Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and im...Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and improvement in quality of life, both in reversible(bronchial asthma) and partially reversible(chronic obstructive airway disease) obstructive airway diseases. β2-adrenoceptor expressed in human airway is the main β-receptor subtype, and its activation in airway smooth muscle cells leads to bronchodilatation. Drugs targeting β-adrenoceptors have been around for many years, for which agonists of the receptors are used in bronchodilation while antagonists are used in cardiovascular diseases. This review article summarizes the effect and usage of β2-agonist in obstructive airway disease, addressing the benefits and potential risks of β2-agonist. The article also looks at the safety of β-blocker usage for cardiovascular disease in patients with obstructive airway disease. There is also emerging evidence that non-selective β-blockers with inverse agonism ironically can have longterm beneficial effects in obstructive airway disease that is beyond cardiovascular protection. Further trials are urgently needed in this area as it might lead to a dramatic turnaround in clinical practice for obstructive airway diseases as has already been seen in the usage of β-blockers for heart failure.展开更多
The aim of this study was to compare the binding profile of a range of β2-adrenoceptor (β2-AR) agonists and antagonists in human lung tissue. Radioligand saturation and competition binding experiments were performed...The aim of this study was to compare the binding profile of a range of β2-adrenoceptor (β2-AR) agonists and antagonists in human lung tissue. Radioligand saturation and competition binding experiments were performed by filtration with a β2-AR antagonist ([3H]propranolol) or agonist ([3H]vilanterol) radioligand and membrane fragments generated from lung parenchyma in the presence of 100 μM guanosine 5’-[β,γ-imido]triphosphate (Gpp(NH)p). In membranes prepared from human lung parenchyma, carmoterol, formoterol, ICI118551, propranolol and salbutamol resulted in inhibition of [3H]vilanterol binding to levels that were significantly different from indacaterol, salmeterol and vilanterol (ANOVA, Bonferroni post-test, P < 0.001 except formoterol vs indacaterol where P < 0.01). Indacaterol and salmeterol resulted in inhibition of [3H]vilanterol binding to levels that were not significantly different from vilanterol (ANOVA, Bonferroni post-test, P > 0.05). Indacaterol, salmeterol and vilanterol resulted in full inhibition of [3H]propranolol binding to levels not significantly different from ICI118551 (ANOVA, Bonferroni post-test, P > 0.05). Indacaterol, salmeterol and vilanterol bind to an additional site in human lung parenchyma membranes that is distinct from the β2-AR.展开更多
Clonidine is a classically categorized α2-adrenoceptor (α2-AR) agonist that produces vascular contractions by stimulating arterial smooth muscle α2-ARs. However, clonidine inhibits α1-AR-mediated arterial contract...Clonidine is a classically categorized α2-adrenoceptor (α2-AR) agonist that produces vascular contractions by stimulating arterial smooth muscle α2-ARs. However, clonidine inhibits α1-AR-mediated arterial contractions. Recently, it was suggested that repeated stimulation with clonidine induces desensitization of α2-ARs, thus inhibiting noradrenaline-induced smooth muscle contractions. In the present study, we examined whether clonidine-mediated inhibition of α1-AR contractions involves interactions with α2-ARs in rat thoracic aortae. 1) Clonidine and guanfacine inhibited electrical field stimulation-induced contractions in a concentration-dependent, yohimbine-sensitive manner in isolated rat vas deferens preparations. 2) Clonidine almost completely suppressed phenylephrine-induced sustained contractions of rat thoracic aortae. 3) Clonidine competitively inhibited phenylephrine-induced contractions with a pA2 value of 6.77 at concentrations between 10-7 and 10-6 M. At 10-5 M, clonidine inhibited phenylephrine-induced contractions and dramatically reduced maximum contractions. 4) In contrast, clonidine did not inhibit contractions produced by high KCl or prostaglandin F2α. 5) Inhibition of phenylephrine-induced sustained contractions by clonidine was also produced in the presence of yohimbine. However, guanfacine did not inhibit phenylephrine-induced sustained contractions. These findings suggest that clonidine inhibits phenylephrine-induced contraction of rat thoracic aortae by competitive antagonism of α1-ARs, which is mediated through a mechanism independent of α2-AR stimulation.展开更多
Antibodies against &-adrenoceptor can be detected in serum of patients with dilated cardiomyopathy (DCM), which have 5-agonist-like activity, and induce a positive chronotropic effect on cardiac myocytes by its pe...Antibodies against &-adrenoceptor can be detected in serum of patients with dilated cardiomyopathy (DCM), which have 5-agonist-like activity, and induce a positive chronotropic effect on cardiac myocytes by its persistence at full strength. Effects of the antibodies against Padrenoceptor from sera of patients with DCM on myocardial cytotoxicity and cytoplasmic free Ca2+-concentration (LCa2+ji) were observed in the cultured single layer SD rat ventricular cells by using the cytotoxicity assay and fluorescent Ca2+- indicat0r fura-2/AM. The positive sera of the anti-&adrenoceptor antibodies from patients with DCM markedly enhanced myocardial [Ca2+]i. Betaloc, a 5, -receptor blocker, might inhibit the increase of the antibody-mediated myocardial [Ca2+]i, and the sera from healthy donors had no effect on myocardial [Ca2+]i,. Our results suggest that the anti-β-adrenoceptor antibody might increase myocardial [Ca2+]i, and result in myocardial damage. The antibodies might activate receptor-gating Ca2+-channel, thereby causing myocardial [Ca2+]i, rise and calcium overload. Early use of betaloc is recommended in the treatment of dilated cardiomyopathy.展开更多
Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s dis...Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer＇s disease. To test this hypothe- sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 （APP/PS1） mice using the agonist clenbuterol （intraperitoneal injection, 2 mg/kg）. We found that β2-adrenoceptor ac- tivation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines, lhese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS 1 mice.展开更多
Norepinephrine plays an important role in motor functional recovery after a brain injury caused by ferrous chloride.Inhibition of norepinephrine release by clonidine is correlated with motor deficits after motor corte...Norepinephrine plays an important role in motor functional recovery after a brain injury caused by ferrous chloride.Inhibition of norepinephrine release by clonidine is correlated with motor deficits after motor cortex injury.The aim of this study was to analyze the role ofα-adrenergic receptors in the restoration of motor deficits in recovering rats after brain damage.The rats were randomly assigned to the sham and injury groups and then treated with the following pharmacological agents at 3 hours before and 8 hours,3 days,and 20 days after ferrous chloride-induced cortical injury:saline,clonidine,efaroxan(a selective antagonist ofα-adrenergic receptors)and clonidine+efaroxan.The sensorimotor score,the immunohistochemical staining forα-adrenergic receptors,and norepinephrine levels were evaluated.Eight hours post-injury,the sensorimotor score and norepinephrine levels in the locus coeruleus of the injured rats decreased,and these effects were maintained 3 days post-injury.However,20 days later,clonidine administration diminished norepinephrine levels in the pons compared with the sham group.This effect was accompanied by sensorimotor deficits.These effects were blocked by efaroxan.In conclusion,an increase inα-adrenergic receptor levels was observed after injury.Clonidine restores motor deficits in rats recovering from cortical injury,an effect that was prevented by efaroxan.The underlying mechanisms involve the stimulation of hypersensitiveα-adrenergic receptors and inhibition of norepinephrine activity in the locus coeruleus.The results of this study suggest thatαreceptor agonists might restore deficits or impede rehabilitation in patients with brain injury,and therefore pharmacological therapies need to be prescribed cautiously to these patients.展开更多
Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations,including insulin resistance,visceral fat accumulation,and dyslipidemias,which increase the risk for develo...Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations,including insulin resistance,visceral fat accumulation,and dyslipidemias,which increase the risk for developing cardiovascular disease.Metabolic syndrome is associated with augmented sympathetic tone,which could account for the etiology of pre-diabetic cardiomyopathy.This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustainedβ-adrenergic response in pre-diabetes,focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy.The research reviewed indicates that both protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ play important roles in functional responses mediated byβ1-adrenoceptors;therefore,alterations in the expression or function of these kinases can be deleterious.This review also outlines recent information on the role of protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ in abnormal Ca^(2+)handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.展开更多
The α2-adrenoceptor agonists are widely applied in perioperative period because they have antinociceptive, sedative, anxiolytic, sympatholytic effects. With the development of investigation, the α2-adrenoceptor agon...The α2-adrenoceptor agonists are widely applied in perioperative period because they have antinociceptive, sedative, anxiolytic, sympatholytic effects. With the development of investigation, the α2-adrenoceptor agonists’ indications are expanded and have not been investigated as a kind of adjuvant. They will not only reduce anesthetic requirements during operation, cause sedation in ICU postoperatively, offer benefits in the prophylaxis of perioperative myocardial ischaemia but probably become some kind of anesthetic by themselves in perioperative application.展开更多
