Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Effects of gene polymorphisms of β1 adrenergic receptor G1165C and A145G locus on myocardial hypertrophy and the efficacy in patients with hypertension / 中国医师进修杂志

Objective:To investigate the effect of gene polymorphism of β1 adrenergic receptor (β1-AR) G1165C and A145G locus on myocardial hypertrophy and the efficacy in patients with hypertension.Methods:Two hundred and twenty-seven cases of patients with hypertension admitted to Binhai County People′s Hospital from January to December 2019 were enrolled. Among them, there were 113 cases of hypertension with myocardial hypertrophy and 114 cases of hypertension without myocardial hypertrophy. In addition, 115 patients with normal physical examination during the same period were selected as the control group. DNA in the peripheral blood leukocytes was extracted, polymerase chain reaction-restriction fragment length polymorphism method was used to detect β1-AR G1165C and A145G locus gene polymorphism, and the differences in the efficacy of β blockers in hypertensive patients with different genotypes were compared.Results:There was no statistically significant differences in the distribution of β1-AR A145G genotypes among the three groups ( P>0.05). Compared with the healthy control group, the frequency of Gly/Gly genotype carrying β1-AR G1165C locus was higher in hypertension with myocardial hypertrophy group, and the frequency of Gly/Arg and Arg/Arg gene were lower; compared with hypertension without myocardial hypertrophy group, the frequency of Gly/Arg+Gly/Gly gene in hypertension with myocardial hypertrophy group was higher; taking Arg/Arg genotype as the control group, carrying Gly/Gly genotype could increase the risk of cardiac hypertrophy in hypertensive patients by 3.159 times ( OR = 3.159, 95% CI 1.240 - 7.412, P<0.05).The frequency of G1165C allele Arg in the hypertension with myocardial hypertrophy group was significantly lower than that in the control group and the hypertension without myocardial hypertrophy group ( P<0.05); the frequency of G1165C allele Gly was significantly higher than that in the control group and the hypertension without myocardial hypertrophy group ( P<0.05); taking Arg/Arg genotype as the control, carrying Gly/Gly genotype could increase the risk of cardiac hypertrophy in hypertensive ( OR = 3.417, 95% CI 1.357 - 7.965, P<0.05). The left ventricular mass index of Gly/Gly genotype patients was (120.38 ± 28.41) g/m 2, which was significantly higher than (99.76 ± 25.16) g/m 2 and (90.30 ± 19.54) g/m 2 of Gly/Arg and Arg/Arg, with statistically significant differences ( F = 10.89, P<0.01). After the treatment, the resting heart rate, systolic blood pressure, diastolic blood pressure and mean arterial blood pressure of patients with G1165C allele Arg hypertension with myocardial hypertrophy were lower than those with G1165C allele Gly, with statistically significant differences ( P<0.05). Conclusions:β1-AR G1165C gene polymorphism is related to the risk of myocardial hypertrophy in hypertensive patients. Carrying the G1165C allele Gly may increase the risk of susceptibility to cardiac hypertrophy, and β-blockers are more effective in hypertensive patients with myocardial hypertrophy who carry the G1165C allele Arg.

Beta-adrenergic pathway activation in head and neck cancer: a comprehensive analysis of the clinical and genomic features using integrated bioinformatics / Ativação da via beta-adrenérgica no câncer de cabeça e pescoço: uma análise abrangente das características clínicas e gênomicas utilizando a bioinformática

O estresse crônico leva à ativação da via de sinalização beta-adrenérgica. Sua ativação tem sido implicada na progressão de diferentes tipos de câncer, mas seu papel nos carcinomas espinocelulares de cabeça e pescoço (CECPs) permanece indefinido. O objetivo deste estudo foi investigar o papel da ativação da via betaadrenérgica na progressão dos CECPs, avaliar seu impacto na sobrevida dos pacientes e buscar possíveis terapias para pacientes que encontravam-se com a via beta-adrenérgica ativa. Quinhentos e vinte pacientes do The Cancer Genome Atlas com CECPs primários foram divididos em dois grupos: ADRB2baixa / SLC6A2baixa e ADRB2alta / SLC6A2alta. A associação de características clinicopatológicas e genômicas entre os grupos foram analisadas utilizando bioinformática. Os genes diferencialmente expressos (DEGs) foram identificados através da análise da expressão diferencial. A análise de sobrevida também foi realizada com base nas expressões ADRB2 e SLC6A2. Foram identificados medicamentos em potencial para tratamento de CECPs com base nos DEGs. Houve associação entre as expressões ADRB2 e SLC6A2 com idade, raça, localização do tumor, grau histológico, invasão perineural e status do HPV p16. Foram identificados 898 DEGs entre os grupos. Foi demonstrado que a expressão ADRB2alta / SLC6A2alta influenciou a proliferação, adesão e invasão de células CECPs além da angiogênese. Pacientes com carcinomas espinocelular de laringe e faringe apresentando expressão ADRB2alta / SLC6A2alta tiveram menor sobrevida. Por fim, 56 drogas antineoplásicas e imunoterápicas aprovadas pelo Food Drugs Administration foram identificadas como potenciais alvos para o tratamento personalizado. Significância: Estes achados sugerem fortemente um papel proeminente da sinalização beta-adrenérgica no CECPs ao estimular um fenótipo tumoral mais agressivo. Estas alterações tiveram um impacto negativo no prognóstico dos pacientes com CECP em região de faringe e laringe(AU)

