cyclic-gmp and Asthma

Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension.. The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed.. Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Cyclic AMP; Cyclic GMP; Drug Development; Drugs, Investigational; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

Nitric oxide (NO) is a gaseotransmitter, which is involved in many signaling processes in health and disease. Three enzymes generate NO from l-arginine, with citrulline formed as a by-product: neuronal NO synthase (nNOS or NOS1), endothelial NOS (eNOS or NOS3) and inducible NOS (iNOS or NOS2). NO is a ligand of soluble guanylyl cyclase (sGC), an intracellular heterodimer enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP further activates protein kinase G that eventually reduces the smooth muscle tone in bronchi or vessels. Phosphodiesterase 5 (PDE5) degrades cGMP to GMP. However, NO reacts with superoxide anion (O2(-)), leading to formation of the pro-inflammatory molecule peroxynitrite. Under physiological conditions, NO plays a homeostatic bronchoprotective role in healthy subjects. In obstructive airway diseases, NO can be beneficial by its bronchodilating effect, but could also be detrimental by the formation of peroxynitrite. Since asthma and COPD are associated with increased levels of exhaled NO, chronic inflammation and increased airway smooth muscle tone, the NO/sGC/cGMP pathway could be involved in these highly prevalent obstructive airway diseases. Here we review the involvement of NO, NO synthases, guanylyl cyclases, cGMP and phophodiesterase-5 in asthma and COPD and potential therapeutic approaches to modulate this pathway.

Topics: Animals; Asthma; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanylate Cyclase; Humans; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Disease, Chronic Obstructive; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Superoxides

Topics: Asthma; Biomarkers; Cyclic GMP; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hyperparathyroidism; Liver Diseases; Myocardial Infarction; Neoplasms; Nitric Oxide; Radioimmunoassay; Reference Values; Specimen Handling

Nitric oxide (NO) plays diverse roles in physiological and pathological processes. During immune and inflammatory responses, for example in asthma, NO is generated at relatively high and sustained levels by the inducible form of nitric oxide synthase (NOS-2). NOS-2 derived NO regulates the function, growth, death and survival of many immune and inflammatory cell types. In the case of mast cells, NO suppresses antigen-induced degranulation, mediator release, and cytokine expression. The action of NO on mast cells is time dependent, requiring several hours, and noncGMP mediated, most probably involving chemical modification of proteins. NO inhibits a number of mast cell-dependent inflammatory processes in vivo, including histamine mediated vasodilatation, vasopermeation and leucocyte-endothelial cell attachment. In human asthma and animal models of lung inflammation the role of NO is harder to define. However, although there are conflicting data, the balance of evidence favours a predominantly protective role for NO. Mimicking or targeting NO dependent pathways may prove to be a valuable therapeutic approach to mast cell mediated diseases.

Topics: Animals; Asthma; Cyclic GMP; Cytokines; Cytoplasmic Granules; Disease Models, Animal; Endopeptidases; Heparin; Histamine Release; Humans; Hypersensitivity; Inflammation; Mast Cells; Mice; Mice, Knockout; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Signal Transduction; Swine

The cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an important role in the regulation of airway smooth muscle tone and activation of inflammatory cells. Intracellular concentrations of these nucleotides are tightly regulated by phosphodiesterases (PDEs). Several families of PDEs are now recognized and, within each isoenzyme family, molecular cloning has revealed multiple members. PDE III and IV are important in the breakdown of cAMP; PDE III is involved in the regulation of airway smooth muscle tone, whereas PDE IV is more important in inflammatory cells, including mast cells, macrophages, eosinophils, T-lymphocytes and epithelial cells. PDE V is involved in the breakdown of cGMP in airway and vascular smooth muscle. Regulation of PDE expression in health and disease is now under investigation. Several selective PDE inhibitors have recently been developed, and experimental studies indicate that PDE IV inhibitors may be useful as anti-inflammatory treatments in asthma. Clinical trials in asthma are now in progress.

Topics: Animals; Asthma; Cyclic AMP; Cyclic GMP; Humans; Isoenzymes; Muscle, Smooth; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Respiratory Physiological Phenomena; Respiratory System; Theophylline

Atopy is not the most common factor causing asthma in adults. Recent elucidations of pathophysiologic mechanisms involving the autonomic nervous system, cyclic nucleotide metabolism, and arachnoidonic biochemistry give us a better understanding of the similarities and unique differences among asthma events related to exercise, aspirin, emotions, occupational environments, atmospheric conditions, and respiratory tract infections. The ultimate value of this information is no greater than its potential to aid the physician in decreasing the interference of asthma in the daily lives of patients.

Topics: Aerosols; Air Pollution; Aspirin; Asthma; Asthma, Exercise-Induced; Autonomic Nervous System; Cyclic AMP; Cyclic GMP; Emotions; Humans; Humidity; Immunoglobulin E; Occupational Diseases; Parasympathetic Nervous System; Receptors, Adrenergic; Respiratory Tract Infections; Tobacco Smoke Pollution

Topics: Arachidonic Acid; Arachidonic Acids; Asthma; Calcium; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Humans; Lung Diseases, Obstructive; Mast Cells; Muscle, Smooth; Respiratory Hypersensitivity

Topics: Adenylyl Cyclases; Adult; Asthma; Calcium; Child; Cromolyn Sodium; Cyclic AMP; Cyclic GMP; Dermatitis, Atopic; Humans; Hypersensitivity; Immunoglobulin E; Muscle, Smooth; Phosphodiesterase Inhibitors

Topics: Animals; Asthma; Bradykinin; Carcinoid Tumor; Cardiovascular Diseases; Cardiovascular System; Cyclic AMP; Cyclic GMP; Humans; Infant, Newborn; Kallikreins; Kidney; Kinins; Prostaglandins; Sodium

We talk about a hypersensitive bronchial system, when under certain endogen prepositions or exogen influences, upon which a healthy persons reacts hardly or not at all, it comes to a significant raise of the airway resistances. Probably this is the prestadium of a chronic obstructive airway disease, which often occurs with patients suffering from an existant bronchial disease. Therefore it is important for actual clinical practice to discuss those problems, which interfere with the raise of sensitivity of the bronchial airways. The discussion should be based on the actual state of science, because several therapeutic problems and consequences ensue.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Airway Obstruction; Allergens; Asthma; Bacterial Infections; Bronchi; Bronchial Provocation Tests; Cyclic AMP; Cyclic GMP; Parasympatholytics; Pulmonary Embolism; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Virus Diseases

Topics: Airway Obstruction; Asthma; Autonomic Nervous System; Cyclic AMP; Cyclic GMP; Epinephrine; Humans; Hypoxia; Muscle, Smooth; Parasympathomimetics; Receptors, Adrenergic

Topics: Adenylyl Cyclases; Asthma; Central Nervous System; Cyclic AMP; Cyclic GMP; Endocrine System Diseases; Gastrointestinal Diseases; Humans; Muscles; Myocardial Infarction; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Protein Kinases

Topics: Adenylyl Cyclases; Animals; Anti-Inflammatory Agents; Antiviral Agents; Asthma; Cardiovascular Diseases; Cricetinae; Cyclic AMP; Cyclic GMP; Disease; Enzyme Activation; Extracellular Space; Guanylate Cyclase; Humans; Hypoglycemic Agents; Isoenzymes; Kinetics; Mental Disorders; Mice; Neoplasms; Obesity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psoriasis; Rats

Topics: Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Humans; Muscle Contraction; Muscle, Smooth; Prostaglandins; Respiratory System; Trachea

Topics: Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Adult; Airway Obstruction; Asthma; Cyclic AMP; Cyclic GMP; Histamine H1 Antagonists; Humans; Male; Psychology

Topics: Adenylyl Cyclases; Adrenergic beta-Antagonists; Animals; Asthma; Cyclic GMP; DNA; Epinephrine; Histamine; Histamine Release; Humans; Parasympathomimetics; Platelet Adhesiveness; Synaptic Transmission