Background β2-adrenoceptor （β2AR） desensitization is a common problem in clinical practice, β2AR desensitization proceeds by at least such three mechanisms as heterologous desensitization, homologous desensitizat...Background β2-adrenoceptor （β2AR） desensitization is a common problem in clinical practice, β2AR desensitization proceeds by at least such three mechanisms as heterologous desensitization, homologous desensitization and a kind of agonist-induced rapid phosphorylation by a variety of serine/threonine kinases. It is not clear whether there are other mechanisms, This study aimed to investigate potential mechanisms of β2AR desensitization.Methods Twenty-four BALB/c （6-8 weeks old） mice were divided into three groups, which is, group A, phosphate buffered saline （PBS）-treated; group B, ovalbumin （OVA）-induced; and group C, salbutamol-treated. Inflammatory cell counts, cytokine concentrations of bronchoalveolar lavage fluid （BALF）, pathological sections, total serum IgE, airway responsiveness, membrane receptor numbers and total amount of β2AR were observed. Asthmatic mouse model and β2AR desensitization asthmatic mouse model were established. Groups B and C were selected for two-dimensional gel electrophoresis （2DE） analysis so as to find key protein spots related to β2AR desensitization.Results Asthmatic mouse model and β2AR desensitization asthmatic mouse model were verified by inflammatory cell count, cytokine concentration of BALF, serum IgE level, airway hyperreactivity measurement, radioligand receptor binding assay, Western blot analysis, and pathologic examination. Then the two groups （groups B and C） were subjected to 2DE. Two key protein spots associated with β2AR desensitization, Rho GDP-dissociation inhibitor 2 （RhoGDl2） and peroxiredoxin 5, were found by comparative proteomics （2DE and mass spectrum analysis）.Conclusion Oxidative stress and small G protein regulators may play an important role in the process of β2AR desensitization.v展开更多
Objective： To investigate the β2-adrenoceptor （ β 2AR）-β-arrestin2-nuclear factor- K B （NF- κ B） signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis. Me...Objective： To investigate the β2-adrenoceptor （ β 2AR）-β-arrestin2-nuclear factor- K B （NF- κ B） signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis. Methods： Forty SD rats were randomly divided into four groups, which included the normal control group, the model group, the mesalazine group and the oxymatrine treatment group, with 10 rats per group. Experimental colitis induced with trinitrobenzene sulfonic acid （TNBS） was established in each group except the normal control group, The rats in the oxymatrine treatment group were treated with intramuscular injection of oxymatrine 63 mg/（kg.d） for 15 days and the rats in the mesalazine group were treated with mesalazine solution 0.5 g/（kg.d） by gastric lavage for 15 days. The rats in the normal control group and model group were treated with 3 mL water by gastric lavage for 15 days. Diarrhea and bloody stool were carefully observed. Histological changes in colonic tissue were examined on day 7 in 2 rats per group that were randomly selected. The expression of β 2AR, β -arrestin2 and NF- κ B p65 in colon tissue and spleen lymphocytes were detected with immunohistochemistry and Western immunoblotting techniques on day 16 after fasting for 24 h. Six rats died of lavage with 2 each in the normal control, the model group and the mesalazine group; and were not included in the analysis. Results： The rats in the model group suffered from looser stool and bloody purulent stool after modeling. But in the oxymatrine and mesalazine groups, looser stool and bloody purulent stool reduced after treatment. And the colonic wall in the model group was thickened and the colon length shortened. The colon mucosa was congested in multiple areas with edema, erosion, superficial or linear ulcer and scar formation, while the intestinal mucosa injury reduced in the mesalazine and oxymatrine groups （P〈0.01）. In colonic mucosa and in spleen lymphocytes, compared with the normal control group, the expression of NF- κ Bp65 were significantly increased （P〈0.01） in the model group while the expressions of β 2AR and β-arrestin2 were significantly decreased （P〈0.01）. Compared with the model group, the expression of NF- κ Bp65 was significantly decreased in the mesalazine group （P〈0.01） and oxymatrine treatment group （P〈0.01） while the expressions of β 2AR and β -arrestin2 were significantly increased （P〈0.01）. There were no statistically significant differences in the expression of β 2AR, β -arrestin2 and NF- κ Bp65 between the mesalazine group and oxymatrine group （P〉0.05）. Conclusions： The β 2AR- β -arrestin2-NF- κ B signal transduction pathway participated in the pathologic course of ulcerative colitis. Oxymatrine attenuated ulcerative colitis through regulating the β 2AR- β -arrestin2-NF- κB signal transduction pathway.展开更多
In order to develop a model for screening the agonists of human β2-adrenoceptor from Chinese medicinal herbs extracts, we used a cell-based functional assay based on a common G protein-coupled receptor （GPCR） regul...In order to develop a model for screening the agonists of human β2-adrenoceptor from Chinese medicinal herbs extracts, we used a cell-based functional assay based on a common G protein-coupled receptor （GPCR） regulation mechanism and destabilized enhanced green fluorescent protein （d2EGFP） reporter gene technique. The positive cell clone was confirmed by real-time polymerase chain reaction （PCR） and imaging analysis. To assess the value of this model, we screened over 2000 high performance liquid chromatography （HPLC）-fractionated samples from the ethanol extracts of Chinese medicinal herbs. Six fractions （isolated from Panax japonicus, Veratrum nigrum, Phellodendron amurense, Fructus Aurantii lmmaturus, Chaenomeles speciosa, and Dictamnus dasycarpus） showed significant effects on active reporter gene expression, three of which （isolated from Phellodendron amurense, Fructus Aurantii lmmaturus, and Chaenomeles speciosa） were selected for further concentration response analysis and the half maximal effective concentration （EC1/2 max） values were 4.2, 2.7, and 4.8 μg/ml, respectively. Therefore, this reporter gene assay was suitable for screening β2-adrenoceptor agonists. The results suggest that the six herbal extracts are the possible agonists of β2-adrenoceptor.展开更多