Chronic stress leads to the activation of the beta-adrenergic pathway. Its activation has been implicated in the progression of different types of cancer but its role on head and neck squamous cell carcinomas (HNSCCs) remains undefined. The aim of this study was to investigate the influence of the beta-adrenergic pathway activation in the progression of HNSCCs, assess its impact in the survival of the patients, and explore the potential targets. Five hundred and twenty The Cancer Genome Altas patients with primary HNSCCs were divided in two groups: ADRB2low / SLC6A2low and ADRB2high / SLC6A2high. The association of clinicopathological and genomic features between the groups was analyzed using a bioinformatic approach. Differentially expressed genes (DEGs) were identified through differential expression analysis. Survival analysis was also performed based on ADRB2 and SLC6A2 expressions. Potential drugs for treatment of HNSCC were identified based on the DEGs. There was association between ADRB2 and SLC6A2 expressions with age, race, tumor site, histologic grade, perineural invasion, and HPV p16 status. It was identified 898 DEGs between the groups. It was demonstrated that ADRB2high / SLC6A2high expression influenced HNSCC cells proliferation, adhesion, invasion, and angiogenesis. Patients with larynx and pharynx squamous cell carcinomas presenting ADRB2high / SLC6A2high expression showed had lower survival rates. Finally, 56 Food Drugs Administration-approved antineoplastic and immunotherapeutic drugs were identified as potential targets for the personalized treatment. Significance: These findings strongly suggest a prominent role of beta-adrenergic pathway in HNSCC by stimulating a more aggressive tumoral phenotype. These alterations were shown to negatively impact the prognosis of patients with larynx and pharynx squamous cell carcinomas(AU)

In vitro effects of propranolol and isoproterenol on the expression of beta-2 adrenergic receptor on infantile hemangioma endothelial cells / 中华皮肤科杂志

Objective To explore the role of beta-2 adrenergic receptor in the pathogenesis of infantile hemangioma.Methods In vitro cultured infantile hemangioma endothelial cells were divided into propranolol and isoproterenol groups.The propranolol groups were further classified into 5 groups to be treated with propranolol solutions at concentrations of 10,15,20 μg/ml,EGM-2 medium (blank control group 1),and EGM-2 medium containing 0.16％ DMSO (DMSO group) respectively,while the isoproterenol groups were classified into 4 groups to be treated with isoproterenol solutions at concentrations of 5,10,20 μg/ml and EGM-2 medium (blank control group 2) respectively.After 24-and 48-hour treatment,enzyme-linked immunosorbent assay (ELISA) was performed to measure the expression of beta-2 adrenergic receptor in cell culture supernatants in the above groups.Results After 24-hour treatment,15-μg/ml and 20-μg/ml propranolol groups showed significantly decreased expression of beta-2 adrenergic receptor compared with blank control group 1 and DMSO group (all P ＜ 0.05).After 48-hour treatment,all the propranolol groups showed significantly decreased expression of beta-2 adrenergic receptor compared with the blank control group 1 (all P ＜ 0.05).However,the expression of beta-2 adrenergic receptor was significantly higher in the 10-and 20-μg/ml isoproterenol groups than in the blank control group 2 after 24-hour treatment (all P ＜ 0.05),and higher in the 20-μg/ml isoproterenol group than in the blank control group 2 after 48-hour treatment (P ＜ 0.05).Conclusion Propranolol can down-regulate the expression of beta-2 adrenergic receptor on the surface of vascular endothelial cells,while isoproterenol can up-regulate its expression.

