SNP Identification in α_(2A)-Adrenergic Receptor Gene in Chinese and the Effect on Gene Expression

Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR gene was analyzed with automated DNA sequencer to scanSNPs. Genomic DNA was extracted from whole blood and a 239 bp fragment containing the G/Cpolymorphism was amplified with PCR using a pair of. specific primers. PCR-RFLP was used to performthe genotyping of the SNP at the site-1 296 bp of the people in the North of China. Electrophoresismobility shift assay ( EMSA ) was used to study the binding of the 390 bp fragments (- 1 414-1 025bp) with G or C at the site-1 296 bp and nuclear extracts . Results: In our study, two SNPs werefound in α_(2A)-AR gene. Allele frequencies of the SNP at the site-1 296 bp were 0.61 and 0.39 forG and C , and the genotype frequencies were 0.34 , 0.54 and 0.13 for GG, GC and CC respectively fromthe people in the North of China. In the EMSA, a specific binding appeared in the complex ofnuclear extracts and DNA with C at-1 296 bp . Conclusion: Two SNPs exist in α_(2A)-AR gene from thepeople in the North of China , and DNA fragment with allele C of the SNP at the site-1 296 bp couldbind with a specific protein, which could influence the gene expression.

Regulation of bone metabolism mediated byβ-adrenergic receptor and its clinical application

Recent studies have confirmed thatβ-adrenergic receptors(β-ARs)are expressed on the surface of osteoblasts and osteoclasts,and that the sympathetic nervous system can regulate bone metabolism by activating them.β-AR blockers(BBs)are commonly used in the treatment of cardiovascular diseases in the elderly.It is important to investigate whether BBs have a beneficial effect on bone metabolism in the treatment of cardiovascular diseases,so as to expand their clinical application.This article reviews the effects of BB on bone metabolism and the progress of clinical research.

Developmental changes in functional expression andβ-adrenergic regulation of If in the heart of mouse embryo

The hyperpolarization-activated current (If) plays an important role in determining the spontaneous rate of cardiac pacemaker cells. The automatic rhythmicity also exists in working cells of embryonic heart, therefore we studied developmental changes in functional expression and β-adrenergic regulation of Iy in embryonic mouse heart. The expression of If is high in early developmental stage (EDS) (10.5 d after coitus) ventricular myocytes, low in intermediate developmental stage (IDS) (13.5 d) atrial or ventricular myocytes and even lower in late developmental stage (LDS) (16.5 d) atrial or ventricular myocytes, indicating that these cells of the EDS embryonic heart have some properties of pacemaker cells.β-adrenergic agonist isoproterenol (ISO) stimulates If in LDS but not in EDS cardiomyocytes, indicating that the β-adrenergic regulation of If is not mature in EDS embryonic heart. But forskolin (a direct activator of adenylate cyclase) and 8-Br-cAMP (a membrane-permeable analogue of cAMP) increase the amplitude of If in EDS cells, indicating that adenylate cyclase and cAMP function fairly well at early stage of development. Furthermore, the results demonstrate that If is modulated by phosphorylation via cAMP dependent PKA both in EDS and LDS cells.

Effects ofβ_2-Adrenergic Antagonist on Cytosolic Ca^(2+) in Ventricular Myocytes from Infarcted Rat Heart

Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca^2 ＋ （[Ca^2＋ ]i） in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated. Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction （MI） and [Ca^2＋]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absence of betal-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1, 2- adrenergic antagonists propranolol was examined. Results The followings were found that ICI 118, 551 had no significant effects on the rise of [Ca^2＋]i induced by isoproterenol in normal ventricular myocytes （P 〉 0.05）, ICI118, 551 only significantly attenuated the rise of [Ca^2＋]i induced by isoproterenol at four weeks and eight weeks after MI （24.5%±5.7% vs 57.8% ± 13.2%, P〈 0.01; 12.2%±7.9% vs 44.6%±11.3%, P〈 0.01）. Atenolol had suppressive effects only in the control group and the post-MI group of two weeks （P 〈 0.05）, and propranolol had suppressive effects in the control and all the three post-MI groups （P 〈 0.01）. Conclusions Beta2-adrenergic antagonist ICI118, 551 may exert negative effects on Ca^2＋ overload initiated by sympathetic stimulation after MI.