Background Imbalance of the sympathetic nervous system was involved in the pathogenesis of idiopathic ventricular outflow-tract tachycardia （IVOT）. We aimed to investigate whether the major genetic variants in β1-a...Background Imbalance of the sympathetic nervous system was involved in the pathogenesis of idiopathic ventricular outflow-tract tachycardia （IVOT）. We aimed to investigate whether the major genetic variants in β1-and β2-adrenoceptors and GNB3 C825T were associated with IVOT and verapamil sensitive idiopathic left ventricular tachycardia （ILVT）.Methods Patients with IVOT and ILVT from December 2005 to December 2007 were consecutively enrolled into this study. Controls were randomly selected from the community-based inhabitants. Five genetic variants, Ser49Gly and Gly389Arg in the β1-adrenoceptor, Arg16Gly and Gln27Glu in the β2-adrenoceptor and GNB3 C825T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis.Results A total of 227 patients with IVOT and 110 patients with ILVT were included. Genotyping revealed that the 16Gly allele of Arg16Gly variant of β2-adrenoceptor was associated with a higher risk of IVOT （OR：1.40, 95% CI： 1.12-1.75,P=0.003 in the addictive model and OR：. 1.62, 95% CI： 1.14-2.31, P=0.007 in the dominant model）. Patients with Gly16Gln27 haplotype also had a higher risk of IVOT （OR： 1.38, 95% CI： 1.11-1.73, P=0.012）. Other four variants,including Ser49Gly and Arg389Gly in β1-adrenoceptor, GIn27Glu in β2-adrenoceptor and GNB3 C825T, did not differ between patients with IVOT and controls. In patients with ILVT, no significant difference was found in these five variants compared with controls.Conclusions Arg16Gly in β2-adrenoceptor is significantly associated with IVOT in Chinese Han population. Major genetic variants in β1- and β2-adrenoceptor and GNB3 C825T may not be associated with ILVT. These data suggest a different arrhythmogenic mechanism in IVOT and ILVT.展开更多
β-Adrenoceptors（β-ARs） play a critical role in regulating cardiac functions under both physiological and pathological conditions. To further explore the mechanisms through which β-ARs perform its actions, proteom...β-Adrenoceptors（β-ARs） play a critical role in regulating cardiac functions under both physiological and pathological conditions. To further explore the mechanisms through which β-ARs perform its actions, proteomic approaches were adopted to study the global protein patterns in cultured neonatal rat cardiomyocytes exposed to iseproterenol （ISO）. A modified method, ＂Mirror Images in One Gel＂, was used to improve the reproducibility and resolution power of two-dimensional electrophoresis. A 2-DE map with a good reproducibility was obtained in which 1281 ± 70 spots were detected and about 1191± 54 spots were matched, with an average matching rate of 92. 9%. Nine proteins with significant changes were identified by using peptide mass fingerprinting（PMF） data obtained vht MALDI-MS.展开更多
<b><span style="font-family:Verdana;">The objective of our study</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;&qu...<b><span style="font-family:Verdana;">The objective of our study</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> was to investigate the association between the Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-АR gene and body mass index (BMI) in patients with bronchial asthma (BA) with regard to the age of onset. </span><b><span style="font-family:Verdana;">Materials and methods</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> 553 patients were examined. The control group consisted of 95 apparently healthy individuals. The patients were divided into 2 groups depending on the age of BA onset: 282 patients with late onset (Group I) and 271 patients with early onset (Group II). Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-АR gene (rs1042713) was determined using polymerase chain reaction-</span></span><span style="font-family:;" "=""> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">restriction fragment length polymorphism analysis. Statistical analysis of obtained results was performed using SPSS–17 program. </span><b><span style="font-family:Verdana;">Results</span></b></span><b><span style="font-family:Verdana;">:</span><span style="font-family:;" "=""> </span></b><span style="font-family:;" "=""><span style="font-family:Verdana;">There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-AR gene depending on BMI (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 5.74;р = 0.22), and no association was found with obesity risks disregarding the age of BA onset. The study on the frequency of genotypes for this polymorphism with regard to the age of asthma onset and BMI