Topics: Adrenergic beta-Antagonists; Allergens; Allergy and Immunology; Asthma; Austria; Autonomic Nervous System; Bronchodilator Agents; Cyclic AMP; Cyclic GMP; Emotions; Expectorants; Histamine Release; History, 20th Century; Humans; Hypersensitivity; Hypersensitivity, Delayed; Lymphokines; Phosphates; Phosphoric Diester Hydrolases; Potassium Iodide; Prostaglandins; Reflex; Respiratory Tract Infections; SRS-A; Temperature; United States

Topics: Adolescent; Albuterol; Asthma; Beclomethasone; Bronchodilator Agents; Carboxylic Acids; Child; Child, Preschool; Cromolyn Sodium; Cyclic AMP; Cyclic GMP; Humans; Hypertension, Pulmonary; Immunoglobulin E; Metaproterenol; Phenols; Prostaglandins; Pulmonary Atelectasis; Pulmonary Edema; Radiography; Respiratory Function Tests; Terbutaline; Tetrazoles; Xanthenes

Topics: Affective Symptoms; Animals; Asthma; Caffeine; Calcitonin; Calcium; Catecholamines; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Dermatitis, Atopic; Diabetes Insipidus; Glucagon; Growth Hormone; Humans; Hypercalcemia; Hyperparathyroidism; Hypocalcemia; Hypoparathyroidism; Insulin; Organ Specificity; Parathyroid Hormone; Psoriasis; Vasopressins

Atrial natriuretic peptide (ANP) has bronchodilator and vasodilator properties thought to be mediated through the generation of cyclic guanylyl monophosphate (cGMP). The current study was designed to examine the effects of infused ANP on respiratory (FEV1), cardiovascular (blood pressure and pulse), and metabolic (plasma cGMP) function in asthmatic patients. Eight patients with a mean +/- SD age of 45.6 +/- 8.2 yr and mean FEV1 of 56.4 +/- 15.4% of predicted were studied using a randomized double-blind crossover design. On one study day after baseline measurements (FEV1, blood pressure, pulse, and plasma cGMP), ANP was infused for 20-min periods at 5 pmol/kg/min and at 25 pmol/kg/min; a placebo (saline) inhalation was then administered. On the other day the placebo infusion was followed by inhalation of 5 mg albuterol. Measurements were repeated at the end of each 20-min period. The highest rate of ANP infusion increased the FEV1 by 0.50 +/- 0.09 L compared with 0.09 +/- 0.05 after the placebo infusion (p < 0.001). The increase in FEV1 produced by ANP plus placebo inhalation (0.50 +/- 0.28 L) was similar to that produced by placebo infusion plus albuterol inhalation (0.61 +/- 0.30 L). There was no clinically significant fall in systolic or diastolic blood pressure (torr) at the 25 pmol/kg/min infusion rate. The mean basal cGMP was 602 +/- 242 fmol/ml and increased to 5,883 +/- 1,460 and 21,182 +/- 2,509 with the two rates of ANP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuterol; Asthma; Atrial Natriuretic Factor; Blood Pressure; Bronchi; Cyclic GMP; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Infusions, Intravenous; Male; Middle Aged; Pulse

A subset of asthmatics develop a severe form of the disease whose etiology involves airway inflammation along with inherent drivers that remain ill-defined. To address this, we studied human airway smooth muscle cells (HASMC), whose relaxation drives airway bronchodilation and whose dysfunction contributes to airway obstruction and hypersensitivity in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, we questioned if HASMC from severe asthma donors might possess inherent defects in their sGC or in redox enzymes that support sGC function. We analyzed HASMC primary lines derived from 17 severe asthma and 16 normal donors and corresponding lung tissue samples regarding sGC activation by NO or by pharmacologic agonists, and also determined expression levels of sGC α1 and β1 subunits, supporting redox enzymes, and related proteins. We found a majority of the severe asthma donor HASMC (12/17) and lung samples primarily expressed a dysfunctional sGC that was NO-unresponsive and had low heterodimer content and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting redox enzymes cytochrome b5 reductase, catalase, and thioredoxin-1, and higher expression of heme oxygenases 1 and 2. Together, our work reveals that severe asthmatics are predisposed toward defective NO-sGC-cGMP signaling in their airway smooth muscle due to an inherent sGC dysfunction, which in turn is associated with inherent changes in the cell redox enzymes that impact sGC maturation and function.

Topics: Asthma; Cyclic GMP; Guanylate Cyclase; Humans; Nitric Oxide; Oxidation-Reduction; Signal Transduction; Soluble Guanylyl Cyclase

This research was set up to explore the neural mechanisms of acupuncture in the treatment of bronchial asthma in rats by detecting the content of substance P(SP), vasoactive intestinal peptide (VIP), neurokinin A(NKA), neurokinin B (NKB), cyclic adenosine monophosphate/cyclic guanosine monophosphate ratio (cAMP/cGMP) and hematoxylin-eosin (HE) staining for the pathological changes of lung tissue, in order to Institute Certain Experimental and Theoretical Foundation for Traditional Chinese Medicine (TCM) Prevention and Treatment of Bronchial Asthma. For this purpose, fifty healthy adult Wistar male rats, weighing 200-250 g, were randomly divided into 5 groups: normal control group A, asthma control group B, asthma acupuncture group C, adrenalectomy (ADX)-asthma  group D, adrenalectomy (ADX)-asthma acupuncture group E. Group A was raised with other groups at the same period; Group B was induced asthma by ovalbumin; Group C was induced asthma as Group B and then acupunctured five acupoints (bilateral Feishu, bilateral Fengmen, and Dazhui); Group D was induced asthma after adrenalectomy; group E was treated with acupuncture on the basis of group D. HE staining was performed in the lung tissue of rats from each group, and histopathologic changes were observed. SP, VIP, NKA, NKB in each rat lung tissue were measured by immunohistochemistry. cAMP/cGMP was measured with ELISA to speculate the neural mechanisms of acupuncture in the treatment of bronchial asthma. The results were as: decrease of cAMP/cGMP and VIP and increase of SP, NKA, NKB in the lung tissue are the neural mechanisms of an asthma attack. The increase of cAMP/cGMP and decrease of NKA, NKB, SP and VIP in the lung tissue of group C indicated the improvement of bronchial asthma symptoms. It is possible that the decrease of NKA and NKB, increase of cAMP/cGMP and a slight change of SP and VIP in group E were related to the reduction of glucocorticoid after ADX which influenced the effect of acupuncture. The neural regulation mechanisms of acupuncture in the treatment of bronchial asthma were related to bronchiectasis caused by stimulation of adrenergic nerve and inhibition of the vagus nerve function by acupuncture, and related to the release of inflammatory mediators.

Topics: Acupuncture Therapy; Animals; Asthma; Cyclic AMP; Cyclic GMP; Immunohistochemistry; Inflammation Mediators; Lung; Male; Neurokinin B; Rats; Rats, Wistar; Substance P; Vasoactive Intestinal Peptide

The soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate signaling pathway evokes vascular smooth muscle relaxation; whether this pathway mediates airway smooth muscle relaxation remains controversial. We posit that sGC activators are equi-effective as β-agonists in reversing contractile agonist-induced airway smooth muscle shortening. To provide clarity, we tested the efficacy of sGC stimulator and activator drugs, BAY 41-2272 and BAY 60-2270, respectively, in reversing bronchoconstriction of human small airways using human precision-cut lung slices (hPCLS). Both BAY drugs reversed carbachol-induced bronchoconstriction to a maximal degree comparable to that of formoterol. Moreover, the sGC drugs remained effective bronchodilators despite formoterol-induced desensitization of the airways. Analysis of the hPCLS after their activation by sGC or β

Topics: Asthma; Bronchoconstriction; Bronchodilator Agents; Cyclic GMP; Humans; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Respiratory System; Signal Transduction; Soluble Guanylyl Cyclase; Trachea

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Benzoates; Biphenyl Compounds; Bronchial Hyperreactivity; Bronchodilator Agents; Coculture Techniques; Cyclic GMP; Drug Evaluation, Preclinical; Enzyme Activation; Female; Guanylate Cyclase; Humans; Hydrocarbons, Fluorinated; Lung; Mice; Mice, Inbred BALB C; Muscle, Smooth; Nitric Oxide; Pyrazoles; Pyridines; Solubility; Trachea