Inhibition of central sympathetic nervous tone improves cardiomyocyte contraction by increasing the response of beta 2-adrenergic receptor in aged rats

In the present study,selective β1-adrenergic receptor antagonist CGP20712A and selective β2-adrenergic receptor antagonist ICI 118551 were administered to isolated cardiomyocytes from young （4-6 months）,aged （18-20 months）,and clonidine-pretreated aged （18-20 months） Sprague-Dawley rats.Cardiomyocyte contraction amplitude was measured to assess cardiomyocyte response to the β-adrenergic receptor agonist,isoprenaline.CGP20712A reduced cardiomyocyte contraction amplitude in young and aged groups and significantly reduced contraction amplitude in cells from young rats.ICI 118551 had no effect on cardiomyocyte contraction amplitude in young rats,but significantly decreased contraction amplitude in the aged groups,in particular in the clonidine-pretreated aged rats.Results demonstrated that reduced central sympathetic tone improved cardiomyocyte contraction in aged rats by improving the response of β2-adrenergic receptor to isoprenaline.

Gene transfer of a β_2-adrenergic receptor kinase inhibitor up-regulates the level of β_2-adrenergic receptor and cAMP in the asthmatic murine lung

Objective： To investigate the effects of gene transfer of a β-adrenergic receptor（β-AR） kinase inhibitor（β ARIct） on pulmonary β2-adrenergic receptor and cAMP following β2-AR agonist treatment in asthmatic mice, and to analyze the relationship between the routes of gene delivery and the changes of β2AR and cAMP. Methods： BALB/c mice were sensitized and challenged by ovalbumin to establish the asthmatic model treated with βAR agonist （salbutamol injected intramuscularly）. The plasmid with the expression of βARKct was constructed and βARKct gene transfer was performed through intravenous injection or intratracheal instillation in asthmatic mice. The gene expression was measured with Western blot analysis, and the changes of pulmonary β-AR and cAMP evaluated by Radioimmunoassay. Results： The expression of tranfered βARKct gene was detectable in lungs and it was expressed more in the lungs of the mice receiving intratracheally plasmid than those receiving intravenously. The levels of βAR and cAMP were upregulated after using plasmid-βARKct to the asthmatic mice treated with βAR agonist. Conclusion： Our results indicated that there were down-regulation of βAR and cAMP in asthmatic mice treated with βAR agonist. Gene transfer of βARKct could inhibit the extent of the down-regulation of βAR and cAMP. The route of gene delivery could also affect the degree of up-regulation of βAR and cAMP. Gene transfer βARKct may provide a novel approach to the therapeutic strategy for asthma.

Effects of Propranolol on β-Adrenergic Receptor ofExperimental Acute Myocardial Infarction in Rats

By using receptor autoradiography to observe the distribution and density of receptors, the effects of propranolol, a β-blocker, on β-adrenergic receptor of experimental acute myocardial infarction (AMI) were studied. One week after ligation of proximate left anterior descend (LAD) coronary artery, [3H] DHA binding sites were markedly decreased in both infarctregion and non-infarct region. After treatment of propranolol (100μg/kg), the [3H] DHA binding sites were obviously increased in the infarct region, and they were further decreased in the non-infarct region. The ratio of [3H] DHA binding sites of the infarct region to non-infarct region was from 0. 24 at LAD ligation to 0. 87 after propranolol treatment, which was close to 0. 97 of control group (sham operation). The results indicated that the propranolol acted directly on myocardial β-adrenergic through the receptor regulation of the balance of β-receptors between the infarct region and non-infarct region, and improvement of the myocardial consonation and contraction synergism, thereby protecting the heart affected by AMI.

Genetic variations of beta 2-adrenergic receptor gene are associated with essential hypertension in Xinjiang Kazakans

