Β2-adrenoreceptor Agonist Research Articles

Inhibitory effects of albuterol and fenoterol on RANTES and IP-10 expression in bronchial epithelial cells

Short-acting β2-adrenoreceptor agonist (SABA) is the major asthma reliever as indicated in the GINA guidelines. Regulated on activation, normal T expressed and secreted (RANTES) is a chemokine that attracts eosinophils, mast cells, and basophils toward site of allergic inflammation. Interferon γ-inducible protein (IP)-10 is a Th1-related chemokine that is also important in asthmatic inflammation and also involved in our immune defense against pathogens. Bronchial epithelial cells are first-line barrier against invasive pathogen and also have immunomodulatory function. However, whether albuterol and fenoterol (two SABAs) have modulatory effects on RANTES and IP-10 expression in bronchial epithelial cells is unknown. The human bronchial epithelial cell lines, BEAS-2B cells, were pre-treated with different concentrations of albuterol, fenoterol or dibutyryl-cAMP (a cyclic AMP analog) before polyinosinic-polycytidylic acid (poly I:C) stimulation. In some condition, BEAS-2B cells were pre-treated with ICI-118551, a selective β2-adrenoreceptor antagonist, 30 min before albuterol or fenoterol treatment. The levels of RANTES and IP-10 were measured by ELISA. Intracellular signaling was investigated using cAMP assay, mitogen-activated protein kinase (MAPK) inhibitor, nuclear factor (NF)-κB inhibitor, and western blot. Albuterol and fenoterol suppressed poly I:C-induced RANTES and IP-10 expression of BEAS-2B cells. ICI-118551 could partly reverse the suppressive effects of albuterol and fenoterol on RANTES and IP-10 expression. Albuterol and fenoterol increased intracellular cAMP levels. Dibutyryl-cAMP conferred the similar effects of albuterol and fenoterol. Western blot revealed that albuterol suppressed p-ERK, p-JNK and pp38, and also their associated kinase expression. Albuterol had no effect on pp65 expression. Albuterol and fenoterol could suppress poly I:C-induced RANTES and IP-10 expression in human bronchial epithelial cells via at least partly the β2-adrenoreceptor-cAMP and the MAPK pathways, implicating that albuterol and fenoterol could exert anti-inflammatory effect and benefit asthmatic patients by suppressing RANTES and IP-10 expression. However, these suppressive effects of albuterol and fenoterol may inhibit the defense against viral infection.

Discovery of substituted phenyl urea derivatives as novel long-acting β2-adrenoreceptor agonists

The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their β(1)/β(2)-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship.

Suppressive Effects of Procaterol on Expression of IP-10/CXCL 10 and RANTES/CCL 5 by Bronchial Epithelial Cells

As indicated in the Global Initiative for Asthma guidelines, short-acting β2-adrenoreceptor agonists (SABAs) are important relievers in asthma exacerbation. Interferon γ-inducible protein (IP)-10/CXCL 10 is a T-helper type 1 (Th1) cell-related chemokine which is important in the recruitment of Th1 cells involved in host immune defense against intracellular pathogens such as viral infection. Regulated on activation, normal T expressed and secreted (RANTES)/CCL 5 is a chemokine which plays a role in attractant of eosinophils, mast cells, and basophils toward the site of allergic inflammation. Bronchial epithelial cells are first-line barriers against pathogen invasion. However, whether SABAs have regulatory effects on the expression of IP-10 and RANTES in bronchial epithelial cells is unknown. BEAS-2B cells, the human bronchial epithelial cell lines, were pretreated with procaterol (one of the SABAs) or dibutyryl-cAMP (a cyclic AMP analog) at different doses for 1 h and then stimulated with poly I:C (10 μg/mL). Supernatants were collected 12 and 24 h after poly I:C stimulation to determine the concentrations of IP-10 and RANTES by ELISA. In some cases, the cells were pretreated with selective β2-adrenoreceptor antagonist, ICI-118551, 30 min before procaterol treatment. To investigate the intracellular signaling, the cells were pretreated with mitogen-activated protein kinase (MAPK) inhibitors and a NF-κB inhibitor 30 min before procaterol treatment. Western blot was also used to explore the intracellular signaling. Procaterol significantly suppressed poly I:C-induced IP-10 and RANTES in BEAS-2B cells in a dose-dependent manner. ICI-118551, a selective β2-adrenoreceptor antagonist, could significantly reverse the suppressive effects. Dibutyryl-cAMP could confer the similar effects of procaterol on poly I:C-induced IP-10 and RANTES expression. Data of Western blot revealed that poly I:C-induced p-ERK, p-JNK, and pp38 expression, but not pp65, were suppressed by procaterol. SABAs could suppress poly I:C-induced IP-10 and RANTES expression in bronchial epithelial cells, at least in part, via β2-adrenoreceptor-cAMP and MAPK-ERK, JNK, and p38 pathways.