Activators of soluble guanylyl cyclase (sGC) act preferentially in conditions of enzyme oxidation or haem group removal. This study was designed to investigate the effects of the sGC activator BAY 60-2770 in murine airways inflammation and human eosinophil chemotaxis.. C57Bl/6 mice treated or not with BAY 60-2770 (1 mg/kg/day, 14 days) were intranasally challenged with ovalbumin (OVA). At 48 h, bronchoalveolar lavage fluid (BALF) was performed, and circulating blood, bone marrow and lungs were obtained. Human eosinophils purified from peripheral blood were used to evaluate the cell chemotaxis.. OVA-challenge promoted marked increases in eosinophil number in BAL, lung tissue, circulating blood and bone marrow, all of which were significantly reduced by BAY 60-2770. The IL-4 and IL-5 levels in BALF were significantly reduced by BAY 60-2770. Increased protein expression of iNOS, along with decreases of expression of sGC (α1 and β1 subunits) and cGMP levels were detected in lung tissue of OVA-challenged mice. BAY 60-2770 fully restored to baseline the iNOS and sGC subunit expressions, and cGMP levels. In human isolated eosinophils, BAY 60-2770 (1-5 μM) had no effects on the cGMP levels and eotaxin-induced chemotaxis; however, prior incubation with ODQ (10 μM) markedly elevated the BAY 60-2770-induced cyclic GMP production, further inhibiting the eosinophil chemotaxis.. BAY 60-2770 reduces airway eosinophilic inflammation and rescue the sGC levels. In human eosinophils under oxidized conditions, BAY 60-2770 elevates the cGMP levels causing cell chemotaxis inhibition. BAY 60-2770 may reveal a novel therapeutic target for asthma treatment.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Benzoates; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Chemotaxis; Cyclic GMP; Disease Models, Animal; Eosinophils; Humans; Hydrocarbons, Fluorinated; Inflammation; Male; Mice; Mice, Inbred C57BL; Ovalbumin; Soluble Guanylyl Cyclase

Muscarinic agonists induce the activation of the airway smooth muscle (ASM) leading to smooth muscle contraction, important in asthma. This activation is mediated through M2/M3 muscarinic acetylcholine receptors (mAChRs). Muscarinic receptor activity, expressed as [(3)H]QNB binding at plasma membranes from bovine tracheal smooth muscle (BTSM), increased with cGMP and was augmented significantly cGMP plus ATP but diminished with the PKG-II inhibitor, Sp-8-pCPT-cGMPS. The [(3)H]-QNB binding was accelerated by okadaic acid, (OKA), a protein phosphatase (PPase) inhibitor. These two results indicated the involvement of a membrane-bound PPase. Moreover, a cGMP-dependent-[(32)P]γATP phosphorylation of plasma membranes from BTSM was stimulated at low concentrations of muscarinic agonist carbamylcholine (CC). However, higher amounts of CC produced a significant decrement of [(32)P]-labeling. A selective M3mAChR antagonist, 4-DAMP produced a dramatic inhibition of the basal and CC-dependent [(32)P]-labeling. The [(32)P] labeled membrane sediments were detergent solubilized and immunoprecipitated with specific M2/M3mAChR antibodies. The M3mAChR immuno-precipitates exhibited the highest cGMP-dependent [(32)P]-labeling, indicating it is a PKG-II substrate. Experiments using synthetic peptides from the C-terminal of the third intracellular loop (i3) of both M2mAChR (356-369) and M3mAChR (480-493) as external PKG-II substrates resulted in the i3M3-peptide being heavily phosphorylated. These results indicated that PKG-II phosphorylated the M3mAChR at the i3M3 domain ((480)MSLIKEKK(485)), suggesting that Ser(481) may be the target. Finally, this phosphorylation site seems to be regulated by a membrane-bound PPase linked to muscarinic receptor. These findings are important to understand the role of M3mAChR in the patho-physiology of ASM involved in asthma and COPD.

Topics: Animals; Asthma; Cattle; Cell Membrane; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Feedback, Physiological; Humans; In Vitro Techniques; Muscarinic Agonists; Muscarinic Antagonists; Muscle, Smooth; Phosphorylation; Protein Kinase Inhibitors; Quinuclidinyl Benzilate; Receptor, Muscarinic M3; Signal Transduction; Thionucleotides; Trachea

Asthma is a chronic inflammatory disease in which cell components play important roles. We aimed to evaluate the effects of NO/cGMP cleavage at trachea preparations isolated from ovalbumin-sensitized guinea pigs in vitro. Trachea rings were exposed to 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-12), (±)-(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl-nicotinamide (NOR-4), 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl) methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), and electrical field stimulation (EFS). cGMP levels in trachea tissues were also measured. The relaxation responses of NOC-12, NOR-4, T-0156, and EFS were significantly decreased at ovalbumin-sensitized group. Nitric oxide (NO) donors significantly decreased the relaxation responses in the presence of 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ). L-Nitro-Arginine Methyl Ester (L-NAME) significantly decreased the EFS relaxation responses in both groups (experimental group and control group), but this effect was reversed by L-Arginine addition. In the experimental group, cGMP levels after EFS, carbachol, NOC-12, NOR-4, and T-0156 exposure were significantly lower than control group. In both groups, cGMP levels after NO donors' exposure were significantly lower in the presence of ODQ and the cGMP levels after EFS + L-NAME were significantly lower than EFS alone. These results may show the increased formation of NO because of the increased iNOS activity in airway sensitization leading to the inhibition of cNOS resulting in the decrease of endogen NO and decrease of activation of guanylyl cyclase.

Topics: Animals; Asthma; Bronchodilator Agents; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Isometric Contraction; Male; Muscle, Smooth; Naphthyridines; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Ovalbumin; Pyridines; Pyrimidines; Trachea

Isatin, an endogenous indole compound, prevents atrial natriuretic peptide (ANP) from signaling through its cell-surface receptor, NPRA. Allergic airway inflammation has been linked to natriuretic peptide signaling and blocking this signaling axis in the lung prevents allergen-induced pathology. In this study we encapsulated isatin in chitosan nanoparticles and tested them in a mouse model of allergic asthma by intranasal delivery to the lung. Isatin nanocapsules reduced lung pathology by blocking ANP signaling, but surprisingly also by reducing the expression of NPRA. Ovalbumin-allergic mice were treated intranasally with isatin-containing chitosan nanocapsules either before or after allergen challenge, and lung function, cytokine levels, histopathology and cellular infiltration were determined. ANP activity was quantitated by measuring changes in intracellular cyclic GMP and changes in NPRA levels were determined. For comparison with isatin's effects, the expression of the receptor was inhibited with small interfering RNA against NPRA mRNA. Isatin nanocapsules administered locally to the lung reduced cGMP production and NPRA expression and protected allergic mice from airway hyperreactivity and lung inflammation when given either before or after allergen challenge. Leukocyte infiltration was reduced and lung cytokine profiles showed a repolarization from a Th2-like to a Th1-like phenotype. Isatin nanocapsules administered locally to the lung inhibit NPRA signaling but also are capable of lowering the expression of NPRA, thus effectively reducing inflammation in a mouse model of allergic asthma. Pharmacological intervention to reduce NPRA activity through the inflammatory natriuretic peptide axis in the lung may be a useful adjunct therapy for treating lung disease.

Topics: Administration, Intranasal; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chitosan; Cyclic GMP; Cytokines; Female; Inflammation; Isatin; Leukocytes; Lung; Mice; Mice, Inbred BALB C; Nanocapsules; Ovalbumin; Receptors, Atrial Natriuretic Factor

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.