β3-adrenoceptor activation promotes cholesterol efflux from foam cells by upregulating apoA-Ⅰ expression / 中华老年心脑血管病杂志

Objective To study the mechanism of β3 adrenoceptor (β3-AR) activation underlying cholesterol efflux by activating or inhibiting the β3-AR of HepG2 cells.Methods Cultured HepG2 cells were randomly divided into control group,β3-AR agonist group and β3-AR antagonist group.Serum levels of apoA-Ⅰ,apoA-Ⅱ,and β3-AR in supernatant fluid,and cholesterol,free cholesterol,cholesterol ester in HepG2 cells were measured by ELISA.Cholesterol efflux from macrophages was tested by 3H-labled cholesterol.Expressions of ABCA1 and LXRα mRNA and protein were detected by RT-PCR and Western blot respectively.Results The efflux rate of apoA-Ⅰ,cholesterol and cholesterol ester was significantly higher while the serum levels of cholesterol and cholesterol ester were significantly lower and the expression levels of ABCA1 and LXRα mRNA and protein were significantly higher in β3 AR agonist group than in control group.The serum levels of cholesterol and cholesterol ester were significantly higher while the efflux rate of cholesterol and cholesterol ester and the expression levels of ABCA1 and LXRα mRNA and protein were significantly lower in β3-AR antagonist groupt than in β3-AR agonist group (0.49±0.10 vs 1.24±0.02,0.85±0.05 vs 1.32±0.05,0.38±0.01 vs 1.45±0.20,0.08±0.01 vs 0.76±0.02,P＜0.01).Conclusion β3 AR promotes cholesterol efflux by upregulating the expression of apoA-Ⅰin HepG2 cells.

β3-adrenoceptor in heart and lungs of elderly heart failure rats / 中华老年心脑血管病杂志

Objective To study the β3-adrenoceptor (β3-AR) in heart and lungs of elderly heart failure (HF) rats.Methods Forty-eight elderly HF Wistar rats were included in this study.A HF model of rats was established by ligating the aorta.The rats were divided into sham operation group (n=24) and HF group (n=24).The rats in each group were further divided into 4 subgroups at weeks 5,7,9 and 11 after operation (6 in each group).The hemodynamics,pathology and expression of β3-AR mRNA and protein in heart and lungs were detected at weeks 5,7,9 and 11 respectively after operation.Results The heart rate,LVESP,and dp/dtmax were significantly lower in HF group than in sham operation group at weeks 9 and 11 after operation while the LVEDP was significantly higher in HF group than in sham operation group at weeks 5,7,9 and 11 after operation (P＜0.01).Pulmonary edema occurred at week 7 after operation and myocardial necrosis was detected at week 9 after operation.The expression level of β3-AR mRNA in lungs was significantly lower in HF group at weeks 5,7,9 and 11 than at week 2 after operation (P＜0.05).The expression level of β3-AR mRNA in heart was significantly higher in HF group than in sham operation group at weeks 9 and 11 after operation (1.21±0.26 vs 0.98±0.22,1.26±0.23 vs 1.05±0.24,P＜0.01).Conclusion The β3-AR mRNA expression is downregulated in the lungs and upregulated in the heart.

Impact of the beta-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between beta adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study

BACKGROUND/AIMS: We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF). METHODS: One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year. RESULTS: Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the beta-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 +/- 14.3 to 70.0 +/- 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 +/- 2.62 mg vs. 3.96 +/- 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group. CONCLUSIONS: The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring beta-blocker therapy according to genotype.

Overexpression of β3-adrenoreceptor aggravates cardiac hypertrophy / 实用医学杂志

Objective To investigate the effect of β3-adrenoreceptor (β3-AR)overexpression on cardiac hypertrophy. Method Sprague-Dawley rat neonatal ventricular cardiomyocytes (NRVMs) were isolated and cul-tured in vitro.The infection of lentiviruswas examined after cardiomyocytes were infected with lentivirus at differ-ent multiplicity of infection (MOI) of 20、50、80 and 100. Fluorescence microscopy was used to observe the ex-pression of GFP and to confirm the best MOI for lentivirus infection. Following the enforced expression of β3-AR by lentivirus, 2uM norepinephrine (NE) was used to treatment the infected cardiomyocytes for 48h. Expressions of β3-AR、c-myc and c-fos protein in cardiomyocytes were detected by Western Blot. Results The results of fluorescence microscopy indicated that the best MOI was 50. The protein level of β3-AR was significantly in-creased in β3-AR overexpression group compared with the control group and the NE treatment group (P < 0.05). Following the treatment of NE , the expressions of c-myc and c-fos were also significantly increased in β3-AR overexpression group compared with the control group (P < 0.05). Conclusion Over-expression of β3-AR can aggravate cardiomyocyte hypertrophy.