A New Simple Cell-Based Homogeneous Time-Resolved Fluorescence QRET Technique for Receptor-Ligand Interaction Screening

In this article, a single-label separation-free fluorescence technique is presented as a potential screening method for cell-based receptor antagonists and agonists.The time-resolved fluorescence technique, quenching resonance energy transfer (QRET), relies on a single-labeled binding partner in combination with a soluble quencher. The quencher efficiently suppresses the luminescence of the unbound labeled ligand, whereas the luminescence of the bound fraction is not affected. This approach allows the development of cell-based screening assays in a simple and cost-effective manner. The authors have applied the technique to the screening of beta(2)-adrenoreceptor (beta(2)AR) antagonists and agonists in intact human embryonic kidney HEK293(i) cells overexpressing human beta(2)-adrenergic receptors. Two antagonists (propranolol, alprenolol) and 2 agonists (metaproterenol, terbutaline) for beta(2)AR were investigated in a displacement assay using europium(III)-labeled pindolol ligand. The assay Z' values ranged from 0.68 to 0.78, the coefficient of variation was less than 10%, and the K(i) values were 19 nM for propranolol and alprenolol and 14 and 5.9 microM for metaproterenol and terbutaline, respectively. The QRET technique with beta(2)AR was also applied to LOPAC compound library screening, yielding nearly error-free recognition of known binders. This simple and cost-effective technique can be readily adapted to laboratory and industrial-scale screening.

Peroxidative Metabolism of β2-Agonists Salbutamol and Fenoterol and Their Analogues

Phenolic beta(2)-adrenoreceptor agonists salbutamol, fenoterol, and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm and why the drugs appear to be less effective in patients with severe asthma exacerbations remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these beta(2)-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists' derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from beta(2)-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically relevant concentrations of methimazole and dapsone. In alkaline buffers, radicals from fenoterol and its structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic beta(2)-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the beta(2)-agonists.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-alpha and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > or = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

Rapid Identification of a Putative Interaction between β2‐Adrenoreceptor Agonists and ATF4 using a Chemical Genomics Approach

Chemical genomics. We have uncovered a specific interaction between the β2-adrenoreceptor agonist salbutamol and the DNA binding region of transcription factor ATF4 in a chemical genomics approach using phage display combined with photoimmobilisation.

The discovery of adamantyl-derived, inhaled, long acting β2-adrenoreceptor agonists

The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.

β2-Adrenoreceptor Agonist-Enhanced Recovery of Locomotor Function after Spinal Cord Injury Is Glutathione Dependent

The beta2-adrenoreceptor agonist, clenbuterol, has been shown to spare spinal cord tissue and enhance locomotor recovery in an experimental model of spinal cord contusion injury. A likely mechanism of neurodegeneration following spinal cord injury involves generation of toxic levels of reactive oxygen species (ROS), e.g., O2-*, H2O2 and OH*, which overwhelm endogenous antioxidants. Agents, such as clenbuterol, that oppose neurodegeneration and improve recovery of locomotor function may possibly act by improving redox status. Consistent with reduced oxidative stress by beta2-agonist treatment following injury, prior blockade of synthesis of the antioxidant tripeptide, glutathione, with buthionine sulfoximine completely inhibited the ability of clenbuterol to enhance locomotor recovery and spare spinal cord tissue. Moreover, at 8 h postinjury, clenbuterol caused an increase in glutathione reductase activity, an indicator of cellular redox status, at the injury site that was also blocked by buthionine sulfoximine. Although clenbuterol improved locomotor recovery only when administered within a therapeutic window of several days postinjury, the accumulation of protein carbonyls in the spinal cord at 1 week postinjury, a consequence of ongoing ROS-mediated neurodegeneration, was also decreased by clenbuterol in a glutathione-dependent manner. Together, these results suggest that activation of beta2-adrenoreceptors during the acute phase of injury stimulates glutathione-dependent antioxidative processes, that lead to reduced oxidative damage and greater locomotor function as the injury evolves during the subacute and chronic phases.