Topics: Administration, Inhalation; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Guanylate Cyclase; Hydrazines; Hydrocortisone; Injections, Intraperitoneal; Lipopolysaccharides; Methacholine Chloride; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Ovalbumin; Oxadiazoles; Pneumonia; Quinoxalines; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; Respiration, Artificial; Respiratory Mechanics; Soluble Guanylyl Cyclase

Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Animals; Anti-Inflammatory Agents; Asthma; Bronchoconstriction; Bronchodilator Agents; Budesonide; Consciousness; Cyclic GMP; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Guinea Pigs; Histamine; Male; Nitric Oxide; Nitric Oxide Donors; Receptors, Adrenergic, beta-2; S-Nitroso-N-Acetylpenicillamine

Clinical and biochemical studies considering pathogenetic mechanisms of bronchial asthma supported efficiency of "Singular" preparation and its promising quality for complex therapy of bronchial asthma.

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Cyclic AMP; Cyclic GMP; Cyclopropanes; Humans; Leukotriene Antagonists; Occupational Diseases; Quinolines; Sulfides

Human rhinovirus (HRV) infections trigger exacerbations of asthma and chronic obstructive pulmonary disease. Nitric oxide (NO) inhibits HRV replication in human airway epithelial cells and suppresses HRV-induced epithelial production of several cytokines and chemokines.. We sought to delineate the mechanisms by which NO inhibits HRV-induced epithelial production of CXCL10, a chemoattractant for type 1 T cells and natural killer cells.. Primary human bronchial epithelial cells or cells of the BEAS-2B human bronchial epithelial cell line were exposed to HRV-16 in the presence or absence of the NO donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA NONOate). A cGMP analogue and an inhibitor of soluble guanylyl cyclase were used to examine the role of the cyclic guanosine monophosphate (cGMP) pathway in the actions of NO. BEAS-2B cells were transfected with CXCL10 promoter-luciferase constructs and the effects of PAPA NONOate were examined to study mechanisms of transcriptional regulation. Electrophoretic mobility shift assays were also used.. PAPA NONOate inhibited HRV-16-induced increases in CXCL10 mRNA and protein. Inhibition of CXCL10 production occurred through a cGMP-independent pathway. PAPA NONOate inhibited HRV-16-induced CXCL10 transcription by blocking nuclear translocation, binding, or both of both nuclear factor kappaB and IFN response factors (IRFs) to their respective recognition elements in the CXCL10 promoter.. NO inhibits HRV-16-induced production of CXCL10 by inhibiting viral activation of nuclear factor kappaB and of IRFs, including IRF-1, through a cGMP-independent pathway. The broad-ranging inhibition of HRV-induced epithelial cytokine and chemokine production by NO suggests a potential therapeutic utility of NO donors in viral exacerbations of asthma and chronic obstructive pulmonary disease.

Topics: Active Transport, Cell Nucleus; Asthma; Cell Line; Cell Nucleus; Chemokine CXCL10; Cyclic GMP; Epithelial Cells; Humans; Hydrazines; Interferon Regulatory Factor-1; NF-kappa B; Nitric Oxide; Nitric Oxide Donors; Picornaviridae Infections; Respiratory Mucosa; Response Elements; Rhinovirus; Transcription, Genetic; Transcriptional Activation; Virus Activation

Nitric oxide (NO) levels are elevated in the exhaled breath of asthmatic patients and NO is considered as a biomarker of airway inflammation. However, the functions of NO in the airways are not completely understood. L-arginine, as the substrate of NO synthases, is the precursor of NO which stimulates guanylate cyclase and leads to the formation of cyclic GMP (cGMP). Sildenafil, a phosphodiestérase-5 (PDE-5) inhibitor, prevents the degradation of cGMP. In this study the effects of L-arginine and sildenafil treatment, alone or in combination, were evaluated in ovalbumin-sensitized BP2 mice. These effects concerning the airway responsiveness to inhaled methacholine (MCh) were evaluated by whole-body plethysmography (WBP), the inflammatory response evaluated by bronchoalveolar lavage fluid (BALF) analyses and lung tissue biopsies (eosinophilic inflammation associated with lung remodelling), and NO metabolite measurements (by Griess reaction) in BALF. Ovalbumin sensitization induced: (a) an inflammatory reaction with eosinophil and neutrophil influx in BALF and lung; and (b) an increased bronchial responsiveness to MCh. L-arginine treatment [50 mg/kg intraperitoneally (i.p.), for 7 days] increased the relative amount of eosinophils and neutrophils in BALF, had a tendency to increase the airway responsiveness to inhaled MCh and increased the NO metabolite level in BAL. Sildenafil treatment (20 mg/kg i.p. for 7 days) did not affect the airway responsiveness to MCh and had a lower effect compared with L-arginine on inflammatory reactions. The combination of the two treatments resulted in a dramatic enhancement of the airway responsiveness to inhaled MCh. The relative amount of eosinophils was increased and lung histology showed obvious worsened tissular lesions such as epithelial shedding and hypertrophy, hyperplasia of smooth muscle cells, and fibrosis. These findings are consistent with the notion that NO production plays a role in the development of airway inflammation and hyperresponsiveness of sensitized mice and highlighted the potential risk of the L-arginine dietary complement or PDE5 treatment in asthmatic patients.

Topics: Animals; Arginine; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclic GMP; Eosinophilia; Eosinophils; Lung; Male; Methacholine Chloride; Mice; Nitric Oxide; Ovalbumin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Plethysmography, Whole Body; Purines; Sildenafil Citrate; Sulfones

Increased levels of NO in exhaled air in association with increased NO synthetase (NOS)2 expression in bronchial epithelial are hallmark features of asthma. It has been suggested that NO contributes to asthma pathogenesis by selective down-regulation of TH1 responses. We demonstrate, however, that NO can reversibly limit in vitro expansion of both human TH1 and TH2 CD4+ T cells. Mechanistically, NO induces cGMP-mediated reversible STAT5 dephosphorylation and therefore interferes with the IL-2R activation cascade. Human bronchial epithelial cells (HBEC) up-regulate NOS2 after stimulation with IFN-gamma secreted by TH1 CD4+ T cells and release NO, which inhibits both TH1 and TH2 cell proliferation. This reversible T cell growth arrest depends on NO because T cell proliferation is completely restored after in vitro blocking of NOS2 on HBEC. HBEC thus drive the effector end of a TH1-controlled feedback loop, which protects airway mucosal tissues at the potential lesional site in asthma from overwhelming CD4+ TH2 (and potentially TH1) responses following allergen exposure. Variations in the efficiency of this feedback loop provides a plausible mechanism to explain why only a subset of atopics sensitized to ubiquitous aeroallergens progress to expression of clinically relevant levels of airways inflammation.

Topics: Asthma; Bronchi; Cell Proliferation; Cells, Cultured; Clone Cells; Coculture Techniques; Cyclic GMP; Enzyme Induction; Growth Inhibitors; Humans; Interferon-gamma; Lymphocyte Activation; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Respiratory Mucosa; STAT5 Transcription Factor; Th1 Cells; Th2 Cells; Up-Regulation

Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Ovalbumen exposure caused early- and late-phase bronchoconstrictor responses, measured in conscious animals by whole-body plethysmography. Twenty-four hours after ovalbumen exposure there was airway hyperreactivity (AHR) to inhaled histamine and significantly elevated macrophages, eosinophils, and nitric oxide (NO) metabolites in bronchoalveolar lavage fluid. Sildenafil treatment (1 mg/kg, intraperitoneally) failed to affect the early and late responses but significantly reduced AHR, leukocyte influx, and elevated NO. LPS exposure (30 microg/ml) caused AHR to histamine at 1 hour and macrophage, eosinophil, and neutrophil influx at 24 hours with raised NO. Sildenafil pretreatment inhibited LPS-induced AHR, leukocyte influx, and NO generation. The effectiveness of sildenafil was not dependent on endogenous NO because inhibition of NO synthase with Nomega-nitro-L-arginine methyl ester did not prevent its action. Inhibition of PDE5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicillamine-induced cGMP generation in isolated lungs. These antiinflammatory actions of sildenafil in guinea pig models suggest that PDE5 inhibitors may have potential in treating airways disease.