Relationship Between β2-Adrenergic Receptor Gln27Glu Gene Polymorphism and Essential Hypertension Occurrence in Tibetan Population Living at High Altitude Area / 中国循环杂志

Objective: To investigate β2 adrenergic receptor (β2-AR) gene polymorphism, Arg16Gly, Gln27Glu and essential hypertension (EH) occurrence in Tibetan population living at high altitude area. Methods: Our research included in 2 groups: EH group, n=385 patients and Control group,n=297 normal healthy subjects. β2-AR polymorphisms of Arg16Gly and Gln27Glu were detected by Snapshot mini-sequencing technique and their frequencies were compared between 2 groups and male, female genders. Results: The genotype and allele frequency distributions of Arg16Gly and Gln27G1u were similar between 2 groups, P>0.05; there were no signiifcant differences between male and female genders,P>0.05. Conclusion: No obvious relationship was found between β2-AR gene polymorphism (Arg16Gly, Gln27Glu) and EH occurrence in Tibetan population living at high altitude area.

Role of β2-adrenergic receptor polymorphisms in prognosis of myasthenia gravis with other autoimmune diseases / 中华神经科杂志

Objective To explore the correlation of β2-adrenergic receptor (β2-AR)polymorphisms (Arg16Gly) with the prognosis of myasthenia gravis (MG) complicated with other autoimmune diseases.Methods Among the 75 MG patients in analysis,17 cases were complicated with other autoimmune diseases (AIDMG),58 cases without other autoimmune diseases (NAIDMG).MG patients,AIDMG patients,NAIDMG patients were separately divided into recurrence groups and nonrecurrence groups according to the progression at 2 years after onset.The genotypes of β2-AR in 75 MG patients were determined by gene sequecing.Results The frequencies of three genotypes (Arg/Arg,Arg/Gly and Gly/Gly) in position 16 were 30.8％,50.0％,19.2％ in recurrence MG group and 42.9％,38.8％,18.3％ in non-recurrence MG group respectively.The difference in distribution of the genotypes between recurrence MG group and non-recurrence MG group was not statistically significant (x2 =1.150,P=0.563).The frequencies of Arg and Gly allele were 55.8％ and 44.2％ in recurrence MG group,and 62.2％ and 37.8％ in non-recurrence MG group.The difference in distribution of the alleles between the two groups was not statistically significant.The frequencies of 3 genotypes in position 16 were 27.3％,63.6％ and 9.1％ in recurrence AIDMG group and 100.0％,0,0 in non-recurrence AIDMG group,respectively.The frequencies of Arg and Gly allele were 59.1％,40.9％ in recurrence AIDMG group,and 100.0％,0 in non-recurrence AIDMG group.The difference in distribution of the genotypes between recurrence AIDMG group and non-recurrence AIDMG group was statistically significant (P =0.009).There also was significant difference in distribution of alleles between recurrence and non-recurrence AIDMG groups (x2 =6.676,P =0.010).The frequencies of 3 genotypes in position 16 were 33.3％,40.0％ and 26.7％in recurrence NAIDMG group and 34.9％,44.2％,20.9％ in non-recurrence NAIDMG group,respectively.The frequencies of Arg and Gly allele were 53.3％,46.7％ in recurrence NAIDMG group,and 57.0％,43.0％ in non-recurrence NAIDMG group.There was no significant difference in distribution of genotypes or alleles between recurrence and non-recurrence NAIDMG groups.Conclusion β2-AR gene polymorphism in position 16 may predict the prognosis of AIDMG,and there is no correlation between the polymorphism in position 16 of β2-AR and the prognosis of MG and NAIDMG.

Effects of right stellate ganglion block on expression of β3-adrenoceptor in rabbits with heart failure / 中华麻醉学杂志

Objective To evaluate the effects of the right stellate ganglion block on the expression of β3adrenoceptor (β3-AR) in rabbits with heart failure.Methods Forty-eight Japanese white rabbits of both sexes,weighing 2.5-3.0 kg,were randomly divided into 3 groups (n =16 each):sham operation group (group S),heart failure group (group HF) and right stellate ganglion block group (group RSGB).Heart failure was induced by occlusion of left anterior descending branch of coronary artery and confirmed by ultrasonic cardiography 4 weeks later.A PE-10 catheter was inserted into the right stellate ganglion for administration of drugs.0.25％ bupivacaine 2 ml was injected through the catheter once a day for 2 weeks in group RSGB,while the equal volume of normal saline was injected instead of bupivacaine in S and HF groups.The left ventricular end-diastolic diameter (LVEDD),left ventricular end-systolic diameter (LVESD),ejection fraction (EF) and left ventricular fractional shortening (LVFS) were measured at 1 day before ligation (T0),before catheter insertion (T1),before 8th administration (T2),and 1 day after the last administration (T3).Eight rabbits were sacrificed at T1 and T3 in each group and myocardial specimens were obtained from the apex of the left ventricle for determination of the expression of β3-AR by Western blot.Results Compared with group S,the LVEDD and LVESD were significantly enlarged and LVEF and LVFS were decreased at T1-3,and the expression of β3-AR was up-regulated at T1,3 in groups HF and RSGB (P ＜ 0.05).Compared with group HF,the LVEDD and LVESD were significantly decreased,LVEF and LVFS were increased,and the expression of β3-AR was significantly down-regulated at T3 in group RSGB (P ＜ 0.05).Conclusion The right stellate ganglion block can improve the cardiac function of rabbits with heart failure through down-regulating the expression of β3-AR in myocardium.