Drug use by the elderly in general practice: effects on upper gastrointestinal symptoms

To evaluate the prevalence of drug use by elderly outpatients in Italy and to identify the association between drug use and gastrointestinal symptoms. The study was carried out by 133 general practitioners (GPs) who referred to 24 geriatric units in Italy. All consenting elderly patients seen at the GPs' offices were evaluated for gender, age, disability, current medications, and upper gastrointestinal symptoms. The study included 5,515 elderly subjects. The prevalence of drug use was 91.6%, and the mean number of drugs taken was 2.86 per person. Both the prevalence and the mean number of drugs significantly increased with advancing age. Regarding gastrointestinal symptoms, 32.7% of patients reported at least one upper gastrointestinal symptom: 25% with indigestion syndrome, 16.2% with abdominal pain, and 14.2% with reflux symptoms. A significantly higher prevalence of symptoms was observed in females, patients who were taking a higher number of drugs, and those who had higher disability. Adjusted multivariate analysis demonstrated that the use of nonsteroidal antiinflammatory drugs, steroids, psycholeptics, diuretics, selective beta2 adrenoreceptor agonists or adrenergics, and antiplatelet drugs was significantly associated with upper gastrointestinal symptoms. The prevalence of drug use is very high in this elderly outpatient population. The number of drugs and the use of some specific drug classes are significantly associated with the presence of upper gastrointestinal symptoms.

CNS Mitochondria in Neurodegenerative Disorders

Antioxidants & Redox SignalingVol. 7, No. 9-10 Forum EditorialCNS Mitochondria in Neurodegenerative DisordersJanet M. DubinskyJanet M. DubinskySearch for more papers by this authorPublished Online:22 Aug 2005https://doi.org/10.1089/ars.2005.7.1089AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited ByFDA-approved 5-HT1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injuryExperimental Neurology, Vol. 341Combination therapy with astaxanthin and epidermal neural crest stem cells improves motor impairments and activates mitochondrial biogenesis in a rat model of spinal cord injuryMitochondrion, Vol. 52Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseasesExperimental Neurology5-HT1F Receptor Agonist Induces Mitochondrial Biogenesis and Promotes Recovery from Spinal Cord Injury27 November 2019 | Journal of Pharmacology and Experimental TherapeuticsPharmacological Stimulation of Mitochondrial Biogenesis Using the Food and Drug Administration-Approved β2-Adrenoreceptor Agonist Formoterol for the Treatment of Spinal Cord Injury Natalie E. Scholpa, Hannah Williams, Wenxue Wang, Daniel Corum, Aarti Narang, Stephen Tomlinson, Patrick G. Sullivan, Alexander G. Rabchevsky, and Rick G. Schnellmann1 March 2019 | Journal of Neurotrauma, Vol. 36, No. 6Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy Pan Fan, Xing-Hui Xie, Chang-Hong Chen, Xin Peng, Po Zhang, Cheng Yang, and Yun-Tao Wang7 January 2019 | DNA and Cell Biology, Vol. 38, No. 15-HT 1F receptor-mediated mitochondrial biogenesis for the treatment of Parkinson's disease22 December 2017 | British Journal of Pharmacology, Vol. 175, No. 2Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target21 September 2017 | Journal of Pharmacology and Experimental Therapeutics, Vol. 363, No. 3Hypoxia Activation of Mitophagy and Its Role in Disease Pathogenesis Hao Wu and Quan Chen7 April 2015 | Antioxidants & Redox Signaling, Vol. 22, No. 126.4 Mitochondrial Permeability Transition in the CNS—Composition, Regulation, and Pathophysiological Relevance1 January 2007 Volume 7Issue 9-10Sep 2005 InformationCopyright 2005, Mary Ann Liebert, Inc.To cite this article:Janet M. Dubinsky.CNS Mitochondria in Neurodegenerative Disorders.Antioxidants & Redox Signaling.Sep 2005.1089-1091.http://doi.org/10.1089/ars.2005.7.1089Published in Volume: 7 Issue 9-10: August 22, 2005PDF download