Topics: Airway Resistance; Allergens; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclic GMP; Eosinophils; Guinea Pigs; Histamine; In Vitro Techniques; Lipopolysaccharides; Lung; Macrophages; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ovalbumin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Occupational bronchial asthma with its prevalence amounting to 14% is one of the main entities in occupational morbidity structure. Clinical evidence in recent decades demonstrates changed phenotype of occupational bronchial asthma. Changes are increased number of patients suffering from the severe asthma, higher occurrence of occupational bronchial asthma which pathogenesis is more significantly mediated by nonimmune mechanisms. Prevalence of these types of occupational bronchial asthma approaches 9.7-22%.

Topics: Adenylyl Cyclases; Asthma; Cyclic AMP; Cyclic GMP; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Infections; Middle Aged; Occupational Diseases; Pituitary-Adrenal System

In asthma, human airway epithelial cells (HAECs) regulate the intensity of mucosal inflammation, in part, by releasing the pro-inflammatory cytokine interleukin (IL)-1beta. However, the IL-1beta inhibitors, IL-1 receptor antagonist (IL-1RA) and soluble IL-1 receptor type II (sIL-1RII), regulate IL-1beta bioactivity. In order to better understand the control of IL-1beta activity in the airway mucosa, the role(s) of tumour necrosis factor (TNF)-alpha, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the release of IL-1beta and its inhibitors by cultured HAECs were examined. HAECs were treated with TNF-alpha (2-200 ng.mL(-1)), dibutyryl cAMP (0.01-1 mM), 8-bromo-cGMP (0.01-1 mM) or vehicle for 24 h, and cytokine levels in the HAEC-conditioned medium were measured by enzyme-linked immunosorbent assay. HAECs produced IL-1beta, IL-1RA and sIL-1RII constitutively, but the inhibitor concentrations greatly exceeded that of IL-1beta (by approximately 100- and approximately 550-fold, respectively). TNF-alpha dose-dependently increased the levels of all IL-1beta cytokine family members. However, over the range of TNF-alpha concentrations studied, IL-1beta concentration increased more than those of its inhibitors. cAMP increased constitutive and TNF-alpha-stimulated IL-1beta release but reduced that of sIL-1RII. In contrast, cGMP had no effect on IL-1beta but reduced IL-1RA and sIL-1RII release. Under basal conditions, the disproportionate release of inhibitors relative to interleukin-1beta by human airway epithelial cells probably prevents interleukin-1beta-mediated biological effects. Tumour necrosis factor-alpha, cyclic adenosine monophosphate and cyclic guanosine monophosphate may potentiate mucosal inflammation by increasing interleukin-1beta levels relative to those of its inhibitors in the airway mucosa.

Topics: Asthma; Cell Line; Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1; Tumor Necrosis Factor-alpha

To investigate the changes of beta-adrenergic receptor (beta AR) in peripheral lymphocytes and beta 2AR mRNA levels at different stages of bronchial asthma.. beta 2AR density and beta 2AR mRNA level in peripheral lymphocytes, cAMP and cGMP levels in blood plasma were estimated by radioligand binding assay, radioimmunoassay and RT-PCR.. (1) Maximum bound volume (Bmax) and equilibrium dissociation constant (Kd) of beta 2AR of lymphocyte in asthma patients at remission stage were markedly higher than that in normal subjects, while cAMP levels in blood plasma showed no difference. Bmax of beta 2AR and cAMP levels in asthma patients at acute exacerbation stage were significantly lower than that in normal subjects, and Kds between these two groups were not much different. (2) Expression of beta 2ARmRNA in peripheral lymphocytes of asthmatics at remission stage was not significantly different compared with that in normals.. Amount and function of beta AR and beta 2ARmRNA levels are related to asthmatic conditions. Changes of beta AR and beta 2ARmRNA in asthma might rather be a pathological change accompanied by the course of the disease than a primary defect.

Topics: Adult; Aged; Asthma; Cyclic AMP; Cyclic GMP; Female; Gene Expression; Humans; Lymphocytes; Male; Middle Aged; Receptors, Adrenergic, beta-2; RNA, Messenger

Airway smooth muscle (ASM) hypertrophy and hyperplasia are important determinants of bronchial responsiveness in asthma, and agents that interfere with these processes may prevent airway remodeling. We tested the hypothesis that activators of soluble and particulate guanylyl cyclases would inhibit human ASM cell (HASMC) proliferation. We report that the nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine (SNAP; 10(-6) to 10(-4) M) and sodium nitroprusside (10(-5) to 10(-3) M) and human atrial natriuretic peptide [ANP-(1-28); 10(-8) to 10(-6) M], which activate soluble and particulate guanylyl cyclases, respectively, inhibited serum- and thrombin-induced proliferation of cultured HASMCs. The antimitogenic effect of SNAP was reversed by hemoglobin (10(-5) M), an NO scavenger, suggesting that NO donation was involved. The antiproliferative effects of SNAP and ANP-(1-28) were potentiated by the cGMP-specific phosphodiesterase zaprinast and mimicked by 8-bromo-cGMP (10(-6) to 10(-3) M), suggesting that cGMP-dependent mechanisms were involved. However, first, ANP-(1-28) produced a smaller antiproliferative effect than SNAP in contrast to their abilities to elevate cGMP, and second, rat ANP-(104-126), which binds selectively to ANP clearance receptors without elevating cGMP, had a small antiproliferative effect, suggesting that cGMP-independent mechanisms were also involved. These results provide evidence for a novel antiproliferative effect of NO and ANP in HASMCs mediated through cGMP-dependent and cGMP-independent mechanisms.

Topics: Asthma; Atrial Natriuretic Factor; Blood Proteins; Cell Division; Cells, Cultured; Coloring Agents; Cyclic GMP; Diuretics; Hemoglobins; Hemostatics; Humans; Hyperplasia; Lung; Mitogens; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Penicillamine; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Tetrazolium Salts; Thiazoles; Thrombin; Vasodilator Agents

To explore the expression and pathogenic mechanism of heme oxygenase-1(HO-1) in asthma.. Two groups of guinea pigs (10 in each) were treated with the specific stimulator(hemin) and inhibitor(Sn-PP) of HO-1 respectively. Their effects on the levels of HO-1 activity, COHb, cGMP and IgE in serum or blood and lung tissues were compared with each other. Acute asthmatic group (AAG), dexamethasone-prevented group(DPG), stable asthmatic group, ovalbumin-sensitized group and normal control group(NCG) were also included. Lung tissues of tested animals were pathologically observed and immunohistochemically stained.. In the AAG and hemin stimulated group, the levels of COHb, cGMP and IgE were significantly increased with higher levels of activity and expression of HO-1 protein compared with the NCG (t = 4.575-10.188, P < 0.01). In DPG and Sn-PP inhibited groups, however, all measured parameters were markedly reduced compared with the AAG(P < 0.01). The other groups were normal.. The increased production and activity of HO-1 resulted in increases of endogenous CO and cGMP and promoted inflammation and immunoreaction in asthma.

Topics: Animals; Asthma; Carbon Monoxide; Cyclic GMP; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Guinea Pigs; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Male; Nitric Oxide

We compared the effects of natriuretic peptides on antigen-induced bronchoconstriction and airway microvascular leakage in sensitized guinea pigs. Anesthetized male guinea pigs, ventilated via a tracheal cannula, were placed in a plethysmograph to measure pulmonary mechanics for 10 min after challenge with 1 mg/kg of ovalbumin, and then Evans blue dye was extravasated into airway tissue in order to indicate and evaluate microvascular leakage. Three separate intravenous pretreatments using atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) significantly inhibited the ovalbumin-induced bronchoconstriction and microvascular leakage in a dose-dependent manner. These inhibitory effects were mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate. We showed that the rank order of inhibitory potencies, which were mediated by cyclic guanosine 3',5'-monophosphate, was BNP > or = ANP > or = CNP. These results gave us some clues for the clinical application of the natriuretic peptides.