The study of single nucleotide polymorphisms of β2-adrenergic receptor in pancreatic carcinoma / 中华肝胆外科杂志

Objective To investigate the single nucleotide polymorphisms (SNPs) at codons 16 and 27 of β2-AR gene in pancreatic carcinoma and non-neoplastic pancreatic tissues,and the correlations between these SNPs and the expression of β2-AR protein in pancreatic carcinoma.Methods A total of 64 cases of pancreatic carcinoma (PC) and 20 non-neoplastic pancreatic tissues (NPC) were genotyped at codons 16 and 27 by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing.The correlations between the distribution of genotypes and clinicopathological characteristics of pancreatic carcinoma were analyzed.The expression of β2-AR protein was detected by immunohistochemistry in pancreatic carcinoma.Results The distributions of genotype frequency at codons 16 and 27 in PC and NPC were in accordance with the Hardy-Weinbery equeilibrium.The frequencies of their genotypes (AA,AG and GG) and frequencies of alleles A and G at codon 16 between PC and NPC showed no difference.The genotype frequencies were associated with TNM grade,lymph node metastasis,one-year survival rate (P=0.03,0.05,0.04),but they were not associated with patients' gender,age,histological differentiation and size of tumor.The allele G at codon 16 was frequently appeared in tumors with high TNM grade,lymph node metastasis,low one-year survival rate (P＝ 0.01,0.03,0.02),and high expressions of β2-AR protein (P =0.02).The frequencies of two genotypes (CC and CG) and frequencies of alleles C and G at codon 27 showed no difference between PC and NPC.The genotype frequencies and allele frequencies of codon 27 were not associated with patients' clinicopathological features,and expressions of β2-AR protein.Conclusions SNPs of β2-AR gene were associated with biological behaviors of pancreatic carcinoma.Allele G at codon 16 was associated with high risks of lymph node metastasis,high TNM grade,low one-year survival rate,and high expressions of β2-AR protein.Allele G at codon 16 might facilitate the progression and metastasis of pancreatic carcinoma through elevating the expression of β2-AR.SNPs at codon 16 of β2-AR are new useful biomarkers for predicting biological behaviors and survival of pancreatic carcinoma and might be used as a new gene therapeutic target.

Role of β-adrenergic receptor in the occurrence and development of tumor / 国际外科学杂志

The β-adrenergic receptor has close relationship with the occurrence and development of tumor.The β-adrenergic receptors were expressed in a variety of tumors.Its activation can stimulate tumor growth by promoting cell proliferation,inhibite apoptosis,promote angiogenesis,and enhance tumor invasion and metastasis.The β-adrenergic receptor blockers can suppress the tumor growth,which may become one of the effective methods of cancer prevention and treatment.

Combination therapy with single inhaler of long-acting β2-adrenoceptor agonists/inlaled corticosteroids compared with higher dose of inhaled corticosteroids in asthmatic patients / 中国基层医药

Objective To provide a quantitative summary estimate on the efficacy and safety measures of the combination therapy.Methods We searched databases(Medline and Embase)from January 1997 to December 2009 using‘ Fluticasone and salmerterol' or‘ Seretide' or‘ Advair' or‘ budesonide/formoterol' or‘ Symbicort Turbuhaler' in combination with ‘ Randomised controlled trial'.The databases of GlaxoSmithKline Clinical Trial Register and Cochrane Controlled Trials Register,or relevant original studies and review articles were approached for additional studies or details of all relevant studies.Results Morning peak expiratory flow(PEF),evening PEF and clinic FEV1 were 17.59L/min,14.95L/min and 0.08L/min higher with combination therpy than with increasing ICSs by two fold or more at endpoint,respectively.The risk of asthmatic exacerbation was reduced in the combination therpy group compared with the increased doses of ICS groups,with OR being 0.61(95 ％ CI 0.53 ～ 0.70,P ＜ 0.01).Significantly increases in the percent of symptom-free days 6.30(95％ CI 3.52 ～9.10),asthma-control days 9.49(95％ CI 4.74 ～14.25)and relieve-free days 6.59(95％ CI 6.10 ～ 7.08)were observed in patients treated with ICS/LABA compared with increased doses of ICSs at endpoint.Reduction in reliever medication use(inhalations/day)0.22(95 ％ CI 0.11 ～0.33)with significant difference was also observed at endpoint.Conclusion Combination products of ICS/LABA were more effective than a high dose of ICSs in improving lung function,reducing asthmatic exacerbation and use of reliever medication and improving control of asthma.

