Changes of pulmonary beta-adrenergic receptors and their relationship with membranous phospholipid metabolism in endotoxin-induced lung injury in rats

The changes of beta-adrenergic receptors (AARs) in lung tissue in endotoxin-induced acute lung injury was investigated with radioligand bindig assay in rats. The lipid fluidity and phospholipid content of the cellular membrane of lung tissue were measured with fluorescent polarization and high performance liquid chromatography respectively. The findings were as follows:1- Four hours after endotoxin injection, there was a 47% decrease of the maximal binding capacity of fyARsas compared with the control.2. Endotoxin was able to decrease the lipid fluidity and phospholipid content of the pulmonary cellular membrane markedly and at the same time. There was an elevated activity of phospholipase A2 in the pulmonary tissueThese findings suggest that the decrease of the binding capacity of &ARs results in a decrease of the PAR mediated functions, which plays a ro1e in the pathogensis of endotoxin-induced acute lung injury and the activation of phospholipase A2 which is an important factor to reduce the phospholipid content of cell membrane and subsequently to decrease its lipid fluidity, can result in a reduction of the lateral diffusion and rotatory movement of β-ARs and to decrease the chances of β-ARs to bind with the ligands.

AB033.Implication of beta-adrenergic receptor in choroidal neovascularization

Background:We investigated the role of beta-adrenergic receptor(B-AR)on choroidal neovascularization(CNV)in an animal model of age-related macular degeneration in mice.Methods:The angiogenic effect of the B-AR was evaluated in retinal pigment epithelium(RPE)-choroid explants from C57Bl6 mice stimulated with propranolol or isoproterenol(10μM)(respectively antagonist and agonist of the B-AR)during 24 h.Conversely,a classic choroidal neovascularization(CNV)model induced by laser burn in C57Bl6 mice(8 weeks)was used to assess the anti-angiogenic effect of propranolol.In this experiment,mice were treated with intraperitoneal propranolol(6 mg/kg/d)or vehicle(saline solution)daily for 10 days,starting on day 4 after laser burn and until sacrifice(day 14).Immunostaining analysis on retinal flatmounts and cryosections were performed to determine the surface of CNV,the distribution of B-AR and the number and morphology of microglia/macrophages associated with CNV.To explore if the antiangiogenic effect of propranolol involved the modulation of the inflammatory microenvironment associated with CNV,we used RPE primary cells,J774 macrophages cell line and polarized M1 and M2 bone marrow-derived macrophage(BMDM).Choroidal explants treated with conditioned media(CM)from J774 or polarized M1/M2 BMDM pre-treated with propranolol to confirm the anti-angiogenic effect of propranolol.Expression of angiogenic factors was evaluated by RT PCR and Elisa.Results:The expression and distribution of the B-1,B-2 and B-3 adrenergic receptors were localized in the choroid and RPE cells.The stimulation of RPE-choroid explants with isoproterenol increased CNV compared to vehicle,while propranolol decreased CNV.In vivo,propranolol inhibited significantly the levels of VEGF and CNV growth in laser burn model compared to the vehicle.Additionally,the treatment with propranolol decremented the number of activated(amoeboid shape)microglia/macrophages but surprisingly,the number of non-activated microglia/macrophages around the CNV was higher than with the vehicle treatment.In vitro,propranolol modulated the angiogenic balance in macrophages promoting anti-angiogenic factors expression,especially with M2 BMDM.CM from macrophages pre-treated with propranolol reduced CNV on choroidal explants.Conclusions:These ex vivo and in vivo studies highlight the importance of B-adrenergic receptor in the CNV.Propranolol can inhibit CNV by decreasing the levels of VEGF and modulating microglia/macrophages activation.Further work will investigate the role of B-adrenergic receptor on suppression of the inflammatory environment in order to understand the link between neovascularization and inflammation in CNV during age-related macular degeneration.

Beta-adrenergic signaling on neuroendocrine differentiation, angiogenesis, and metastasis in prostate cancer progression

Prostate cancer is a complex, heterogeneous disease that mainly affects the older male population with a high-mortality rate. The mechanisms underlying prostate cancer progression are still incompletely understood. Beta-adrenergic signaling has been shown to regulate multiple cellular processes as a mediator of chronic stress. Recently, beta-adrenergic signaling has been reported to affect the development of aggressive prostate cancer by regulating neuroendocrine differentiation, angiogenesis, and metastasis. Here, we briefly summarize and discuss recent advances in these areas and their implications in prostate cancer therapeutics. We aim to provide a better understanding of the contribution of beta-adrenergic signaling to the progression of aggressive prostate cancer.