Objective The aims of the present study were to investigate the associations of 46 A〉G, 79 C〉G, 491 C〉T and 659 C〉G genetic variants of the human beta 2-adrenergic receptor （β2-AR）, ADRB2, gene with essential hypertension （EH） in Xinjiang Kazakans population.Methods A gender-matched case-control （271 hypertensive cases and 267 normotensive controls） study was used to investigate the associations of the four variations in the coding region of ADRB2 with EH. The genotypes of the variants were identified by the polymerase chain reaction and restriction fragment length polymorphism （PCR-RFLP） methods. Results 46 A〉G, 79 C〉G and 659 C〉G polymorphisms were common in the Kazakan population, but 491 C〉T was a mutation （frequency ofT allele was only 0.003） and only found in EH group. The fxequency distributions of genotypes and alleles for 659 C〉G between the EH and control groups was significantly different （P〈0.05）, while those for 46 A〉G and 79 C〉G polymorphisms were not statistically different. Logistic regression analysis suggested that the G allele of 659 C〉G polymorphism was a risk factor for hypertension （minor allele vs common homo; odds ratio, 13.240, 95% CI, 4.052-43.274; P〈0.05）. Covariance analysis showed that systolic and diastolic blood pressure levels in GG＋CG group of 659 C〉G were significantly higher than those in the CC group, but no significant difference of blood pressure were found between common homo and minor allele for 46 A〉G and 79C〉G polymorphisms. Haplotype analysis showed that two hyplotypes, HI： 46A-79C-491C-523C（48%）and H5：46A-79C-491C-659G, were associated with EH.Conelusion ADRB2 genetic variants may play independent roles in the molecular genetic mechanism of EH in Xinjiang Kazakans population （d Geriatr Cardio12010; 7：52-57）.

Beta-adrenergic receptor polymorphisms: A basis for pharmacogenetics

Aims: Polymorphisms of the β-adrenergic receptor, the frequency of which may differ in ethnic groups, alters β-receptor function. The aim of this study was to elucidate the frequency of β1 and β2-adrenergic receptor polymorphisms in healthy Greeks and to compare with those of Caucasian European (Euro) and African American (AA) origin. Methods: Ninety-nine individuals with a median age of 63 without clinical evidence of any disease were studied. Blood samples were obtained and common β1 and β2-adrenergic receptor polymorphisms that change the en-coded amino acid were determined by pyrosequencing. Results: The most common β1-adrenergic receptor polymorphism in Greeks is nucleotide substitution cytosine for guanine at position 1165 (1165 C/G) resulting in amino acid substitution arginine for glycine at position 389 (389 Arg/Gly) with a minor allele frequency of 28% (Euro 27%, AA 42%);this polymorphism increases the sensitivity of the β1-receptor. The most common β2-adrenergic receptor polymorphism in Greeks is the nucleotide substitution guanine for adenine at position 46 (46 G/A) resulting in amino acid substitution glycine for arginine at position 16 (16 Gly/Arg) with a minor allele frequency of 38% (Euro 41%, AA 50%);this polymerphism facilitates receptor down-regulation during chronic adrenergic stimulation. Conclusion: The most common β1 and β2-adrenergic receptor polymorphisms in the Greek population are similar to those of other European ancestry, and less common than in those of African origin indicating variability in ethnic groups. This information provides insight into common polymorphisms that may assist in optimizing β-antagonist and agonist therapy.

Activation of β_2-Adrenergic Receptor Induced by Three Catecholamine Agonists:a Docking and Molecular Dynamics Study

We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.

Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon β-adrenergic insult

Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18),however,the process of inflammation cascades has not been fully illustrated.The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation.With bioinformatics analysis,galectin-3 was identified as a potential key downstream effector of β-AR and IL-18 activation.The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain.In the heart of mice treated with β-AR agonist isoproterenol (ISO,5 mg kg^(-1)),galectin-3 expression was upregulated markedly later than IL-18 activation,and Nlrp3^(-/-)and Il18^(-/-)mice did not show ISO-induced galectin-3 upregulation.It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment.Moreover,galectin-3deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase.Treatment with a galectin-3 inhibitor,but not a β-blocker,one day after ISO treatment effectively attenuated cardiac inflammation and injury.In conclusion,galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute β-AR activation,a galectin-3 inhibitor effectively blocks cardiac injury one day after β-AR insult.

Ginsenoside F1 administration promotes UCP1-dependent fat browning and ameliorates obesity-associated insulin resistance

Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance.Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia.Ginsenoside is a natural active component in Panax ginseng C.A.Meyer,and some of them enhance thermogenesis.However,there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis.Using thermogenic protein uncoupling protein 1(UCP1)-luciferase reporter assay,we identifi ed ginsenoside F1 as a novel UCP1 activator in the ginsenosides library.Using pull down assay and inhibitor interference,we found F1 binds toβ3-adrenergic receptors(β3-AR)to enhance UCP1 expression via cAMP/PKA/CREB pathway.We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice,including body weight,body composition and energy expenditure.The results of proteomics showed that F1 signifi cantly up-regulated thermogenesis proteins and lipolytic proteins,but down-regulated fatty acid synthesis proteins.Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifi cally by promoting the browning of white adipose tissue in obese mice.Additionally,ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes,and shows a stronger mitochondria respiration ability than norepinephrine.These fi ndings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.