Disfunção miocárdica e alterações no trânsito de cálcio intracelular em ratos obesos / Myocardial dysfunction and abnormalities in intracellular calcium handling in obese rats

FUNDAMENTO: Vários mecanismos têm sido propostos contribuir para a disfunção cardíaca em modelos de obesidade, tais como alterações nas proteínas do trânsito de cálcio (Ca+2) e nos receptores beta-adrenérgicos. Todavia, o papel desses fatores no desenvolvimento da disfunção miocárdica induzida pela obesidade ainda não está claro. OBJETIVO: Este estudo pretende investigar se a obesidade induzida por um ciclo de dieta hipercalóricas resulta em disfunção cardíaca. Além disso, foi avaliado se essa alteração funcional em ratos obesos está relacionada com o prejuízo do trânsito de Ca+2 e do sistema beta-adrenérgico. MÉTODOS: Ratos Wistar machos, 30 dias de idade, foram alimentados com ração padrão (C) e um ciclo de cinco dietas hipercalóricas (Ob) por 15 semanas. A obesidade foi definida pelo aumento da porcentagem de gordura corporal dos ratos. A função cardíaca foi avaliada mediante análise isolada do músculo papilar do ventrículo esquerdo em condições basais e após manobras inotrópicas e lusitrópicas. RESULTADOS: Em comparação com o grupo controle, os ratos obesos apresentaram aumento da gordura corporal e intolerância a glicose. Os músculos dos ratos obesos desenvolveram valores basais semelhantes; entretanto, as respostas miocárdicas ao potencial pós-pausa e aumento de Ca+2 extracelular foram comprometidas. Não houve alterações na função cardíaca entre os grupos após a estimulação beta-adrenérgica. CONCLUSÃO: A obesidade promove disfunção cardíaca relacionada com alterações no trânsito de Ca+2 intracelular. Esse prejuízo funcional é provavelmente ocasionado pela redução da atividade da bomba de Ca+2 do retículo sarcoplasmático (SERCA2a) via Ca+2 calmodulina-quinase.

BACKGROUND: Several mechanisms have been proposed to contribute to cardiac dysfunction in obesity models, such as alterations in calcium (Ca2+) handling proteins and β-adrenergic receptors. Nevertheless, the role of these factors in the development of myocardial dysfunction induced by obesity is still not clear. OBJECTIVE: The purpose of this study was to investigate whether obesity induced by hypercaloric diets results in cardiac dysfunction. Furthermore, it was evaluated whether this functional abnormality in obese rats is related to abnormal Ca2+ handling and the β-adrenoceptor system. METHODS: Male 30-day-old Wistar rats were fed with standard food (C) and a cycle of five hypercaloric diets (Ob) for 15 weeks. Obesity was defined as increases in body fat percentage in rats. Cardiac function was evaluated by isolated analysis of the left ventricle papillary muscle under basal conditions and after inotropic and lusitropic maneuvers. RESULTS: Compared with the control group, the obese rats had increased body fat and glucose intolerance. The muscles of obese rats developed similar baseline data, but the myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ were compromised. There were no changes in cardiac function between groups after β-adrenergic stimulation. CONCLUSION: Obesity promotes cardiac dysfunction related to changes in intracellular Ca2+ handling. This functional damage is probably caused by reduced cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activation via Ca2+ calmodulin kinase.

The protective effect of the 27-β2 adrenergic receptor genetic polymorphisms in airway hyperreactivity / 中国基层医药

Objective To analyze the association between β2-AK 27 locus genetic polymorphisms and asthma, and the protective effect in airway hyperreactivity. Methods The allel polymerase chain reaction were used to determine β2-AR 27 locus genetic polymorphisms in 149 patients with cough variant asthma who have the airway hyperreactivity. To observe these people for two years in order to know the proportion of changed to typical asthma. And compare with 90 people in healthy group. Results (1) The distribution frequency of β2-AR 27 locus genetic polymorphisms is major in heterozygote (57 % ) , and the Glu/Glu homozygote has the least ( 20% ) , (2) There was a significant decrease in the frequency of Glu/Glu genotype in asthmatics compared with healthy group(9% VS 20% ) ,OR = 0.4(P<0.05) ,95% CI (0.2 ～0. 9) ,but there was no significant difference in the allele frequency of asthmatics compared with healthy group,(3)The frequency of Glu/Glu genotype in severe asthma was lower than stable asthma group(P<0. 05). Conclusion These results suggesteded that β2-AR 27 locus genetic polymorphisms is correlated with asthma,and the Glu27 could have the protective effect to the airway.