Topics: Animals; Antigens; Asthma; Atrial Natriuretic Factor; Blood Pressure; Bronchi; Bronchoconstriction; Capillary Permeability; Cyclic GMP; Disease Models, Animal; Guinea Pigs; Leukotriene D4; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Ovalbumin; Proteins; Trachea

1. To clarify part of the bronchodilating effects of theophylline, lymphocyte cyclic AMP (cAMP) and phosphodiesterase (PDE) activity in asthmatic patients and healthy adults were measured. 2. No clear differences in lymphocyte PDE activity were found regarding sexes, ages or the types of asthma. 3. Lymphocyte PDE activity in the asthma group was significantly higher than that in the control group. 4. Lymphocyte cAMP significantly increased at 30 and 60 min after intravenous injection of aminophylline in the asthma group. 5. Lymphocyte PDE activity significantly decreased 60 min after intravenous injection of aminophylline in the asthma group.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adult; Age Factors; Aminophylline; Asthma; Bronchodilator Agents; Cyclic AMP; Cyclic GMP; Female; Humans; Injections, Intravenous; Lymphocytes; Male; Middle Aged; Phosphodiesterase Inhibitors; Sex Factors; Terbutaline; Theophylline; Time Factors

Prognostic evaluation of patients with primary pulmonary hypertension (PPH) requires right heart catheterisation. The development of accurate non-invasive methods for monitoring these patients remains an important task. Cyclic guanosine monophosphate (cGMP) is an indicator of the action of natriuretic peptides and nitric oxide on target cells. Plasma and urinary cGMP concentrations are raised in patients with congestive heart failure in whom they correlate closely with haemodynamic parameters and disease severity. The aim of the present study was to determine whether the urinary concentration of cGMP could be used as a non-invasive marker of haemodynamic impairment in patients with severe PPH.. Urinary cGMP concentrations were measured in 19 consecutive patients with PPH, seven with acute asthma, and 30 normal healthy controls.. Patients with PPH had higher urinary cGMP concentrations than asthmatic patients or normal healthy controls (p = 0.001). Urinary cGMP concentrations were higher in patients with severe haemodynamic impairment--that is, those with a cardiac index (CI) of < or = 2 l/min/m2 (p = 0.002)--and urinary cGMP concentrations were inversely correlated with CI (r = -0.69, p = 0.002) and venous oxygen saturation (r = -0.65, p = 0.003).. Urinary cGMP concentrations may represent a non-invasive indicator of the haemodynamic status of patients with severe PPH.

Topics: Adult; Asthma; Biomarkers; Cardiac Catheterization; Cardiac Output; Cyclic GMP; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged

In the patients with bronchial asthma, the chemiluminescence (CL) of polymorphonuclear (PMN) and lymphocyte (LY) in blood had two peaks, maximal peak value decreased and peak time prolonged: cAMP, cAMP/cGMP, SOD in plasma decreased, IgE increased. The authors suggest that the pathogenetic mechanism of bronchial asthma may related to activated inflammatory cells, released mediators and inbalanced immuno opsonic functions.

Topics: Adolescent; Adult; Aged; Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Female; Humans; Immunoglobulin E; Infant; Luminescent Measurements; Lymphocytes; Male; Middle Aged; Neutrophils

Sinesterases that intervene in cAMP and oGMP equilibrium in the cytoplasm of mast cells are activated by the adrenergic system through beta-receptors. A study was made on 96 atopic patients with mono sensitization to Dermatophagoides pteronissinus, in 3 groups. Radioligands were used to quantitate the number of beta receptors. In the control group mean no/cell was 541, bronchial symptomatic patients had 327 and nasal symptomatics 348. Asymptomatic patients were similar to controls. The results were similar with pollen-sensitive patients. Beta receptor decrease is a consequence of clinical allergy in atopic patients and is secondary to the immunological events that follow antigen-antibody reactions and cell membrane changes.

Topics: Adenylyl Cyclases; Allergens; Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Cyclic AMP; Cyclic GMP; Enzyme Activation; Humans; Hypersensitivity, Immediate; Mast Cells; Mites; Phosphoric Diester Hydrolases; Receptors, Adrenergic, beta; Rhinitis, Allergic, Seasonal; Signal Transduction

Topics: Asthma; Cyclic GMP; Humans; Liver Diseases; Myocardial Infarction; Neoplasms; Radioimmunoassay

The content of beta-endorphins was studied in 64 children aged 6 to 14 years with atopic bronchial asthma (BA). The phasic relationship was established in the time course of changes in the content of beta-endorphins. In the paroxysmal period of BA, the concentration of beta-endorphins in blood was lowered, whereas after attacks and in the stage of remission, the level of beta-endorphins was increased and differed significantly from the indicators in the control group. The reduction of the content of beta-endorphins during exacerbation correlated with the disease gravity. The content of endorphins was found to be affected by the age and sex: the greater reduction of the level of beta-endorphins was recorded in children aged 6 to 11 years and in boys. The reduction of the level of beta-endorphins was followed by the impairment of interhormonal relations between ACTH and beta-endorphins, ACTH and hydrocortisone in all the disease phases. A correlation was discovered between the level of beta-endorphins and ACTH, cAMP as well as the level of IgE in blood plasma. It is suggested that derangements in the endorphin system may influence the mechanisms by which bronchial hyperreactivity is formed.

Topics: Adolescent; Adrenocorticotropic Hormone; Aging; Asthma; beta-Endorphin; Child; Cyclic AMP; Cyclic GMP; Female; Humans; Hydrocortisone; Immunoglobulin E; Male; Radioimmunoassay; Sex Characteristics

Topics: Adrenergic alpha-Antagonists; Asthma; Bronchial Spasm; Cyclic AMP; Cyclic GMP; Humans; Receptors, Adrenergic; Respiratory Function Tests

Topics: Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Drugs, Chinese Herbal; Female; Humans; Leukocytes; Male; Receptors, Glucocorticoid

Experiments were carried out to investigate the effects of anti-asthma drugs on cGMP levels. In vitro, theophylline (5 X 10(-4) M) increased basal and 5-hydroxytryptamine stimulated cGMP formation by platelets (p less than 0.05) while salbutamol and prednisolone produced no change. No significant differences were found in urine cGMP levels in healthy subjects, after short term treatment with theophylline, isoprenaline or prednisolone. Urinary cGMP levels were lower than normal in the majority (7/10) of asthma patients tested and in female patients this difference was significant (p less than 0.05). Severity of asthma symptoms were not found to be associated with particular changes in urinary cGMP levels. Fluctuations in the cGMP levels were, however, greater (p less than 0.01) in asthma patients with a more unstable respiratory condition. The differences between in vitro and in vivo results may demonstrate that beta-stimulants and theophylline have different acute and chronic effects on cGMP formation, or show that in vivo these drugs primarily affect tissue enzymes that differ from those on platelets.

Topics: Adrenergic beta-Agonists; Adult; Aged; Albuterol; Aminophylline; Asthma; Blood Platelets; Cyclic GMP; Ethanolamines; Female; Humans; Isoproterenol; Male; Middle Aged; Prednisolone; Procaterol; Theophylline

A parallel study of the activity of serum cholinesterase and excretion of cyclic guanosine monophosphate made it possible to distinguish 3 types of disorders of cholinergic regulation in exacerbation of bronchial asthma: cholinergic compensation, subcompensation and decompensation. The nature of correlations of the degree of disturbance of cholinergic regulation, intensity of allergic reaction and its type was established. The role and place of the choline blocking agents in multiple modality therapy of bronchial asthma were defined.