Effect of Phenylephrine on Alveolar Fluid Clearance in Ventilator-induced Lung Injury

Objective To investigate the effect of phenylephrine （an α-adrenergic agonist） on alveolar fluid clearance （AFC） in ventilator-induced lung injury and the possible mechanism involved. Methods A total of 170 male Wistar rats were randomly allocated into 17 groups （n= 10） using ran- dom number tables. Short-term （40 minutes） mechanical ventilation with high tidal volume （HVT） was per- formed to induce lung injury, impair active Na＋ transport and lung liquid clearance in the rats. Unventilated rats served as controls. To demonstrate the effect of phenylephrine on AFC, phenylephrine at different con- centrations （1×10^-5, 1 ×10^-6, 1×10^-7, 1×10^-8, and 1×10^-9 mol/L） was injected into the alveolar space of the HVT ventilated rats. To identify the influence of adrenergic antagonists, Na＋ channel, and microtubular sys- tem on the effect of phenylephrine, phenylephrine at 1×10^-5mol/L combined with prazosin （an α1-adrener- gic antagonist, 1×10^-4 mol/L）, yohimbine （an α2-adrenergic antagonist, 1×10^-4 mol/L）, atenolol （a β1- adrenergic antagonist, 1×10^-5 mol/L）, ICI- 118551 （an β2-adrenergic antagonist, 1×10^-5 mol/L）, amiloride （a Na＋ channel blocker, 51×10^-4mol/L）, ouabain （a Na＋/K＋-ATPase blocker, 5~×10^-4mol/L）, colchicine （a mi- crotubular disrupting agent, 0.25 mg/100 g body weight）, or β-lumicolchicine （an isomer of colchicine, 0.25 mg/100 g body weight） were perfused into the alveolar space of the rats ventilated with HVT for 40 minutes. AFC and total lung water content were measured. Results Basal AFC in control rats was （17.47±2.56）%/hour, which decreased to （9.64± 1.32）%/hour in HVT ventilated rats （P=0.003）. The perfusion of phenylephrine at 1 ×10^-8, 1×10^-7, 1×10^-6, and 1×10^-5 mol/L significantly increased the AFC in HVT ventilated rats （all P〈0.05）. This effect of phenylephrine on AFC was suppressed by prazosin, atenolol, and ICI-118551 in HVT ventilated rats by 53%, 31%, and 37%, respectively （all P〈0.05）. The AFC-stimulating effect of phenylephrine was lowered by 33% and 42% with amiloride and ouabain, respectively （both P〈0.05）. Colchicine significantly inhibited the effect of phenylephrine （P=0.031）. Conclusion Phenylephrine could increase the AFC in HVT-ventilated rats and accelerate the ab- sorption of pulmonary edema.

Shengmai Suppressed Vascular Tension in Umbilical Arteries and Veins of Human and Sheep

Objective—The umbilical cord is a critical pathway between mothers and fetuses, and regulations of umbilical vessel tension are important for fetal growth. Shengmai is an herbal medicine being used in treatments of cardiovascular diseases. However, effects of Shengmai on human blood vessels and related pharmacological mechanisms are unclear. Methods—This study investigated the effects of related mechanisms of Shengmai and its key compounds on human and sheep umbilical arteries and veins using organ bath systems. Key Findings—Shengmai significantly suppressed phenylephrine-stimulated vasoconstriction in umbilical arteries and veins. NG-Nitro-L-arginine Methyl Estercould not change the Shengmai-suppressed vasoconstriction in human and sheep umbilical vessels. Among four key compounds of Shengmai, Ginsenoside Re, Ginsenoside Rb1, Ginsenoside Rg1, and Schisandrin, only Ginsenoside Re showed the significant effect similar to Shengmai’s in the umbilical vessels. In Ca2+-free solution, Ginsenoside Re did not affect vasoconstriction. In addition, caffeine- or phenylephrine-stimulated vasoconstriction were not changed by Ginsenoside Re. Either charybdotoxin or glibenclamide could inhibit Ginsenoside Re-caused inhibition of the stimulated vasoconstriction in both human and sheep umbilical vessels, where 4-aminopyridine did not show the similar inhibitory effect. Conclusion—The results provide new information on Shengmai’s effects and underlying mechanisms in umbilical vessels. Importantly, the information gained offers interesting potential for developing new drugs acting on umbilical cords for fetal medicine.

