type 1 (AGTR1) have been investigated. The T174M polymorphism in AGT showed a significant difference in HAPE and HAN and also HAN and controls. Also, genotyping in the CYP11B2 T-344C promoter region resulted in a significant difference between HAPE and HAN both at genotypic and allelic levels. The genotypic difference was statistically insignificant for the AGTR1 A1166C 3' UTR. The present investigation demonstrates a possible association between the polymorphisms existing in the RAAS pathway T174M and CYP11B2 C-344T and sensitivity of an individual to develop HAPE. The results also indicate the existence of ethnic variation between the HAN and the other two groups comprising lowlanders.
Assuntos
Doença da Altitude/genética , Angiotensinas/genética , Citocromo P-450 CYP11B2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único/genética , Sistema Renina-Angiotensina/genética , Adulto , Doença da Altitude/enzimologia , Epistasia Genética , Frequência do Gene/genética , Humanos , Hipertensão Pulmonar/enzimologia , Masculino , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
BACKGROUND AND OBJECTIVE: High-altitude pulmonary oedema (HAPE) is a non-cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data. MATERIALS AND METHODS: We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate. RESULTS: A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98-1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15-2.08; p = 0.004). Funnel plot and Egger's test suggested no evidence of publication bias. CONCLUSIONS: Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE.
Assuntos
Doença da Altitude/enzimologia , Doença da Altitude/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Mutação INDEL/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Alelos , Altitude , Humanos , Viés de PublicaçãoRESUMO
High altitude (HA) generates a deleterious effect known as hypobaric hypoxia (HBH). This causes severe physiological and psychological changes such as acute mountain sickness (AMS) and cognitive functions in terms of learning and memory. The present study has evaluated the effect of cholinesterase inhibitors on memory consolidation following HBH. Adult male Sprague Dawley rats (80-90 days old) with an average body weight of 250 ± 25 g were used. Rats were assessed memory consolidation by using Morris water maze (MWM) for 8 days. After assessment of memory consolidation, rats were then exposed to HBH in stimulated chamber for 7 days at 6,100 m. After exposure to HBH, the memory consolidation of rats has been assessed in MWM. The results showed that there was memory consolidation impairment in HBH-exposed rats as compared to normoxic rats in terms of time spent in quaradents, rings, and counters. The rats which have been treated with physostigmine (PHY) and galantamine (GAL) showed better time spent in quaradents, rings, and counters as compared with hypoxic rats. In conclusion, the cholinesterase inhibitors could ameliorate the impairment of memory consolidation following HBH.
Assuntos
Doença da Altitude/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Hipóxia Encefálica/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Acetilcolina/agonistas , Acetilcolina/fisiologia , Pressão do Ar , Doença da Altitude/complicações , Doença da Altitude/enzimologia , Animais , Modelos Animais de Doenças , Galantamina/farmacologia , Hipóxia Encefálica/complicações , Hipóxia Encefálica/enzimologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Transtornos da Memória/enzimologia , Transtornos da Memória/etiologia , Fisostigmina/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Resultado do TratamentoRESUMO
The pathogenesis of chronic mountain sickness (CMS) may involve vasoactive peptides. The aim of this study was to investigate associations between CMS and levels of B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS). A total of 24 patients with CMS and 50 control subjects residing at 4,300 m participated in this study. Mean pulmonary arterial pressure (mPAP) was measured by echocardiography. Serum BNP, VEGF, ET-1, and eNOS were measured. Receiver operator characteristic curves to assess the balance of sensitivity and specificity for CMS were constructed. As a result, patients with CMS had significantly greater mPAP compared with controls and had lower arterial O(2) saturation (Sa(O(2))). Both BNP and ET-1 correlated positively with mPAP and negatively