Topics: Acid Phosphatase; Acute Disease; Adult; Aged; Asthma; Cholinesterases; Cyclic GMP; Female; Histamine; Humans; Immunoglobulin E; Male; Middle Aged; Status Asthmaticus

Topics: Adult; Aged; Asthma; Cholinesterases; Cyclic GMP; Female; Humans; Male; Middle Aged; Parasympathetic Nervous System; Parasympatholytics

Topics: Acupuncture Therapy; Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Female; Humans; Hydrocortisone; Immunoglobulin E; Lymphocyte Activation; Male; Relaxation Therapy

Airway smooth muscle contraction and the extreme sensitivity of the airway smooth muscle responses to various stimuli are accepted as key factors in the pathogenesis of asthma and are recognized to be important in other diseases (e.g., bronchitis and cystic fibrosis). A Workshop on Airway Smooth Muscle sponsored by the National Heart, Lung and Blood Institute (September 25 to 27, 1983) identified various avenues of future research. Smooth muscle anatomists pointed to the paucity of quantitative information on airway smooth muscle structure, especially electron microscopic information and details of the neural arrangement. Investigations of the neural network, similar to those that have led to important discoveries in the gut, are urgently needed. Now that intramural ganglia can be studied electrophysiologically (and in vivo!), new information concerning possible local neural modulation can be examined. A similar lack of information was found in the biochemical study of airway smooth muscle. Among potential causes of abnormalities in asthmatic muscles are alterations in membrane channels and pumps, receptor transduction processes, cGMP-mediated processes, and other metabolic pathways. Inflammation and inflammatory mediators appear to play important roles in disease of airway smooth muscle. Utilization of cell isolation and culture, and immunologic and other cell biologic and biochemical methods will accelerate the study of the various cells in the airways, their interactions, and their roles in disease. Of special potential importance are peptide and lipid mediators produced by various airway cells. Development of synthetic analogues and antagonists, including monoclonal antibodies, will provide more specific tools for dissecting these cell-to-cell interactions. Regardless of the level of study--from examination of the whole organism to molecular mechanisms--the fact is that there is no entirely satisfactory animal "model" of asthma or asthmatic muscle, presumably because we do not fully understand the etiology and pathogenesis of asthma. This makes it all the more important to take appropriate opportunities to obtain tissue from asthmatics for laboratory study. Relatively simple, careful studies of asthmatic smooth muscle may prove important, unique insights into its possible abnormalities.

Topics: Asthma; Cyclic GMP; Humans; Ion Channels; Muscle Contraction; Muscle, Smooth; Respiratory Hypersensitivity; Respiratory Physiological Phenomena

Topics: Adolescent; Adult; Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Prostaglandins; Thromboxane B2; Thromboxanes

Topics: Adult; Airway Resistance; Asthma; Bronchial Provocation Tests; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Aminophylline; Asthma; Bronchial Spasm; Child; Cyclic AMP; Cyclic GMP; Drug Evaluation; Histamine; Humans; Prostaglandins E

Leukosuspensions from 217 patients with bronchial asthma and 73 normal subjects were examined for alterations in the levels of cAMP and cGMP under the effect of incubation with adrenaline, propranolol, acetylcholine. A study was also made of the activity of cAMP PDE and glycogen metabolism. Simultaneous measurement of the basal and stimulated levels of cyclic nucleotides and their ratios revealed a decrease in cell adrenoreactivity and a rise in cholinoreactivity. Variation of the beta-adrenoblocking action of propranolol typical for the atopic mechanism of bronchial asthma was demonstrated. Comparison of the adrenodependent glycogenolysis and alterations in the cAMP level, analysis of the action of analgin on these characteristics allowed the conclusion about the secondary nature of alterations in cAMP metabolism dependent on the features of prostaglandin metabolism. A significant decrease in the adrenodependent glycogenolysis was revealed in lymphocytes, with that decrease induced by drug, dust and pollen allergens. It was demonstrated that in verified viral infection, cAMP PDE was significantly reduced.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Asthma; Cyclic AMP; Cyclic GMP; Glycogen; Humans; In Vitro Techniques; Leukocytes

Topics: Asthma; Child, Preschool; Chronic Disease; Cyclic AMP; Cyclic GMP; Humans; Leukocytes; Pneumonia

Topics: Adolescent; Adult; Aged; Asthma; Bronchitis; Cyclic AMP; Cyclic GMP; Female; Humans; Leukocytes; Lipid Peroxides; Lung Diseases; Male; Middle Aged; Pneumonia

Topics: Aged; Asthma; Autonomic Nervous System Diseases; Cholinesterases; Cyclic GMP; Humans; Male; Parasympatholytics; Vagus Nerve

Topics: Adult; Aged; Asthma; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged

Topics: Asthma; Cyclic AMP; Cyclic GMP; Humans; Hypersensitivity; Receptors, Adrenergic, beta

The authors studied urine excretion of cyclic-AMP and cyclic-GMP in normal and allergic children before and after hyposensitization to house dust. The cyclic-AMP excretion was found to b diminished in the asthmatic group before the treatment. The hyposensitization did not modify these low levels. No significant variation of cyclic-GMP excretion was found among the normal, ante or post-hyposensitization asthmatic groups.

Topics: Asthma; Child; Child, Preschool; Creatinine; Cyclic AMP; Cyclic GMP; Desensitization, Immunologic; Female; Humans; Hypersensitivity; Male; Time Factors

It is known that sympatho-adrenal control of airways is increased in asthma since beta blockade can cause severe bronchoconstriction in asthmatic individuals. It has not been established whether an altered catecholamine response to exercise plays any part in the production of the common symptom of exercise-induced asthma (EIA). We have investigated this indirectly by measuring arterial plasma cyclic nucleotide levels in 10 subjects with EIA and five normal subjects. Cyclic AMP, which in this context reflects beta stimulation, rose significantly by 25.4% in the normal subjects during exercise, while there was no significant change during or after exercise (less than 5%) in the asthmatic subjects. Cyclic GMP rose significantly after exercise in the asthmatic subjects. Six normal subjects repeated the protocol before and after inhalation of salbutamol aerosol, 1600 microgram daily for 18 days. This did not reduce the cAMP response to exercise, and we conclude that the diminished cAMP response of the asthmatic subjects was not caused by their medication. The results may indicate either impaired catecholamine production or endogenous beta receptor hyporesponsiveness in some asthmatic subjects and this may contribute to the development of EIA.

Topics: Adult; Albuterol; Asthma; Asthma, Exercise-Induced; Cyclic AMP; Cyclic GMP; Humans; Male; Middle Aged

Topics: Adenylyl Cyclases; Asthma; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Humans; Prostaglandins E; Prostaglandins F; Receptors, Cholinergic; Sympathetic Nervous System

Topics: Acetylcholine; Adult; Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Prostaglandins F

Topics: Asthma; Cyclic AMP; Cyclic GMP; Glycogen; Humans; Leukocytes

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Albuterol; Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Epinephrine; Humans; Hydrocortisone; Isoproterenol; Lymphocytes; Norepinephrine; Receptors, Adrenergic; Receptors, Adrenergic, beta

Topics: Asthma; Cyclic AMP; Cyclic GMP; Humans; Hypersensitivity, Immediate; Lymphocytes; Mast Cells

Topics: Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Cyclic AMP; Cyclic GMP; Dopamine beta-Hydroxylase; Humans; Male; Middle Aged; Norepinephrine; Prostaglandins E

Topics: Adolescent; Adult; Aged; Asthma; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Radioimmunoassay

Asthmatic children suffering from nocturnal asthmatic paroxysms showed not only a reduced peak exspiratory flow rate (PEER) but also a diminished excretion of cyclic AMP (cAMP) at night. In contrast, in asthmatic children without nocturnal asthmatic attacks, neither in PEFR nor in cAMP excretion did a circadian rhythm occur. Prednisolone, theophylline, and sleep withdrawal were able to reestablish normal airway function and cAMP excretion in those patients with nocturnal bronchoconstriction. Cyclic GMP (cGMP), which has been suggested as a mediator for cholinergic mechanisms, shows the exact opposite behavior of that of cAMP. In children suffering from nocturnal asthmatic attacks, cGMP increases during the night, whereas under sleep withdrawal it decreases. Hence we propose that a reduced responsiveness of beta-adrenergic receptors as well as an increased cholinergic activity are due to nocturnal asthmatic attacks. Therapeutic interventions taking the form of increasing cAMP or decreasing cGMP levels may thus be most helpful in treating nocturnal asthma.