found statistically significant differences between early-onset (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 11.27;p = 0.02) and late-onset (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 10.66;p = 0.03) asthma. It was found that the risk of obesity in Group I patients was 1.57 times higher in the additive model and 2.67 times higher—in the recessive model of inheritance. In patients with late-onset asthma, Gly16 allele in the recessive model of inheritance was found to have a protective role against obesity. </span><b><span style="font-family:Verdana;">Conclusions</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-AR gene with regard to BMI, and no association was found with obesity risks in BA patients disregarding the age of BA onset. The risk of obesity in patients with early-onset asthma was 1.6 times higher in the additive model and 2.7 times higher—in the recessive model of inheritance.</span></span>展开更多
基金Supported by NMRC/CBRG/0027/2012 from the National Medical Research Council of Singapore(in part)by NUHS Seed Fund R-184-000-238-112
文摘Obstructive airway disease is a complex disease entity including several maladies characterized by bronchoconstriction and abnormal airway inflammation. Reversing bronchoconstriction leads to symptomatic relief and improvement in quality of life, both in reversible(bronchial asthma) and partially reversible(chronic obstructive airway disease) obstructive airway diseases. β2-adrenoceptor expressed in human airway is the main β-receptor subtype, and its activation in airway smooth muscle cells leads to bronchodilatation. Drugs targeting β-adrenoceptors have been around for many years, for which agonists of the receptors are used in bronchodilation while antagonists are used in cardiovascular diseases. This review article summarizes the effect and usage of β2-agonist in obstructive airway disease, addressing the benefits and potential risks of β2-agonist. The article also looks at the safety of β-blocker usage for cardiovascular disease in patients with obstructive airway disease. There is also emerging evidence that non-selective β-blockers with inverse agonism ironically can have longterm beneficial effects in obstructive airway disease that is beyond cardiovascular protection. Further trials are urgently needed in this area as it might lead to a dramatic turnaround in clinical practice for obstructive airway diseases as has already been seen in the usage of β-blockers for heart failure.
文摘The aim of this study was to compare the binding profile of a range of β2-adrenoceptor (β2-AR) agonists and antagonists in human lung tissue. Radioligand saturation and competition binding experiments were performed by filtration with a β2-AR antagonist ([3H]propranolol) or agonist ([3H]vilanterol) radioligand and membrane fragments generated from lung parenchyma in the presence of 100 μM guanosine 5’-[β,γ-imido]triphosphate (Gpp(NH)p). In membranes prepared from human lung parenchyma, carmoterol, formoterol, ICI118551, propranolol and salbutamol resulted in inhibition of [3H]vilanterol binding to levels that were significantly different from indacaterol, salmeterol and vilanterol (ANOVA, Bonferroni post-test, P < 0.001 except formoterol vs indacaterol where P < 0.01). Indacaterol and salmeterol resulted in inhibition of [3H]vilanterol binding to levels that were not significantly different from vilanterol (ANOVA, Bonferroni post-test, P > 0.05). Indacaterol, salmeterol and vilanterol resulted in full inhibition of [3H]propranolol binding to levels not significantly different from ICI118551 (ANOVA, Bonferroni post-test, P > 0.05). Indacaterol, salmeterol and vilanterol bind to an additional site in human lung parenchyma membranes that is distinct from the β2-AR.
文摘Clonidine is a classically categorized α2-adrenoceptor (α2-AR) agonist that produces vascular contractions by stimulating arterial smooth muscle α2-ARs. However, clonidine inhibits α1-AR-mediated arterial contractions. Recently, it was suggested that repeated stimulation with clonidine induces desensitization of α2-ARs, thus inhibiting noradrenaline-induced smooth muscle contractions. In the present study, we examined whether clonidine-mediated inhibition of α1-AR contractions involves interactions with α2-ARs in rat thoracic aortae. 1) Clonidine and guanfacine inhibited electrical field stimulation-induced contractions in a concentration-dependent, yohimbine-sensitive manner in isolated rat vas deferens preparations. 2) Clonidine almost completely suppressed phenylephrine-induced sustained contractions of rat thoracic aortae. 3) Clonidine competitively inhibited phenylephrine-induced contractions with a pA2 value of 6.77 at concentrations between 10-7 and 10-6 M. At 10-5 M, clonidine inhibited phenylephrine-induced contractions and dramatically reduced maximum contractions. 4) In contrast, clonidine did not inhibit contractions produced by high KCl or prostaglandin F2α. 5) Inhibition of phenylephrine-induced sustained contractions by clonidine was also produced in the presence of yohimbine. However, guanfacine did not inhibit phenylephrine-induced sustained contractions. These findings suggest that clonidine inhibits phenylephrine-induced contraction of rat thoracic aortae by competitive antagonism of α1-ARs, which is mediated through a mechanism independent of α2-AR stimulation.