with Sa(O(2)), whereas serum VEGF levels were inversely correlated with Sa(O(2)); eNOS correlated negatively with mPAP and positively with Sa(O(2)). Median concentrations of BNP were greater in patients with CMS compared with those without CMS: 369 pg/ml [interquartile range (IQR) = 336-431] vs. 243 pg/ml (IQR = 216-279); P < 0.001. Similarly, concentrations of VEGF [543 pg/ml (IQR = 446-546) vs. 243 pg/ml (IQR = 216-279); P < 0.001] and ET-1 [14.7 pg/ml (IQR = 12.5-17.9) vs. 11.1 pg/ml (IQR = 8.7-13.9); P = 0.05] were higher in those with CMS compared with those without, whereas eNOS levels were lower in those with CMS [8.90 pg/ml (IQR 7.59-10.8) vs. 11.2 pg/ml (9.13-13.1); P < 0.001]. The areas under the receiver operator characteristic curves for diagnosis of CMS were 0.91, 0.93, 0.77, and 0.74 for BNP, VEGF, ET-1, and eNOS, respectively. In age- and biomarker-adjusted logistic regression, BNP and VEGF were positively predictive of CMS, whereas eNOS was inversely predictive. In conclusion, severe chronic hypoxemia and consequent pulmonary hypertension in patients with CMS may stimulate release of natriuretic peptides and angiogenic cytokines. These vasoactive peptides may play an important role in the pathogenesis and clinical expression of CMS and may indicate potential prognostic factors in CMS that could serve as targets for therapeutic trials or clinical decision making.
Assuntos
Doença da Altitude/sangue , Endotelina-1/sangue , Peptídeo Natriurético Encefálico/sangue , Óxido Nítrico Sintase Tipo III/sangue , Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Doença da Altitude/diagnóstico , Doença da Altitude/enzimologia , Pressão Sanguínea/fisiologia , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/enzimologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Curva ROC , Sensibilidade e Especificidade , UltrassonografiaRESUMO
A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was approximately 10-fold greater in fetal (17.6 +/- 1.6) than adult (1.7 +/- 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP.microg sGC(-1).min(-1)) was similar in fetal (255 +/- 64) and adult (280 +/- 75) arteries and was inhibited by chronic hypoxia in both fetal (120 +/- 10) and adult (132 +/- 26) arteries. Rates of cGMP degradation (in pmol cGMP.mg protein(-1).min(-1)) were similar in fetal (159 +/- 59) and adult (134 +/- 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 +/- 25) or adult (108 +/- 25) arteries. The cGMP analog 8-(p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD(2) = 4.7 +/- 0.1) than adult (pD(2) = 4.3 +/- 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.
Assuntos
Artérias Cerebrais/enzimologia , Feto/irrigação sanguínea , Guanilato Ciclase/metabolismo , Hipóxia/enzimologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Ovinos/fisiologia , Doença da Altitude/complicações , Doença da Altitude/enzimologia , Animais , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiologia , Doença Crônica , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Fatores Relaxantes Dependentes do Endotélio/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Guanilato Ciclase/antagonistas & inibidores , Hipóxia/etiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiologia , Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Gravidez , Quinoxalinas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Guanilil Ciclase Solúvel , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
The I-allele rather than the D-allele of the human angiotensin converting enzyme (ACE) gene has been associated with high-altitude mountaineering success. We investigated whether the I-allele was associated with summit success, and also with AMS development, in altitude-naïve trekkers. Subjects ascended from 1,860 m to the summit over 4 days (n = 34, 'direct-profile') or 5 days (n = 82, 'slower-profile'). Proportionally more II direct-profile subjects were successful than ID or DD, although the difference was not significant (100% of II subjects, 52% ID and 43% DD, P = 0.09). There was no difference in success amongst subjects on the slower-profile (50% II, 45% ID and 58% DD, P = 0.54). There was a non-significant trend for increasing AMS scores in ID/DD subjects. Amongst tourist trekkers on Mt. Kilimanjaro the I-allele is not associated with summit success. No evidence is found to support an association between ACE genotype and AMS development.