Antiinflammatory Effects of Salmeterol after Inhalation of Lipopolysaccharide by Healthy Volunteers

Salmeterol is a beta2-adrenoreceptor agonist used in the treatment of obstructive pulmonary disease. Salmeterol inhibits inflammatory responses by neutrophils and mononuclear cells in vitro and in mouse models of lung inflammation in vivo. To determine the effect of salmeterol on LPS-induced lung inflammation in humans. Thirty-two healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg salmeterol or placebo (t=-0.5 h) followed by 100 microg LPS or normal saline (t=0 h; n=8/group). Measurements were performed in bronchoalveolar lavage fluid and purified alveolar macrophages obtained 6 h post-challenge. Inhalation of LPS was associated with neutrophil influx, neutrophil degranulation (myeloperoxidase, bactericidal/permeability-increasing protein and elastase), release of cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines (interleukin 8, epithelial cell-derived neutrophil attractant 78, macrophage inflammatory proteins 1alpha and 1beta), activation of alveolar macrophages (upregulation of HLA-DR and CD71; enhanced expression of mRNAs for 13 different mediators of inflammation), and protein leakage (all p<0.05 vs. placebo/saline). Pretreatment with salmeterol inhibited LPS-induced neutrophil influx, neutrophil degranulation (myeloperoxidase), tumor necrosis factor alpha release, and HLA-DR expression (all p<0.05 vs. placebo/LPS), while not significantly influencing other responses. Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.

What Are the Clinical Implications of β2-adrenoreceptor Polymorphisms for the Treatment of Asthma?

See related article page 22 haps someday, but certainly not yet. Rather, we must consider the implications of this new knowledge for clinical care on a more empirical basis. Population studies identify increased risk from continuous scheduled use of β2-receptor agonists but don’t identify those individuals most at risk.3,4 The studies of β2-adrenoreceptor polymorphisms reviewed by Binaei et. al.2 suggest that it is a sub-population who may be most at risk because of down-regulation of the β2adrenoreceptor when there is repeated use of β2adrenoreceptor agonists. Despite the common practice of prescribing regularly scheduled use of shorter-acting β2-adrenoreceptor agonists such as albuterol, there is no therapeutic rationale for such continuous use. These agents are primarily indicated for as-needed use to relieve acute symptoms. The current standard of care further mandates that frequent use of a bronchodilator for relief of acute symptoms indicates the need for anti-inflammatory therapy. A short course of an oral corticosteroid is the agent of choice for an acute exacerbation associated with subresponsiveness to a β2-agonist, and an inhaled corticosteroid is the agent of choice for persistent symptoms of asthma.5 While the inhaled corticosteroids alone are often sufficient to control the daily symptoms of chronic asthma, not all patients are adequately controlled on conventional low doses, and higher doses are associated with progressive risk of small but measurable systemic effects that can include growth suppression in addition to suppression of the hypothalamic-pituitary axis in children.6 Data have demonstrated that the addition of Adrenoreceptor agonists have long been the agents of choice for relieving acute symptoms of asthma since the first report of epinephrine use for acute asthma in 1900. Considerable pharmacologic research has subsequently gone into the development of variations of these receptor agonists. The extraction of ephedrine from the ancient Chinese herb Ma Huang provided an oral alternative to epinephrine.1 The progressive alteration of the molecule to isoproterenol (isoprenaline), isoetharine, albuterol (salbutamol), metaproterenol (orciprenaline), terbutaline, bitolterol, and pirbuterol eventually permitted more specific targeting of the β2-adrenoreceptor and also longer duration of action than epinephrine. More recently, even longer acting β2adrenoreceptor agonists, salmeterol and formoterol, have been introduced, not for acute intervention but as maintenance therapy for chronic asthma. The manuscript by Binaei and colleagues2 in the issue of the Journal elegantly describes the current growing literature that relates polymorphisms in the β2-adrenoreceptor to both asthma severity and variability in the response to these pharmacological agents that have played such a major role in treating asthma over the years. Are we entering a brave new world where pharmacologic agents are chosen following pharmacogenetic analysis of the individual patient? Per-