文摘Antibodies against &-adrenoceptor can be detected in serum of patients with dilated cardiomyopathy (DCM), which have 5-agonist-like activity, and induce a positive chronotropic effect on cardiac myocytes by its persistence at full strength. Effects of the antibodies against Padrenoceptor from sera of patients with DCM on myocardial cytotoxicity and cytoplasmic free Ca2+-concentration (LCa2+ji) were observed in the cultured single layer SD rat ventricular cells by using the cytotoxicity assay and fluorescent Ca2+- indicat0r fura-2/AM. The positive sera of the anti-&adrenoceptor antibodies from patients with DCM markedly enhanced myocardial [Ca2+]i. Betaloc, a 5, -receptor blocker, might inhibit the increase of the antibody-mediated myocardial [Ca2+]i, and the sera from healthy donors had no effect on myocardial [Ca2+]i,. Our results suggest that the anti-β-adrenoceptor antibody might increase myocardial [Ca2+]i, and result in myocardial damage. The antibodies might activate receptor-gating Ca2+-channel, thereby causing myocardial [Ca2+]i, rise and calcium overload. Early use of betaloc is recommended in the treatment of dilated cardiomyopathy.
基金supported by the National Natural Science Foundation of China,No.81601121,31500968the Natural Science Foundation of Jiangsu Province of China,No.BK20150163the Fundamental Research Fund for the Central Universities of China,No.JUSRP11567
文摘Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer＇s disease. To test this hypothe- sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 （APP/PS1） mice using the agonist clenbuterol （intraperitoneal injection, 2 mg/kg）. We found that β2-adrenoceptor ac- tivation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines, lhese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS 1 mice.
基金supported by Consejo Nacional de Ciencia y Tecnología(CONACy T)project CB 2016-287614(to RGP and ABN)by Scholarship Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica de la Universidad Nacional Autónoma de México(PAPIIT-UNAM)IA203319 and PAPIIT-UNAM IN216221 to(LERL)。
文摘Norepinephrine plays an important role in motor functional recovery after a brain injury caused by ferrous chloride.Inhibition of norepinephrine release by clonidine is correlated with motor deficits after motor cortex injury.The aim of this study was to analyze the role ofα-adrenergic receptors in the restoration of motor deficits in recovering rats after brain damage.The rats were randomly assigned to the sham and injury groups and then treated with the following pharmacological agents at 3 hours before and 8 hours,3 days,and 20 days after ferrous chloride-induced cortical injury:saline,clonidine,efaroxan(a selective antagonist ofα-adrenergic receptors)and clonidine+efaroxan.The sensorimotor score,the immunohistochemical staining forα-adrenergic receptors,and norepinephrine levels were evaluated.Eight hours post-injury,the sensorimotor score and norepinephrine levels in the locus coeruleus of the injured rats decreased,and these effects were maintained 3 days post-injury.However,20 days later,clonidine administration diminished norepinephrine levels in the pons compared with the sham group.This effect was accompanied by sensorimotor deficits.These effects were blocked by efaroxan.In conclusion,an increase inα-adrenergic receptor levels was observed after injury.Clonidine restores motor deficits in rats recovering from cortical injury,an effect that was prevented by efaroxan.The underlying mechanisms involve the stimulation of hypersensitiveα-adrenergic receptors and inhibition of norepinephrine activity in the locus coeruleus.The results of this study suggest thatαreceptor agonists might restore deficits or impede rehabilitation in patients with brain injury,and therefore pharmacological therapies need to be prescribed cautiously to these patients.
文摘Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations,including insulin resistance,visceral fat accumulation,and dyslipidemias,which increase the risk for developing cardiovascular disease.Metabolic syndrome is associated with augmented sympathetic tone,which could account for the etiology of pre-diabetic cardiomyopathy.This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustainedβ-adrenergic response in pre-diabetes,focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy.The research reviewed indicates that both protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ play important roles in functional responses mediated byβ1-adrenoceptors;therefore,alterations in the expression or function of these kinases can be deleterious.This review also outlines recent information on the role of protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ in abnormal Ca^(2+)handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.
文摘The α2-adrenoceptor agonists are widely applied in perioperative period because they have antinociceptive, sedative, anxiolytic, sympatholytic effects. With the development of investigation, the α2-adrenoceptor agonists’ indications are expanded and have not been investigated as a kind of adjuvant. They will not only reduce anesthetic requirements during operation, cause sedation in ICU postoperatively, offer benefits in the prophylaxis of perioperative myocardial ischaemia but probably become some kind of anesthetic by themselves in perioperative application.
基金This study was supported by grants from the National Youth Natural Science Foundation of China （No. 30400191）, the National Natural Science Foundation China （No. 30570797）, and the Key Subject of＂135＂ Project of Jiangsu Province （No. 20013102）.