A seven-year follow-up study on the relationship between Trp64Arg mutation in the β3-adrenergic receptor gene and hypertension in obese subjects / 中国医师进修杂志

Objective To investigate the relationship between Trp64Arg mutation in the β3-adrenergic receptor (β3-AR) gene and the incidence of hypertension in obese subjects. Methods A seven-year follow-up study was conducted in 377 simple obese subjects who had Trp64Arg mutation in the β3-AR gene and some clinical metabolic parameters, such as body mass index, waist circumference, waist-hip ratio, blood pressure, lipid profile, fasting blood glucose, fasting insulin and insulin resistance index (HOMA-IR) were measured in the year of 2000 and 2007. Results The results of follow-up indicated that the incidence of hypertension in Trp64Arg heterozygote subjects were higher than that in Trp64Trp homozygote subjects (52.7% ,69/131 vs 37.0% ,91/246,P < 0.01), the difference was only seen in male (59.5%, 50/84 vs 45.1%, 64/142, P < 0.05). The incidence of hypertension in both Trp64Trp homozygote and Trp64Arg heterozygote subjects were higher in obese male than those in obese female (P < 0.01 or <0.05). After seven years, the blood pressure increased (9.7 ± 4.3)/(5.4 ± 4.0) mm Hg(1 mm Hg = 0.133 kPa) in Trp64Trp homozygote,and (12.8 ± 5.2)/ (7.9 ± 4.7) mm Hg in Trp64Trp heterozygote subjects. Compared with that in Trp64Trp homozygote subjects, lipid profile, fasting insulin and HOMA-IR was increased significantly in Trp64Trp heterezygote subjects (P < 0.05). Logistic analysis showed that β3-AR gene mutation, male, central obesity and insulin resistance were associated with the incidence of hypertension in obese subjects. Conclusion The β3-AR gene Trp64Arg mutation is the independent risk factor in the incidence of hypertension in male.

Avaliação do bloqueio simpático cervico-torácico esquerdo por clipagem em portadores de insuficiência cardíaca sistólica sintomática com terapia medicamentosa otimizada / Left sympathetic surgical blockade in systolic heart failure patients with optimal medical therapy

FUNDAMENTO: A modulação adicional do sistema nervoso simpático em pacientes com insuficiência cardíaca sistólica (ICS) sob tratamento clínico otimizado pode ser benéfica. Objetivo: Avaliar a exequibilidade e segurança do BSCTE em pacientes com ICS sintomática, refratária ao tratamento farmacológico incluindo beta-bloqueadores (BB). Secundariamente, avaliamos os seus efeitos no sistema cardiovascular tanto no perioperatório quanto após seis meses de seguimento. MÉTODOS: Ensaio clínico com duplo sorteio com "concealed allocation". Pacientes com ICS e Fração de ejeção do VE (FEVE) = 40%, CF da NYHA II ou III, ritmo sinusal e FC > 65 bpm a despeito do uso adequado de BB foram incluídos. Pacientes com cardiomiopatia chagásica, congênita, valvar e com marcapasso ou comorbidades graves foram excluídos. A cada três pacientes incluídos, era realizado um duplo sorteio com um paciente alocado no grupo controle (G1) e dois pacientes no grupo tratamento (G2). O procedimento consistia em videotoracoscopia esquerda, em posição semi-sentada, com intubação seletiva e sob anestesia geral, com controle de parâmetros hemodinâmicos invasivos nas 24h em UTI. Feita clipagem do 1/3 inferior do gânglio estrelado e do espaço inter-espinhal entre T3 e T4 esquerdos. Critérios previamente estabelecidos de interrupção do estudo e remoção dos clips por via toracoscópica eram morte ou piora grave dos sintomas de IC atribuíveis ao procedimento. Em todos os pacientes, era realizada avaliação clínica, Minnesota Living with Heart Failure Questionnaire (MLHFQ), ecocardiográfica, com Holter de 24h, teste ergoespirométrico, teste de caminhada de 6 minutos, teste de barorreflexo, microneurografia, cintilografia com 123I- metaiodobenzilganidina(MIBG) e ventriculografia radioisotópica(Gated) antes e seis meses após o sorteio. Análise estatística: teste exato de Fischer para proporções; teste t de student não-pareado para variáveis contínuas normais; ANOVA duplo fator quando aplicável...