Relationship between Trp64Arg mutation in the β3-adrenergic receptor gene and metabolic syndrome： a seven-year follow-up study

Background It has been shown that the β3-adrenergic receptor （β3-AR） gene Trp64Arg mutation was closely related to obesity and insulin resistance, and may be related to the prevalence of metabolic syndrome （MS）. The aim of this study was to investigate the relationship between the 33-AR gene mutation and the prevalence of MS. Methods A seven-year follow-up study was initiated in 2000, with 496 samples of simplex obese subjects （body mass index ≥25 kg/m2） and 248 normal-weight subjects. According to the β3-AR genotypes, the subjects were classified as Trp64 homozygote group and Arg64 carrier group and after 7 years the prevalence of MS was determined. Results According to the baseline profile, there were no significant differences in the adiposity, blood pressure, lipid profile, fasting plasma glucose and fasting insulin between Trp64 homozygote group and Arg64 carrier group either in obesity or normal-weight subjects. The results of follow-up study indicated that in obese men the prevalence rate of MS was much higher in Arg64 carrier group than that in Trp64 homozygote group （54.76% vs. 40.85%, P 〈0.05）, but there was no statistical difference in women of the above groups. The prevalence rate of MS in obese men of both Trp64 homozygote group and Arg64 carrier obese group were obviously higher than that in women of the above groups （40.85% vs. 18.27% and 54.76% vs 21.28%, all P 〈0.005）. Differences were not statistically significant in the prevalence of MS for normal weight Trp64 homozygote group and normal weight Arg64 carrier group, either between men, between women, or between men and women. Comparison of populations indicated that no matter with the β3-AR gene mutation or not, the prevalence of MS in obese subjects was significantly higher than normal weight subjects （X2=28.240 and x2=15.586, all P 〈0.005）. Logistic analysis showed that the mutation of β3-AR gene was associated with the prevalence of MS in men.

Shen-Fu injection reduces impaired myocardial β-adrenergic receptor signaling after cardiopulmonary resuscitation

Background Post-resuscitation myocardial dysfunction has been implicated as a major cause of fatal outcome in patients who survive initially successful cardiopulmonary resuscitation （CPR）. In our previous study, we found that impaired myocardial β-adrenergic receptor （AR） signaling is a key mechanism in post-resuscitation myocardial dysfunction and Shen-Fu injection （SFI） can attenuate post-resuscitation myocardial dysfunction. However, whether SFI can prevent impaired post-resuscitation myocardial β-AR signaling is not yet known. In this study, we investigated the effect of SFI on impaired myocardial β-AR signaling occurring post-resuscitation in a porcine model of cardiac arrest. Methods Ventricular fibrillation was induced electrically in anesthetized male landrace domestic pigs. After 4 minutes of untreated ventricular fibrillation, cardiopulmonary resuscitation was initiated. Sixteen successfully resuscitated pigs were randomized to receive a continuous infusion of either SFI （0.5 ml/min; n=8） or saline （placebo; n=8） for 6 hours, beginning 15 minutes after the return of spontaneous circulation （ROSC）. Hemodynamic and echocardiographic data were recorded. β-AR signaling was assessed at 6 hours after the intervention by measuring myocardial adenylate cyclase activity, β-AR density and β-AR kinase expression. Results Treatment with SFI produced better maximum rate of left ventricular pressure increase （dp/dtmax） and maximum rate of left ventricular pressure decline （-dp/dtmax）, cardiac output, and ejection fraction after ROSC. SFI treatment was also associated with lower myocardial β-adrenergic receptor kinase expression, whereas basal and isoproterenol- stimulated adenylate cyclase activity and the total β-AR density were significantly increased in the SFI group when compared with the placebo group. Conclusion SFI attenuated post-resuscitation myocardial dysfunction by preventing impaired myocardial β-AR signaling after CPR.