Topics: Adolescent; Airway Obstruction; Asthma; Child; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Maximal Expiratory Flow Rate; Prednisolone; Sleep; Theophylline

Topics: Acetylcholine; Adult; Airway Resistance; Asthma; Bronchial Provocation Tests; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Occupational Diseases; Rhinitis, Allergic, Perennial

Urinary excretion of cAMP and cGMP was studied in nine normal and 15 asthmatic children. Bronchial lability was studied with a treadmill running test and atopy with serum IgE and skin prick tests. A circadian rhythm was found in both groups for cAMP and cGMP excretion. Cyclic GMP levels were higher in the asthma group, the difference reaching statistical significance around the time of the exercise challenge test. The fall in PEF induced by exercise showed a significant negative correlation with urinary cAMP responsiveness to isoproterenol inhalation. Exercise-induced bronchial lability correlated with 24-h cGMP excretion. High cGMP and low cAMP levels at night could be connected with nighttime exacerbations of symptoms. It is suggested that cGMP might have a more important role in asthma, than previously assumed.

Topics: Adolescent; Asthma; Child; Child, Preschool; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Female; Humans; Immunoglobulin E; Male; Skin Tests

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Asthma; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged

The purpose of this study was to compare exercise-induced changes in urinary cyclic AMP and cyclic GMP of normal and asthmatic subjects. All subjects were exercised to 80% of predicted maximum heart rate for 15 minutes on a bicycle ergometer. FEV1 was measured before and after exercise to determine the degree of bronchoconstriction due to exercise. Five urine specimens were collected by voluntary voiding at 20 minute intervals (one specimen before exercise and four after exercise). Before exercise, the asthmatic subjects excreted less cyclic GMP (p less than 0.05) but the same cyclic AMP as the normal subjects. Creatinine excretion in nine asthmatic subjects decreased by 24% (p less than 0.01) during exercise. In sixteen normal subjects (post-exercise bronchoconstriction less than 10%) cyclic AMP excretion increased by 19% (p less than 0.05) within 20 minutes after exercise, while cyclic GMP excretion did not change significantly. In thirteen asthmatic subjects (post-exercise bronchoconstriction greater than 20%) cyclic AMP excretion did not change significantly, while cyclic GMP excretion increased by 23% (p less than 0.05) within 20 minutes after exercise. This study has shown that exercise affects the excretion of cyclic AMP, cyclic GMP, and creatinine in normal and asthmatic subjects. The response of normal and asthmatic groups to exercise was the same for creatinine but different for cyclic AMP and cyclic GMP.

Topics: Adolescent; Adult; Asthma; Creatinine; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Physical Exertion

The effect of isoproterenol on the cyclic nucleotide level in peripheral lymphocytes and granulocytes with allergic rhinitis patients and normal subjects has been studied. Responsiveness to 10(-5) M isoproterenol of lymphocytes decreased in the case of allergic rhinitis patients. When asthma was complicated to perennial rhinitis, a more significant depression was noted. In granulocytes the same tendency as with lymphocytes was noted although the difference was not significant. Basal level and responsiveness to 5 X 10(-3) M theophylline of both lymphocytes and granulocytes were similar in allergic rhinitis patients to normal subjects. The ratio of plasma cAMP to cGMP concentration was lower in the allergic rhinitis patients although the difference was not significant.

Topics: Adolescent; Adult; Asthma; Child; Cyclic AMP; Cyclic GMP; Granulocytes; Humans; Isoproterenol; Lymphocytes; Middle Aged; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Theophylline

The contents of histamine and cyclic nucleotides were studied in leukocytes before and after a bronchoprovocation test on patients with extrinsic asthma. The bronchospastic response correlated significantly with the reduction of the amount of histamine in leukocytes isolated after the provocation. The leukocytes cyclic AMP and cyclic GMP contents were slightly reduced after the provocation, while the plasma level of cyclic AMP was markedly increased. The beta-adrenoceptor response was tested on leukocytes, before the provocation. A normal elevation of the cyclic AMP content was obtained when the leukocytes were stimulated with isoprenaline, but after the provocation, isoprenaline had no significant effect. Only when a phosphodiesterase inhibitor was present did isoprenaline increase the cyclic AMP level in the postprovocation tests. It is suggested that the mediator release from the immunologic target cells is of importance for the bronchospastic response and that a desensitization of the beta-adrenoceptors of these cells is evident after bronchoprovocation.

Topics: 1-Methyl-3-isobutylxanthine; Adolescent; Adult; Allergens; Asthma; Bronchial Spasm; Cyclic AMP; Cyclic GMP; Female; Histamine; Histamine Release; Humans; Isoproterenol; Leukocytes; Male; Middle Aged; Peak Expiratory Flow Rate; Phosphodiesterase Inhibitors; Receptors, Adrenergic, beta

Topics: Anaphylaxis; Asthma; Cyclic AMP; Cyclic GMP; Desensitization, Immunologic; Epinephrine; Homeostasis; Humans; Lung; Mast Cells; Respiratory Therapy; Vagus Nerve

Topics: Adolescent; Asthma; Child; Cyclic AMP; Cyclic GMP; Humans; Maximal Expiratory Flow Rate; Propranolol; Terbutaline

Topics: Asthma; Cyclic AMP; Cyclic GMP; Humans; Norepinephrine

Topics: Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Humans

A constitutional factor, an imbalance of cAMP/cGMP, a disturbance of adenylcyclase and a vegetative dysregulation influence the allergic type I reaction. An unspecific hyperreactivity of the bronchial system plays an important role in the asthmatic genesis. Own experiments with acetylcholine and anticholinergic drugs are described. The deduction that the complement system participates in bronchial asthma is likely from own in vivo and in vitro experiments.

Topics: Asthma; Complement System Proteins; Cyclic AMP; Cyclic GMP; Humans; Ipratropium; Mast Cells; Receptors, Adrenergic, beta

Topics: Aminopyrine; Asthma; Asthma, Exercise-Induced; Cyclic AMP; Cyclic GMP; Dipyrone; Dopamine beta-Hydroxylase; Histamine; Humans; Norepinephrine

Topics: Airway Resistance; Animals; Asthma; Cyclic AMP; Cyclic GMP; Dogs; Histamine; In Vitro Techniques; Lung; Mast Cells; Neurotransmitter Agents; p-Methoxy-N-methylphenethylamine; Reagins; Respiratory Physiological Phenomena; Respiratory System; Vagus Nerve

In the past decade there has been substantial improvement in the quality of drug therapy for asthma. In part, this reflects the greater sophistication and confidence in the use of bronchodilator drugs, after their role in modifying the intracellular concentration of cyclic nucleotides was discovered. Another advance has come from the appearance of adequate information on theophylline blood levels and half-lives and their variability in man. The increasing availability of theophylline blood levels has aided not only in the selection of therapeutic doses but also in determining the effectiveness of newer products that, for example, promise to have a more sustained effect when given by mouth. The plight of asthmatic patients dependent on oral glucosteroid therapy has been substantially eased with the development of new steroid-sparing drugs that are effective by inhalation.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Asthma; Cyclic AMP; Cyclic GMP; Drug Administration Schedule; Enzyme Activation; Glucocorticoids; Hospitalization; Humans; Parasympatholytics; Phosphodiesterase Inhibitors; Prostaglandins E; Respiratory Therapy

Topics: Administration, Oral; Aerosols; Asthma; Child, Institutionalized; Cyclic AMP; Cyclic GMP; Expectorants; Health Education; Humans; Immunotherapy; Injections, Subcutaneous; Intermittent Positive-Pressure Breathing; Nutritional Physiological Phenomena; Phosphodiesterase Inhibitors; Sodium Chloride; Sympathomimetics; Xanthines

Topics: Acute Disease; Adrenergic beta-Antagonists; Antigen-Antibody Reactions; Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Histamine Release; Humans; Hypersensitivity; Muscle Contraction; Muscle, Smooth; Prostaglandins; Receptors, Drug; SRS-A

Topics: Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Humans; Hypersensitivity; Irritants; Muscle Tonus; Muscle, Smooth; Receptors, Adrenergic; Receptors, Cholinergic

Topics: Adrenergic beta-Agonists; Anesthetics; Animals; Asthma; Bronchi; Bronchodilator Agents; Cyclic AMP; Cyclic GMP; Female; Humans; Muscle Tonus; Muscle, Smooth; Myocardium; Rats