文摘Background β2-adrenoceptor （β2AR） desensitization is a common problem in clinical practice, β2AR desensitization proceeds by at least such three mechanisms as heterologous desensitization, homologous desensitization and a kind of agonist-induced rapid phosphorylation by a variety of serine/threonine kinases. It is not clear whether there are other mechanisms, This study aimed to investigate potential mechanisms of β2AR desensitization.Methods Twenty-four BALB/c （6-8 weeks old） mice were divided into three groups, which is, group A, phosphate buffered saline （PBS）-treated; group B, ovalbumin （OVA）-induced; and group C, salbutamol-treated. Inflammatory cell counts, cytokine concentrations of bronchoalveolar lavage fluid （BALF）, pathological sections, total serum IgE, airway responsiveness, membrane receptor numbers and total amount of β2AR were observed. Asthmatic mouse model and β2AR desensitization asthmatic mouse model were established. Groups B and C were selected for two-dimensional gel electrophoresis （2DE） analysis so as to find key protein spots related to β2AR desensitization.Results Asthmatic mouse model and β2AR desensitization asthmatic mouse model were verified by inflammatory cell count, cytokine concentration of BALF, serum IgE level, airway hyperreactivity measurement, radioligand receptor binding assay, Western blot analysis, and pathologic examination. Then the two groups （groups B and C） were subjected to 2DE. Two key protein spots associated with β2AR desensitization, Rho GDP-dissociation inhibitor 2 （RhoGDl2） and peroxiredoxin 5, were found by comparative proteomics （2DE and mass spectrum analysis）.Conclusion Oxidative stress and small G protein regulators may play an important role in the process of β2AR desensitization.v
基金Supported by the National Natural Science Foundation of China (No.30772878)
文摘Objective： To investigate the β2-adrenoceptor （ β 2AR）-β-arrestin2-nuclear factor- K B （NF- κ B） signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis. Methods： Forty SD rats were randomly divided into four groups, which included the normal control group, the model group, the mesalazine group and the oxymatrine treatment group, with 10 rats per group. Experimental colitis induced with trinitrobenzene sulfonic acid （TNBS） was established in each group except the normal control group, The rats in the oxymatrine treatment group were treated with intramuscular injection of oxymatrine 63 mg/（kg.d） for 15 days and the rats in the mesalazine group were treated with mesalazine solution 0.5 g/（kg.d） by gastric lavage for 15 days. The rats in the normal control group and model group were treated with 3 mL water by gastric lavage for 15 days. Diarrhea and bloody stool were carefully observed. Histological changes in colonic tissue were examined on day 7 in 2 rats per group that were randomly selected. The expression of β 2AR, β -arrestin2 and NF- κ B p65 in colon tissue and spleen lymphocytes were detected with immunohistochemistry and Western immunoblotting techniques on day 16 after fasting for 24 h. Six rats died of lavage with 2 each in the normal control, the model group and the mesalazine group; and were not included in the analysis. Results： The rats in the model group suffered from looser stool and bloody purulent stool after modeling. But in the oxymatrine and mesalazine groups, looser stool and bloody purulent stool reduced after treatment. And the colonic wall in the model group was thickened and the colon length shortened. The colon mucosa was congested in multiple areas with edema, erosion, superficial or linear ulcer and scar formation, while the intestinal mucosa injury reduced in the mesalazine and oxymatrine groups （P〈0.01）. In colonic mucosa and in spleen lymphocytes, compared with the normal control group, the expression of NF- κ Bp65 were significantly increased （P〈0.01） in the model group while the expressions of β 2AR and β-arrestin2 were significantly decreased （P〈0.01）. Compared with the model group, the expression of NF- κ Bp65 was significantly decreased in the mesalazine group （P〈0.01） and oxymatrine treatment group （P〈0.01） while the expressions of β 2AR and β -arrestin2 were significantly increased （P〈0.01）. There were no statistically significant differences in the expression of β 2AR, β -arrestin2 and NF- κ Bp65 between the mesalazine group and oxymatrine group （P〉0.05）. Conclusions： The β 2AR- β -arrestin2-NF- κ B signal transduction pathway participated in the pathologic course of ulcerative colitis. Oxymatrine attenuated ulcerative colitis through regulating the β 2AR- β -arrestin2-NF- κB signal transduction pathway.
基金Project (No. 30873103) supported by the National Natural Science Foundation of China
文摘In order to develop a model for screening the agonists of human β2-adrenoceptor from Chinese medicinal herbs extracts, we used a cell-based functional assay based on a common G protein-coupled receptor （GPCR） regulation mechanism and destabilized enhanced green fluorescent protein （d2EGFP） reporter gene technique. The positive cell clone was confirmed by real-time polymerase chain reaction （PCR） and imaging analysis. To assess the value of this model, we screened over 2000 high performance liquid chromatography （HPLC）-fractionated samples from the ethanol extracts of Chinese medicinal herbs. Six fractions （isolated from Panax japonicus, Veratrum nigrum, Phellodendron amurense, Fructus Aurantii lmmaturus, Chaenomeles speciosa, and Dictamnus dasycarpus） showed significant effects on active reporter gene expression, three of which （isolated from Phellodendron amurense, Fructus Aurantii lmmaturus, and Chaenomeles speciosa） were selected for further concentration response analysis and the half maximal effective concentration （EC1/2 max） values were 4.2, 2.7, and 4.8 μg/ml, respectively. Therefore, this reporter gene assay was suitable for screening β2-adrenoceptor agonists. The results suggest that the six herbal extracts are the possible agonists of β2-adrenoceptor.