The beta-adrenergic blocker carvedilol restores L-type calcium current in a myocardial infarction model of rabbit

Background Carvedilol, an antagonist of α1- and β-adrenergic receptors, has shown efficacy in reducing all-cause death and arrhythmia death for ischemic heart disease and congestive heart failure in several large-scale trials. It has been found to prevent ventricular remodeling, and recently was reported to reverse down-regulation of Na^+ channel in a chronic heart failure model. This study was conducted to investigate whether carvedilol could reverse the ion remodeling in a myocardial infarction model of rabbit.Methods After the procedure of coronary ligation, animals were randomized to placebo or carvedilol treatment (5 mg/kg). Action potentials, L-type calcium current (I_(ca L)) and the effect of isoproterenol stimulation on I_(ca L) were measured using whole-cell patch method. Evaluation of the expression of calcium channel subunits was carried out by RT-PCR and Western blot. Results The results indicate that mean peak I_(ca L) densities (pA/pF) at +10 mV was reduced in postinfarction myocytes (5.33±0.45, n=25) compared to sham myocytes (6.52±0.21, n=20). Treatment of myocardial infarction rabbits with carvedilol could restore it partially (5.91±0.39, n=20, P<0.05). However, steady-state activation parameters were similar in three groups. With stimulation by isoproterenol (1 μmol/L) I_(ca L) increased in all three groups, but the increase was smaller in postinfarction myocytes. mRNA levels of calcium channel subunit CaA1 gene was decreased but CaB2a, CaB2b and CaB3 mRNA levels did not change after MI. Corresponding change in CaA1 protein was also observed. Conclusions The results demonstrate that carvedilol restores I_(ca L) density and reverse the downregulation of CaA1 postinfarction.

THE DISTRIBUTION OF BETA-ADRENERGIC RECEPTORS IN GUINEA PIG LUNGS AND THEIR CHANGES IN EXPERIMENTAL ALLERGIC ASTHMA

In this paper, the distribution of pulmonary beta-adrenergic receptors (beta-receptors) innormal and experimental allergic asthmatic guinea pigs was determined using autoradiograph-ic method. The results showed that the distribution of beta-receptors in the lung sections waswidespread. There was a significant decrease of beta-receptor density in several tissue struc-tures of asthmatic guinea pig lungs compared with the controls, a 23.73% decrease in beta-recep-tor binding sites in bronchiolar smooth muscles and a 18.65% decrease in bronchial smoothmuscles; a 23 .53%. a 14.23% and a 17. 16% decrease in bronchiolar epithelium, in bronchialepithelium and in alveolar epithelium respectively. The results indicated that the beta-recep-tor decrease in smooth muscles in experimental asthmatic guinea pig lungs might be one ofthe important factors which made the tension of smooth muscles increase. The relationshipbetween the beta-receptor decrease of other sites and bronchial asthma needs to be studiedfurther.

肾上腺素、去甲肾上腺素刺激培养的大鼠心肌细胞凋亡

目的 :观察肾上腺素 ( AD)或去甲肾上腺素 ( NA)刺激体外培养的大鼠心肌细胞凋亡 ,探讨其作用机制。方法 :大鼠心肌细胞分别暴露于 10 - 7mol/L 的 NA,10 - 7m ol/L 的 AD,NA+酚妥拉明 ( 10 - 7m ol/L) ,NA+艾司洛尔 ( 10 - 7mol/L) ,AD+酚妥拉明 ( 10 - 7m ol/L)或 AD+艾司洛尔 ( 10 - 7mol/L) 2 4 h。流式细胞仪检测凋亡水平。结果 :NA使凋亡细胞百分率由 ( 4 .2± 1.6) %增加到 ( 10 .0± 5 .0 ) % ( P<0 .0 1;n=8) ,此作用可被艾司洛尔完全抑制 ,而不受酚妥拉明影响。AD与 NA的作用相仿 ,使凋亡细胞百分率增加到 ( 12 .8± 7.9) % ,且 AD诱导的凋亡同样被艾司洛尔完全抑制但不受酚妥拉明的影响。结论 :AD和 NA可能通过激活 β肾上腺素能通路 。

Finishing Cattle in All-Natural and Conventional Production Systems

Beef cattle producers in the North America have a variety of production and marketing options and must choose the best production system for their situation. This review describes considerations involved in choosing between feeding cattle conventionally versus feeding them in programs that prohibit the use of certain technologies. Data from peer-reviewed journals, extension publications, nutritional consultants, governmental organizations, and feed companies were used to construct this review. Most cattle in North America are fed in conventional production systems. Conventional beef production systems typically use steroidal implants, ionophores, and beta-adrenergic agonists to improve animal productivity;as well as feed grade and injectable antimicrobials to control, treat or prevent disease and improve animal health. These technologies have been shown to lower the cost of production, allowing for beef to be competitive in the global protein market. Some consumers have expressed a preference for beef produced without these technologies. These “All-natural” (AN) cattle may bring a premium price in the market. The economic impact of differing productions systems can be described in relation to 1) cost of production, 2) operating costs of the feedlot, 3) price paid for feeder calves, and 4) price received for fed cattle. Conventional production provides the most favorable outcome for factors 1, 2, and 3, while AN production provides the most favorable outcome for item 4. There are also industry wide and societal aspects related to differing beef production systems related to health and safety of beef, land use, and cost of production allowing for a greater share of the global protein market. Technologies used in conventional production are critical tools to North American beef production. Differences in efficiencies between each type of non-conventional production systems must be re-captured in added premiums when cattle are marketed and sold. Premiums for AN cattle are enticing, but the true differences in the cost of production between the AN and conventional cattle must be evaluated in order for a producer to make the correct decision for their operation.