The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics

In a recent placebo-controlled study in mild atopic asthmatics, we observed a significant decrease in eosinophils in the bronchial submucosa, after 2 months of treatment with inhaled formoterol and budesonide. Biopsy material from each treatment group; formoterol (24μg bid), budesonide (400μg b.i.d.) and placebo has been further assessed to investigate the role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation, IL-4 and IL-5. Treatment with formoterol significantly reduced the number of eosinophils (EG2+) in the submucosa and epithelium, but this was not paralleled by changes in cytokine immunoreactivity. In contrast, treatment with budesonide significantly reduced both the number of eosinophils (EG2+) and immunoreactivity for IL-4 and IL-5 in the submucosa. Thus, while budesonide has effects on cytokines involved in eosinophil recruitment this explanation does not apply to the eosinopaenia observed with the long-acting β2 adrenoreceptor agonist formoterol.

β2- and β3-Adrenoreceptor agonists: Human myometrial selectivity and effects on umbilical artery tone

Objective: The purpose of this study was to investigate the functional selectivity of the β3-adrenoreceptor agonist BRL 37344 and the β2-adrenoreceptor agonist ritodrine for their putative receptors in human pregnant myometrium in vitro and to examine the possibility that BRL 37344 may exert an effect on other β-adrenoreceptor subtypes. This study also aimed comparatively to evaluate the in vitro effects of BRL 37344 and ritodrine on human vascular tissue tone. Study Design: The effects of BRL 37344 (1 nmol/L–100 μmol/L) and ritodrine (1 nmol/L–100 μmol/L) on isometric tension recordings that were performed in isolated myometrial strips that were obtained at elective cesarean delivery and in human umbilical artery rings that were obtained at term were measured. Antagonism of the effects of BRL 37344 and ritodrine in human myometrial tissue was investigated with the antagonists butoxamine (1 μmol/L), propranolol (1 μmol/L), and bupranolol (1 μmol/L). The concentrations that produced a 50% maximal effect, the mean maximal inhibition that was achieved, and the percentage of contractility that was observed were compared. Results: Bupranolol (n = 6), but not butoxamine (n = 6) or propranolol (n = 6), antagonized the relaxant effects of BRL 37344 in human pregnant myometrium; all three compounds (n = 6, respectively) antagonized the effects of ritodrine. At concentrations of >1 μmol/L, ritodrine exerted a significantly more potent vasodilatory effect than BRL 37344 on human umbilical artery tone (P <.01). Conclusion: The relaxant effects of BRL 37344 appear to be mediated solely through the β3-adrenoreceptor agonist, although ritodrine may exert an effect on β1-, β2-, and β3-adrenoreceptor agonists. This and the reduction in vascular tissue effects observed with BRL 37344 suggest that uterine β3-adrenoreceptor modulation may provide a novel scientific approach to tocolysis with fewer vascular adverse effects. (Am J Obstet Gynecol 2002;187:641-7.)

Effects of aerosolized albuterol on physiologic responses to exercise in standardbreds.

To examine the effects of an aerosolized beta2-adrenoreceptor agonist, albuterol, on performance during a standardized incremental exercise test in clinically normal horses. 8 Standardbred pacing mares. Clinically normal horses, as judged by use of physical examination, hematologic findings, serum biochemical analysis, and airway endoscopy, were randomly assigned to 2 groups and were given 900 microg of albuterol via a metered-dose inhaler 30 minutes before beginning a standardized incremental exercise test in a crossover design with a 7-day minimum washout. Further examination included measurement of baseline lung mechanics, response to histamine bronchoprovocation, and bronchoalveolar lavage. No significant differences (albuterol vs placebo) were seen for any incremental exercise test variables (ie, maximum oxygen consumption, maximum carbon dioxide consumption, respiratory quotient, treadmill speed at heart rate of 200 beats/min, or number of steps completed during an incremental exercise protocol). Mast cell percentage was significantly (r = -0.84) associated with the concentration of aerosolized histamine that evoked a 100% increase in total respiratory system resistance. No other direct correlations between bronchoalveolar lavage fluid cell types and any indices of exercise capacity or airway reactivity were found. Although no horse had exercise intolerance, 4 horses had airway hyperreactivity with bronchoalveolar lavage fluid mastocytosis; these horses may have been subclinically affected with inflammatory airway disease. In our study, albuterol did not enhance performance in 8 clinically normal racing-fit Standardbreds.