Assuntos
Doença da Altitude/enzimologia , Doença da Altitude/genética , Frequência do Gene , Predisposição Genética para Doença , Montanhismo/fisiologia , Peptidil Dipeptidase A/genética , Aclimatação/genética , Doença Aguda , Adulto , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tanzânia , Estudos de Tempo e MovimentoRESUMO
The pharmacotherapy of prevention and treatment of acute altitude- related problems - acute mountain sickness, high-altitude cerebral oedema and high-altitude pulmonary oedema - is reviewed. Drug therapy is only part of the answer to the medical problems of high altitude; prevention should include slow ascent and treatment of the more severe illnesses should include appropriate descent. Carbonic anhydrase inhibitors, in particular acetazolamide, remain the most effective drugs in preventing, to a large extent, the symptoms of acute mountain sickness, and can be used in the immediate management of the more severe forms of altitude-related illnesses. Glucocorticoids in relatively large doses are also effective preventative drugs, but at present are largely reserved for the treatment of the more severe acute mountain sickness and acute cerebral oedema. Calcium channel blockers and PDE-5 inhibitors are effective in the management of acute pulmonary oedema. Further work is required to establish the role of antioxidants and anticytokines in these syndromes.
Assuntos
Doença da Altitude/prevenção & controle , Edema Encefálico/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Hipóxia/prevenção & controle , Edema Pulmonar/tratamento farmacológico , Aclimatação , Acetazolamida/uso terapêutico , Doença Aguda , Doença da Altitude/complicações , Doença da Altitude/enzimologia , Antioxidantes/uso terapêutico , Edema Encefálico/enzimologia , Edema Encefálico/etiologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Hipóxia/enzimologia , Hipóxia/etiologia , Montanhismo/lesões , Inibidores da Fosfodiesterase 5 , Edema Pulmonar/enzimologia , Edema Pulmonar/etiologiaRESUMO
Previous genetic association studies in high-risk subjects have suggested that polymorphisms in the gene encoding endothelial nitric oxide synthase (eNOS) may be associated with susceptibility to high altitude pulmonary edema (HAPE). We aimed to determine whether eNOS polymorphisms influence systolic pulmonary artery pressure measurements (PASP) in healthy trekkers ascending to high altitude. We examined two polymorphisms of the eNOS gene in Caucasian volunteers: Glu298Asp variant and 27-base pair (bp) variable number of tandem repeats polymorphism (27-bp VNTR). In 33 subjects, the relationships between polymorphisms and absolute pulmonary artery systolic pressure measurements (PASP), determined by echocardiography, were assessed at sea level and 1, 3, and 7 days after acute ascent by vehicle transport to 5200 m. As expected, there was a significant rise in pulmonary artery pressure on ascent to high altitude. By contrast, at sea level and at each time point at high altitude, no difference was found in mean PASP according to eNOS polymorphism. We found no association of Glu298Asp and 27-bp VNTR polymorphisms in the eNOS gene with PASP in a population of healthy trekkers at low or high altitude.
Assuntos
Doença da Altitude/genética , Altitude , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Artéria Pulmonar/fisiologia , Edema Pulmonar/genética , Adolescente , Adulto , Doença da Altitude/complicações , Doença da Altitude/enzimologia , Pressão Sanguínea/genética , Ecocardiografia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Edema Pulmonar/enzimologia , Edema Pulmonar/etiologiaRESUMO
This study aimed to test the hypothesis that mild hypoxic preconditioning (MHPC)-induced NOS expression would attenuate the neuropathological changes in the nodose ganglion (NG) of severe hypoxic exposure (SHE) rats. Thus, the young adult rats were caged in the altitude chamber for 4 weeks prior to SHE for 4 h to gain hypoxic preconditioning. The altitude chamber was used to set the height at the level from 5500 m (0.50 atm; pO2=79 Torr) to 10,000 m (0.27 atm; pO2=43 Torr) for MHPC and SHE, respectively. The experimental animals were allowed to survive for 0, 7, 14, 30 and 60 successive days, respectively. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry were used to detect NADPH-d/nNOS reactivity in the NG at various time points following hypoxic exposure. The present results showed that about 38% of the neurons in the NG displayed NADPH-d/nNOS positive [NADPH-d/nNOS(+)] in normoxic rats. In SHE rats, a peak in the percentage (71%) and staining intensity (230%) of NADPH-d/nNOS(+) nodose neurons at 0 day, which then gradually decreased at 7-60 days. About 25% of the nodose neurons died 60 days after SHE. However, in MHPC rats subjected to SHE, NADPH-d/nNOS(+) neurons peaked in the percentage (51%) and staining intensity (171%) at 0 day, which then decreased at 7-60 days. In addition, neuronal survival was markedly increased by MHPC. These results suggested that MHPC might have a neuroprotective effect that reduces the susceptibility of the nodose neurons to NOS mediated neuropathy subsequent to SHE.