Effect of β3-adrenergic agonists on alveolar fluid clearance in hypoxic rat lungs

Background Recent research suggests that β2-adrenergic agonists increase alveolar fluid clearance （AFC） under physiologic and pathologic conditions. It is unknown whether β3-adrenergic agonists also increase AFC under pathologic conditions. The aim of this study was to investigate the effect of β3-adrenergic agonists on AFC following hypoxic lung injury and the mechanisms involved. Methods Hypoxic rats were exposed to 10% oxygen. BRL-37344 （133-adrenergic agonist） or CGP-12177 （selective β3-adrenergic agonist） alone or combined with β receptor antagonists, sodium channel blockers, or Na＋/＋^-ATPase blockers were perfused into the alveolar space of rats exposed to 10% oxygen for 48 hours. Total lung water content （TLW） and AFC were measured. Results AFC did not change for the first 24 hours but then decreased after 48-hour exposure to 10% oxygen. The perfusion of BRL-37344 or CGP-12177 significantly increased AFC in normal and hypoxic rats. The AFC-stimulating effect of CGP-12177 was lowered with amiloride （a Na＋ channel blocker） and ouabain （a Na~/K^-ATPase inhibitor） by 37% and 49%, respectively. Colchicine significantly inhibited the effect of CGP-12177. Conclusions These findings suggest that β3-adrenergic agonists can increase AFC during hypoxic lung injury in rats and accelerate the amelioration of pulmonary edema.

Clinical evaluation of valsartan and metoprolol tartrate in treatment of diabetic nephropathy with positive β1-adrenergic and anti-angiotensin Ⅱ type 1 receptor antibody

Background Studies have confirmed that angiotensin II receptor blocker （ARB） and angiotensin converting enzyme inhibitors （ACEI） in the treatment of diabetic nephropathy （DN） has special advantages. We observed the effects of valsartan and metoprolol tartrate hydrchloride in treatment of DN patients with positive β1-adrenergic and anti-angiotensin II type 1 （AT1） receptor antibody. Methods The epitopes of the second extracellular loop of β1 receptor （197-222） and AT1 receptor （165-191）, were synthesized and used respectively to screen serum autoantibodies from patients with DN （n=371, group A）, diabetes mellitus （DM） without renal failure （n=107, group B） and healthy blood donors （n=47, control, group C） by enzyme-linked immunosorbent assay （ELISA）. Metoprolol tartrate 25-50 mg, three times per day, valsartan 160 mg, once a day, aspirin 100 rag, once a day, and nitrendipine 10-20 mg, three times per day, were given to DN patients with positive or negative autoantibodies. The cystatin C level and 24-hour urinary protein were measured before and after treatment. Results In DN patients, the positive rate of the autoantibodies against β1 receptors and AT1 receptor was 47.7% and 51.5%, respectively, which were significantly higher than those in DM patients and healthy controls （all P 〈0.01）. Patients with anormalous cystatin C had higher positive rates of the autoantibodies than patients with normal cystatin C. Valsartan and metoprolol tartrate reduced proteinuria significantly （P 〈0.01） in DN patients with positive autoantibodies. Conclusions The findings suggest that these autoantibodies against β1 and ATl-receptor may play important roles in the pathogenesis of DN. Valsartan and metoDrolol tartrate are effective and safe in the treatment of DN.

Expressions of cardiac sympathetic norepinephrine transporter and β_1-adrenergic receptor decreased in aged rats

Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovascular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine(NE) transporter(NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleft and maintains the sensitivity of the β-adrenergic receptor(β-AR). In the present study,we investigated NET and β1-AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and left ventricular myocardium in 2-and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA,NET protein and β1-AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%,26%,and 43%,respectively,in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.

β-2 Adrenergic receptor gene polymorphism and response to propranolol in cirrhosis

AIM: To evaluate the association of β-2 adrenergic receptor(β2-AR) gene polymorphism with response of variceal pressure to propranolol in cirrhosis.METHODS: Sixty-four non-related cirrhotic patients participated in this study and accepted variceal pressure measurement before and after propranolol administration. Polymorphism of the β 2-AR gene was determined by directly sequencing of the polymerase chain reaction products from the DNA samples that were prepared from the patients.RESULTS: The prevalence of Gly16-Glu/Gln27 and Arg16-Gln27 homozygotes, and compound heterozygotes was 29.7%, 10.9%, and 59.4%, respectively.Patients with cirrhosis with Gly16-Glu/Gln27 homozygotes had a greater decrease of variceal pressure after propranolol administration than those with Arg16-Gln27 homozygotes or with compound heterozygotes(22.4% ± 2.1%, 13.1% ± 2.7% and 12.5% ± 3.1%,respectively, P < 0.01).CONCLUSION: The variceal pressure response to propranolol was associated with polymorphism of β 2-AR gene. Patients with the Gly16-Glu/Gln27 homozygotes probably benefit from propranolol therapy.