BACKGROUND: Sympathetic nervous system modulation is the cornerstone treatment for systolic heart failure (SHF). We sought to evaluate the feasibility, safety and potential beneficial effects of additional surgical sympathetic blockade in SHF patients. METHODS: In this prospective randomised controlled trial, inclusion criteria were: NYHA functional class II or III, left ventricular ejection fraction (LVEF) = 40%, sinus rhythm and resting heart rate >65 bpm, despite optimal medical therapy (MT). Fifteen patients were randomly assigned in a 1:2 basis either to MT alone or MT plus surgical treatment (ST). ST consisted of left lower 1/3 stellar ganglion and T3-T4 thoracic interspinal space videothoracoscopic clipping. Primary endpoints were feasibility and safety. Secondary endpoints were changes in clinical status, exercise capacity, quality of life, LVEF and remodeling by echocardiography and heart rate before and after 6 months of randomisation. RESULTS: 10 patients underwent ST and there were no adverse events attributable to surgery. ST improved: LVEF (25±6.6 vs 33±5.2, p=0.03); 6 -min walking distance in meters (167±35 vs 198±47), p=0.02); 24h-Holter mean HR (77±5 vs 72±4, p=0.0003; MLHFQ score (48±10 vs 40±14, p=0.01. 123IMIBG radionuclide scan heart/mediastinum ratio, LV end diastolic diameter, sympathetic peripheral nerve activity, peak VO2, LVEF by Gated, serum BNP levels and 24h Holter NN standard deviation were unchanged. Two patients died at each group. Clinical status improvement was only observed at ST. CONCLUSIONS: ST was feasible and safe in SHF patients. Its beneficial effects warrant the development of a larger randomized trial.

Activation of PPARgamma induces profound multilocularization of adipocytes in adult mouse white adipose tissues

We sought to determine the effects of activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on multilocularization of adipocytes in adult white adipose tissue (WAT). Male C57BL/6 normal, db/db, and ob/ob mice were treated with agonists of PPAR-gamma, PPAR-alpha, or beta3-adrenoceptor for 3 weeks. To distinguish multilocular adipocytes from unilocular adipocytes, whole-mounted adipose tissues were co-immunostained for perilipin and collagen IV. PPAR-gamma activation with rosiglitazone or pioglitazone induced a profound change of unilocular adipocytes into smaller, multilocular adipocytes in adult WAT in a time-dependent, dose-dependent, and reversible manner. PPAR-alpha activation with fenofibrate did not affect the number of locules or remodeling. db/db and ob/ob obese mice exhibited less multilocularization in response to PPAR-gamma activation compared to normal mice. Nevertheless, all adipocytes activated by PPAR-gamma contained a single nucleus regardless of locule number. Multilocular adipocytes induced by PPAR-gamma activation contained substantially increased mitochondrial content and enhanced expression of uncoupling protein-1, PPAR-gamma coactivator-1-alpha , and perilipin. Taken together, PPAR-gamma activation induces profound multilocularization and enhanced mitochondrial biogenesis in the adipocytes of adult WAT. These changes may affect the overall function of WAT.

Effects of substance P pretreatment on norepinephrine-induced β1-adrenoreceptor expression in cultured rat cardiomyocytes / 中华麻醉学杂志

Objective To investigate the effects of substance P (SP) pretreatment on the expression of β1-adrenoreceptor(β1-R) induced by norepinephrine (NE) in cultured neonatal rat cardiomyecytes.Methods The cardiomyocytes obtained from 1-3 day old SD rats were cultured for 72 h.The experiment was performed in 2 parts.In part 1 the cells were seeded in 15 well plate and randomly divided into 5 groups (n=3 wells each):control group (C1)and 4 NE groups were exposed to NE 10-9, 10-8,10-7,10-6 mol/L respectively (NE1,2,3,4).In part Ⅱ the.cells were seeded in 12 well plate and randomly divided into 4 groups (n=3 wells each): group I control (C2): group II NE 10-7 tool/L; group Ⅲ (SN)was pretreated with SP 10-6 mol/L 30 minbefore NE 10-7 mol/L and group IV (NSN)was treated with NK-1 receptor antagonist (NK-1 tachykinin receptor antagonist,S3144) 30 min before SP pretreatment.After exposure to NE for 3 h the expression of β1-R in the rat cardiomyecytes was detected using flow cytometry.Results In part Ⅰ the expression of β1-R was significantly higher in group NE1-3 than in control group (C1),with the highest expression in group NF3.In part Ⅱ the expression of β1-R was significantly higher in group Ⅱ (NE) than in control group (C2) while lower in group Ⅲ (SN) than in control group Ⅱ.(NE).There was no significant difference in the expression of β1-R between group Ⅰ (C2) and group Ⅲ and Ⅳ (NSN).Conclusion Substance P pretreatment can inhibit the up-regulation of β1-R expression in cultured rat cardiomyocytes induced by norepinephrine through activating NK-1 receptor.