Inhibitory Activity of Fenoterol on Dermatophagoides-, Parietaria-, Tetanus-Toxoid-, and Candida albicans-Stimulated Blood Mononuclear Cells: Differences in β2-Adrenoreceptor Stimulation but Not in Cell Apoptosis

β2-adrenoreceptor agonists have the ability to downregulate in vitro the proliferative response of peripheral blood mononuclear cells (BMCs). This activity could be related to a variety of β2-adrenoreceptor-mediated functions, including induction of cell apoptosis in activated T-cells. To test this hypothesis, BMCs from atopic subjects, sensitized to house dust mites (Dermatophagoides [Der p]) and/or to Parietaria were incubated with fenoterol (10−8-10−5M) in the presence of (a) purified allergen extracts (Der p [5 μg/mL] or Parietaria [5 μg/mL]) or (b) antigens (tetanus toxoid [1 μg/mL] or Candida albicans [5 ± 105 bodies/mL]). The BMC proliferation was assessed by [3H] thymidine incorporation and cell apoptosis was assessed by evaluating DNA fragmentation by a fluorescence technique, using propidium iodide. In cultures stimulated with Der p or with Parietaria, fenoterol induced a dose-dependent inhibition of BMC proliferation, significant also at the lowest concentration tested (10−8M) (p < 0.05, each comparison). In contrast, the inhibitory activity of the drug on tetanus-toxoid-stimulated BMCs was significant only at the highest dose tested (10−5M) (p < 0.05), whereas no effect was seen when BMCs were stimulated with C. albicans extract (p > 0.05). The different inhibitory efficacy of fenoterol appeared to be related to the degree of activation of pYadrenoreceptors on the different BMC populations that responded to the different stimuli, indeed, in the presence of fenoterol (10−6 and 10−5M), a significant increase in cyclic adenosine monophosphate (cAMP) levels was seen in Der p- or Parietaria-stimulated cells (p < 0.05; each comparison), but not in cell cultures stimulated with tetanus toxoid or with C. albicans extracts (p > 0.05; each comparison). Finally, the percentage of cells with fragmented DNA was lower in cultures stimulated with Der p or Parietaria than in those stimulated with tetanus toxoid or C. albicans, and the presence of fenoterol did not modify cell apoptosis (p > 0.05; each comparison). Thus, the different inhibitory activity of fenoterol on BMCs activated by allergens (Der p or Parietaria) or by antigens (tetanus toxoid or C. albicans) seems to be related to differences in β2-adrenoreceptor expression and/or function in the different antigen-specific T-cell subsets, but it is not influenced by changes in cell apoptosis.

Rapid Reversibility of the Allergen-Induced Pulmonary Late-PhaseReaction by an Intravenous β2-Agonist