Assuntos
Doença da Altitude/enzimologia , Hipóxia/enzimologia , NADPH Desidrogenase/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios Aferentes/enzimologia , Óxido Nítrico Sintase/metabolismo , Gânglio Nodoso/enzimologia , Doença da Altitude/fisiopatologia , Doença da Altitude/prevenção & controle , Animais , Apoptose/fisiologia , Câmaras de Exposição Atmosférica , Contagem de Células , Modelos Animais de Doenças , Hipóxia/fisiopatologia , Imuno-Histoquímica , Masculino , Neurônios Aferentes/citologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I , Gânglio Nodoso/citologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The erythrocytes represent an important source of antioxidant capacity of the blood. Catalase (EC 1.11.1.6.) is one of the enzymatic components of their antioxidant defense system. The objective of this study was to follow erythrocyte catalase (CAT) in 7-, 15-, 21-, 35-, 60- and 90-day-old Wistar rats of both sexes in normoxia and after exposure to intensive acute hypobaric hypoxia. During the development CAT activity increases in both sexes, but the rise was usually higher in females. Hypobaric hypoxia increased CAT activity in all studied age groups of both sexes. However, higher CAT activity in females was less affected by hypoxia than the lower activity in males. This was true for nearly all age groups studied. It can be concluded that both ontogenetic aspects and sex differences play a major role in establishing the activity of CAT, which is an important part of the antioxidant defense of the organism.
Assuntos
Envelhecimento/metabolismo , Doença da Altitude/sangue , Doença da Altitude/enzimologia , Catalase/sangue , Eritrócitos/enzimologia , Doença Aguda , Animais , Ativação Enzimática , Feminino , Masculino , Ratos , Ratos Wistar , Fatores SexuaisAssuntos
Doença da Altitude/sangue , Peroxidação de Lipídeos , Oxirredutases/metabolismo , Doença Aguda , Adulto , Doença da Altitude/enzimologia , Glutationa/sangue , Glutationa Peroxidase/sangue , Humanos , Masculino , Militares , Óxido Nítrico/sangue , Óxido Nítrico Sintase/sangue , Superóxido Dismutase/sangueRESUMO
This study investigates changes of adenylyl cyclase activity in the heart of young and adult Wistar rats exposed to experimental conditions simulating high altitude hypoxia as a model for interpretation of some adaptive changes of adenylyl cyclase observed in human. The exposure of rats to intermittent high altitude (IHA) hypoxia (5000 m) showed significant adaptive changes. The right ventricular weight and the ratio of right/left ventricular weights of adult rats exposed to IHA were significantly increased when compared to appropriate controls; adaptive changes of cardiac adenylyl cyclase being dependent on the age of the animals. The isoprenaline-stimulated activity was higher in the left than in the right ventricle, and in both ventricles it was higher in young rats than in adult rats. When compared to controls, isoprenaline stimulation was decreased in the right ventricles of adapted young rats and, by contrast, it was increased in the left ventricles of adapted adult rats. This decrease and increase of adenylyl cyclase activity evoked by isoprenaline was paralleled by forskolin-induced adenylyl cyclase activity in these experimental groups. It seems therefore that the changes in the pattern of total adenylyl cyclase activity observed under IHA hypoxia may at least be partially explained by the changes of beta-adrenergic receptor susceptibility following IHA hypoxia.