文摘Background Imbalance of the sympathetic nervous system was involved in the pathogenesis of idiopathic ventricular outflow-tract tachycardia （IVOT）. We aimed to investigate whether the major genetic variants in β1-and β2-adrenoceptors and GNB3 C825T were associated with IVOT and verapamil sensitive idiopathic left ventricular tachycardia （ILVT）.Methods Patients with IVOT and ILVT from December 2005 to December 2007 were consecutively enrolled into this study. Controls were randomly selected from the community-based inhabitants. Five genetic variants, Ser49Gly and Gly389Arg in the β1-adrenoceptor, Arg16Gly and Gln27Glu in the β2-adrenoceptor and GNB3 C825T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis.Results A total of 227 patients with IVOT and 110 patients with ILVT were included. Genotyping revealed that the 16Gly allele of Arg16Gly variant of β2-adrenoceptor was associated with a higher risk of IVOT （OR：1.40, 95% CI： 1.12-1.75,P=0.003 in the addictive model and OR：. 1.62, 95% CI： 1.14-2.31, P=0.007 in the dominant model）. Patients with Gly16Gln27 haplotype also had a higher risk of IVOT （OR： 1.38, 95% CI： 1.11-1.73, P=0.012）. Other four variants,including Ser49Gly and Arg389Gly in β1-adrenoceptor, GIn27Glu in β2-adrenoceptor and GNB3 C825T, did not differ between patients with IVOT and controls. In patients with ILVT, no significant difference was found in these five variants compared with controls.Conclusions Arg16Gly in β2-adrenoceptor is significantly associated with IVOT in Chinese Han population. Major genetic variants in β1- and β2-adrenoceptor and GNB3 C825T may not be associated with ILVT. These data suggest a different arrhythmogenic mechanism in IVOT and ILVT.
文摘β-Adrenoceptors（β-ARs） play a critical role in regulating cardiac functions under both physiological and pathological conditions. To further explore the mechanisms through which β-ARs perform its actions, proteomic approaches were adopted to study the global protein patterns in cultured neonatal rat cardiomyocytes exposed to iseproterenol （ISO）. A modified method, ＂Mirror Images in One Gel＂, was used to improve the reproducibility and resolution power of two-dimensional electrophoresis. A 2-DE map with a good reproducibility was obtained in which 1281 ± 70 spots were detected and about 1191± 54 spots were matched, with an average matching rate of 92. 9%. Nine proteins with significant changes were identified by using peptide mass fingerprinting（PMF） data obtained vht MALDI-MS.
文摘<b><span style="font-family:Verdana;">The objective of our study</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> was to investigate the association between the Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-АR gene and body mass index (BMI) in patients with bronchial asthma (BA) with regard to the age of onset. </span><b><span style="font-family:Verdana;">Materials and methods</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> 553 patients were examined. The control group consisted of 95 apparently healthy individuals. The patients were divided into 2 groups depending on the age of BA onset: 282 patients with late onset (Group I) and 271 patients with early onset (Group II). Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-АR gene (rs1042713) was determined using polymerase chain reaction-</span></span><span style="font-family:;" "=""> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">restriction fragment length polymorphism analysis. Statistical analysis of obtained results was performed using SPSS–17 program. </span><b><span style="font-family:Verdana;">Results</span></b></span><b><span style="font-family:Verdana;">:</span><span style="font-family:;" "=""> </span></b><span style="font-family:;" "=""><span style="font-family:Verdana;">There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-AR gene depending on BMI (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 5.74;р = 0.22), and no association was found with obesity risks disregarding the age of BA onset. The study on the frequency of genotypes for this polymorphism with regard to the age of asthma onset and BMI found statistically significant differences between early-onset (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 11.27;p = 0.02) and late-onset (</span><i><span style="font-family:Verdana;">χ</span></i><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> = 10.66;p = 0.03) asthma. It was found that the risk of obesity in Group I patients was 1.57 times higher in the additive model and 2.67 times higher—in the recessive model of inheritance. In patients with late-onset asthma, Gly16 allele in the recessive model of inheritance was found to have a protective role against obesity. </span><b><span style="font-family:Verdana;">Conclusions</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the </span><i><span style="font-family:Verdana;">β</span></i><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;">-AR gene with regard to BMI, and no association was found with obesity risks in BA patients disregarding the age of BA onset. The risk of obesity in patients with early-onset asthma was 1.6 times higher in the additive model and 2.7 times higher—in the recessive model of inheritance.</span></span>