Peebles R Jr, Permutt S, Togias AJ Appl Physiol.84199815001505To determine the degree to which β2-adrenergic receptor agonists can reverse the allergen-induced late reduction in lung function.Seven allergic subjects with mild asthma.In phase I of the study, terbutaline was administered as an initial bolus followed by continuous intravenous infusion over 45 minutes to determine the maximal attainable bronchodilation at baseline. In phase II, the subjects underwent an allergen inhalation (ragweed) challenge until forced expiratory volume in 1 second (FEV1) declined by at least 20%. Seven hours later, subjects were randomized and crossed over to receive terbutaline or a vehicle intravenous infusion identical to the phase I infusion protocol. Forced expiratory spirometry was performed at baseline and every hour after allergen-inhalation challenge. Spirometry was performed before and every 5 minutes through terbutaline (phase II and I) and placebo infusion (phase II) as well.At baseline, there was no significant difference in FEV1 or forced vital capacity (FVC) between phase I and phase II. In phase I, terbutaline infusion led to significant improvement in FEV1compared with preinfusion value (P < .03). After ragweed bronchoprovocation FEV1 decreased <85% at any single timepoint between hour 4 and 7 postallergen inhalation. On the day placebo was infused 7 hours after allergen inhalation, FEV1 values did not change significantly compared with the preinfusion value (P > .2). In contrast, on the day terbutaline was infused, FEV1 was significantly higher than preinfusion (P < .02). The overall pattern of FVC was the same as for FEV1. The kinetic curves for bronchodilator response to terbutaline infusion in phase I and in phase II were superimposable, indicating that the terbutaline induced bronchodilation was driven by the same pharmacologic mechanism.The late reduction in lung function caused by allergen inhalation challenge in asthmatic subjects is rapidly and almost completely reversible by an intravenous β2-adrenoreceptor agonist.Most previous studies have demonstrated that inhaled β2-adrenoreceptor agonists are only partially effective in reversing allergen-inhaled late phase airway obstruction. Interestingly, the ability to reverse this type of airway obstruction appears to be significantly enhanced using an intravenous route for drug administration. These observations challenge the current dogma that the airway obstruction observed 4 to 8 hours after allergen challenge is mostly related to airway edema, inflammation, and mucus secretion as opposed to bronchial smooth muscle spasm. A third arm of the study in which equivalent doses of β-agonist were given by aerosol would have been helpful in determining what role drug delivery may have contributed to the observed results.

Terbutaline, A β2-Adrenoreceptor agonist, inhibits gastric acid secretion and stimulates release of peptide YY and gastric inhibitory polypeptide in dogs

Terbutaline, a beta 2-adrenoreceptor agonist, inhibits pentagastrin-stimulated gastric acid secretion. The purpose of this study was to examine the effect of intravenous administration of terbutaline on plasma levels of peptide YY (PYY) and gastric inhibitory polypeptide (GIP), both of which are known to inhibit gastric acid secretion. Seven dogs with gastric and duodenal fistulas were given pentagastrin (1 microgram/kg/hr) intravenously for 150 min in combination with terbutaline (10 or 20 micrograms/kg/hr) or saline during the 60- to 120-min period of pentagastrin infusion. Pentagastrin-stimulated gastric acid secretion was significantly (P less than 0.05) inhibited by intravenous administration of terbutaline. Terbutaline significantly increased plasma PYY levels, 24% in response to terbutaline at 10 micrograms/kg/hr, and 59% at 20 micrograms/kg/hr. Plasma GIP levels were also increased significantly, 24% with terbutaline at 10 micrograms/kg/hr, and 39% at 20 micrograms/kg/hr. Our data suggest that terbutaline-induced inhibition of pentagastrin-stimulated gastric acid secretion is mediated, at least in part, by the release of PYY and GIP. The adrenergic nervous system may influence gastric acid secretion through the release of PYY and GIP.

Effect of terbutaline, a β2-adrenoreceptor agonist, on gastric acid secretion and serum gastrin concentrations in humans

Because β-adrenoreceptor agonists inhibit gastrinstimulated gastric acid secretion in animals, we postulated that the β2-adrenoreceptor agonist, terbutaline, would inhibit pentagastrin-stimulated acid secretion in humans. Moreover, we hypothesized that terbutaline might inhibit food-stimulated acid secretion, as gastrin is a major mediator of food-stimulated acid secretion. Subcutaneous terbutaline (0.25 mg) reduced acid secretion during intravenous infusion of a submaximal dose of pentagastrin by 30%–40% (p < 0.005), even though terbutaline increased serum gastrin levels (p < 0.05). Furthermore, subcutaneous (0.25 mg) or oral (5 mg) terbutaline, given before a homogenized steak meal was infused into the stomach, lowered mean food-stimulated acid secretion rates, despite enhanced postprandial serum gastrin concentrations. Terbutaline also increased serum gastrin concentrations in patients with Zollinger-Ellison syndrome and in vagotomized individuals. Thus, β2-adrenoreceptor agonists enhance gastrin release while at the same time inhibiting gastrin-stimulated acid secretion in humans.