Effects of thyroxine on cardiac function and lymphocyte β-adrenoceptors in patients with chronic congestive heart failure

Objective To explore the effects of thyroid hormone (TH) on cardiac function and peripheral lymphocyte β-adrenoceptors (β-ARs) of patients with chronic congestive heart failure (CHF).Methods Twenty-eight patients with class III or IV advanced CHF due to dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM) were randomly divided into groups A and B. L-thyroxine (L-T50) was administered to group B. Exercise tolerance, chest X-rays, and echocardiographic parameters were obtained before and after one month of treatment, Ficoll-hypaque solution was used to separate peripheral lymphocytes, and 125l-pindolol radioligand binding was used to measure β-AR levels in peripheral lymphocytes.Results L-T50 therapy improved cardiac output [CO, (2. 98±0. 31 )L/min vs (3. 24 ±0. 28) L/min, P<0. 01], left ventricular ejection fraction (LVEF, 26.21%±3.21% vs 37.93% ±9.01%, P< 0. 01), and decreased isovolumetric relaxation time (IVRT, 0.12 ±0. 04 vs 0.10 ±0. 02, P<0. 01). Serum TH levels and the maximal number of β-AR binding sites (βmax) in peripheral lymphocytes were lower in patients with CHF than in normal healthy people, but L-T50 administration induced a β-AR up-regulation on peripheral lymphocyte surfaces. L-T50 was well tolerated without episodes of ischemia or arrhythmia. There was no significant change in heart rate or metabolic rate.Conclusion TH administration improves cardiac function and β-AR expression in peripheral lymphocytes of patients with CHF.

Influence of drug treatment on glucocorticoid receptor levels in patients with coronary heart disease

Background Glucocorticoid signaling exerts major roles in inflammation, metabolism and depression, which are three crucial factors accompanying or underlying coronary heart disease. Although accumulating evidence indicates the influence of glucocorticoids on the pathology and treatment of coronary heart disease, there is still a dearth of pharmaceutical mechanisms for this relationship. This study aimed to investigate the influence of drug treatment on glucocorticoid receptor levels in coronary heart disease. Methods Eighty hospitalized patients （average age （59.0＋7.5） years, 46 male and 34 female） with coronary heart disease were categorized into four groups with 20 members in each according to one of the four drugs they were treated with. The four drugs were： nitrated derivative isosorbide dinitrate, the beta-adrenergic receptor blocker metoprolol, the calcium antagonist nifedipine, and the HMG-CoA reductase inhibitor Iovastatin. Glucocorticoid receptor protein levels of peripheral blood lymphocytes were tested using immunoblotting analysis before and after one month of treatment. Results Immunoblotting analysis showed increased glucocorticoid receptor levels after treatment with metoprolol and nifedipine. There were no statistically significant changes of glucocorticoid receptor levels after treatment with isosorbide dinitrate or Iovastatin, although there were trends of up-regulation of glucocorticoid receptor expression after both treatments. Conclusions Both the beta-blocker and the calcium blocker can increase glucocorticoid receptor levels after chronic administration. This effect suggests a mechanism for their anti-inflammatory and other therapeutic roles for coronary heart disease and comorbid disorders.

Association of β-adrenergic receptor genes polymorphisms with incidence of subsequent cardiovascular events in Han Chinese patients with coronary artery disease

Background Sequence variants in the 13-adrenergic receptor （ADRB） genes have a close relationship with the development of coronary artery disease （CAD） and the patient＇s prognosis. However, there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD. We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event （MACE） in Han Chinese patients with CAD. Methods A total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention （PCI） were recruited to the study and followed for one year. Three variant sites in ADRB1 （rs1801253） and ADRB2 （rs1042713 and rs1042714） were genotyped. The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed. Results There were 47 cases of MACE during follow-up. There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 （Log-rank, all P 〉0.05）. Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up, the adjusted hazard ratios （95% confidence interval） for rs1801253, rs1042713 and rs1042714 were 1.05 （0.54-2.02）, 1.24 （0.58-2.64）and 1.66 （0.81-3.42）, respectively. Conclusion Our data did not support a relationship between the three polymorphisms of ADRB1 （rs1801253） and ADRB2 （rs1042713 and rs1042714） genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD.