Degranulation of human mast cells: modulation by P2 receptors' agonists.

Since the late 1970s, there has been an alarming increase in the incidence of asthma and its morbidity and mortality. Acute obstruction and inflammation of allergic asthmatic airways are frequently caused by inhalation of exogenous substances such as allergens cross-linking IgE receptors expressed on the surface of the human lung mast cells (HLMC). The degree of constriction of human airways produced by identical amounts of inhaled allergens may vary from day to day and even hour to hour.

DT-0111: a novel P2X3 receptor antagonist.

Extracellular adenosine 5'-triphosphate (ATP) acts as an autocrine and paracrine agent, the actions of which on affected cells are mediated by P2 receptors (P2R), which include trans cell-membrane cationic channels (P2XRs), and G protein coupled receptors (P2YRs). The mammalian P2X receptors form homotrimeric or heterotrimeric cationic channels, each of which contains three ATP-binding sites. There are seven homotrimeric P2X receptors (P2X1-7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5).

Enhancement of Mast Cell Degranulation Mediated by Purinergic Receptors' Activation and PI3K Type δ.

Mast cells express multiple metabotropic purinergic P2Y receptor (P2YR) subtypes. Few studies have evaluated their role in human mast cell (HMC) allergic response as quantified by degranulation induced by cross-linking the high-affinity IgE receptor (FcεRI). We have previously shown that extracellular nucleotides modify the FcεRI activation-dependent degranulation in HMCs derived from human lungs, but the mechanism of this action has not been fully delineated.

Intralaryngeal application of ATP evokes apneic response mainly via acting on P2X3 (P2X2/3) receptors of the superior laryngeal nerve in postnatal rats.

Aerosolized adenosine 5'-triphosphate (ATP) induces cough and bronchoconstriction by activating vagal sensory fibers' P2X3 and P2X2/3 receptors (P2X3R and P2X2/3R). The goal of this study is to determine the effect of these receptors on the superior laryngeal nerve (SLN)-mediated cardiorespiratory responses to ATP challenge. We compared the cardiorespiratory responses to intralaryngeal perfusion of either ATP or α,β-methylene ATP in rat pups before and after ) intralaryngeal perfusion of A-317491 (a P2X3R and P2X2/3R antagonist); ) bilateral section of the SLN; and ) peri-SLN treatment with capsaicin (to block conduction in superior laryngeal C-fibers, SLCFs) or A-317491.

Extracellular adenosine 5'-triphosphate in pulmonary disorders.

Adenosine 5'-triphosphate (ATP) is found in every cell of the human body where it plays a critical role in cellular energetics and metabolism. ATP is released from cells under physiologic and pathophysiologic condition; extracellular ATP is rapidly degraded to adenosine 5'-diphosphate (ADP) and adenosine by ecto-enzymes (mainly, CD39 and CD73). Before its degradation, ATP acts as an autocrine and paracrine agent exerting its effects on targeted cells by activating cell surface receptors named P2 Purinergic receptors.

DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough.

Background: Extracellular adenosine 5'-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals the axon reflex.

Adenosine 5'-triphosphate's role in bradycardia and syncope associated with pulmonary embolism.

Adenosine 5'-triphiosphate (ATP) is released from cells under physiologic and pathophysiologic conditions. Extracellular ATP acts as an autocrine and paracrine agent affecting various cell types by activating cell surface P2 receptors (P2R), which include trans-cell membrane cationic channels, P2XR, and G protein coupled receptors, P2YR. We have previously shown that ATP stimulates vagal afferent nerve terminals in the lungs by activating P2X2/3R.

Contrasting effects of ATP and adenosine on capsaicin challenge in asthmatic patients.

Background: Adenosine 5'-triphosphate (ATP) stimulates pulmonary vagal slow conducting C-fibres and fast conducting Aδ-fibres with rapidly adapting receptors (RARs). Pulmonary C-fibres but not RARs are also sensitive to capsaicin, a potent tussigenic agent in humans. Thus, the aim of this study was to determine the effects of ATP and its metabolite adenosine (given as adenosine 5'-monophosphate, AMP) on capsaicin challenge in asthmatic patients.

IgE Receptor-Mediated Histamine Release in Human Lung Mast Cells: Modulation by Purinergic Receptor Ligands.

Background: Mast cells derived from human lungs (HLMCs) express multiple G-protein coupled purinergic receptors (P2YR) and the so-called α-ketoglutarate receptor GPR99, which is homologous to P2YR. The role of the P2YR of HLMC is not clear. Thus, the aim of the present study was to determine the effects of purinergic and purine-related compounds on allergic histamine release (HR) in HLMCs.

Extracellular Adenosine 5'-Triphosphate in Obstructive Airway Diseases.

In recent years, numerous studies have generated data supporting the hypothesis that extracellular adenosine 5'-triphosphate (ATP) plays a major role in obstructive airway diseases. Studies in animal models and human subjects have shown that increased amounts of extracellular ATP are found in the lungs of patients with COPD and asthma and that ATP has effects on multiple cell types in the lungs, resulting in increased inflammation, induction of bronchoconstriction, and cough. These effects of ATP are mediated by cell surface P2 purinergic receptors and involve other endogenous inflammatory agents.

Adenosine 5'-Triphosphate Test in the Management of Patients With Syncope.

The response to adenosine 5'-triphosphate (ATP) identifies patients with syncope who might benefit from pacemaker therapy (ATP test). Two measures have been used to determine the outcome of the ATP test, which have lead to contrasting conclusions regarding its utility: (1) the duration of cardiac pause (CP) mainly due to AV block and (2) the longest RR interval (RRmax). We tested the hypothesis that the discrepancy regarding the utility of the ATP test is mainly because of the different way the 2 measures determine the outcome of the test.

Effects of Aerosolized Adenosine 5'-Triphosphate in Smokers and Patients With COPD.

Background: Extracellular adenosine 5'-triphosphate (ATP) stimulates vagal C and Aδ fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers, and patients with COPD and compared these responses to the effects of inhaled adenosine, the metabolite of ATP.

Methods: We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity, and ATP in exhaled breath condensate in healthy nonsmokers (n = 10), healthy smokers (n = 14), and patients with COPD (n = 7).

Cardiac purinergic signalling in health and disease.

This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed.

ATPace™: injectable adenosine 5'-triphosphate : Diagnostic and therapeutic indications.

ATPace™, a novel injectable formulation of adenosine 5'-triphosphate (ATP), is developed by Cordex Pharma, Inc. (Cordex) as a diagnostic and therapeutic drug for the management of cardiac bradyarrhythmias. Extracellular ATP exerts multiple effects in various cell types by activating cell-surface receptors known as P2 receptors.

The mechanism of the negative chronotropic and dromotropic actions of adenosine 5'-triphosphate in the heart: an update.

Adenosine 5'-triphosphate (ATP) plays a critical role in intracellular metabolism and energetics. Extracellular ATP is rapidly degraded to adenosine by ectoenzymes. Both ATP and adenosine suppress cardiac pacemakers' automaticity and atrioventricular nodal conduction, albeit via the different mechanism of actions.

Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology.

Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A(1), A(2A), A(2B), and A(3).

Pacing-induced cardiac gap junction remodeling: modulation of connexin43 phosphorylation state.

Background: Altered myocardial distribution of gap junctions and intercellular coupling have been implicated in nonuniform conduction of the depolarization wave and repolarization asynchrony in the mammalian heart. We tested the hypothesis that short-term cardiac pacing is associated with structural remodeling of gap junctions and their altered spatial distribution in cardiac myocytes in the immediate vicinity of the pacing site.

Materials And Methods: Isolated adult male rat hearts (n = 8) were perfused using a Langendorff apparatus.

Anti- and pro-arrhythmic effects of cardiac resynchronization therapy: point of view.

Cardiac resynchronization therapy (CRT) in patients with heart failure and bundle branch block (BBB) improves regional muscle mechanics and mechanical pump function of the heart. In addition, modulation of wall motion timing and contraction can exert an antiarrhythmic effect, reducing the potential of sudden cardiac death. This effect of CRT could also be attributed to the improvement in excitation-contraction coupling, mechanical synchronization, and improved myocardial perfusion.

Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma.

Study Objectives: Extracellular adenosine 5'-triphosphate (ATP) causes neurogenic bronchoconstriction, inflammation, and coughs, and may play a mechanistic role in obstructive airway diseases. The aims of this study were to determine the effects of inhaled ATP on airway function, and to compare these effects with those of adenosine 5'-monophosphate (AMP).

Design: Prospective, randomized, double-blind study.

Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors.

The mechanism of extracellular ATP-triggered vagal depressor reflex was further studied in a closed-chest canine model. Adenosine and ATP were administered individually in equimolar doses (0.01-1.

Adenosine 5'-triphosphate axis in obstructive airway diseases.

In recent years, significant progress has been made in our understanding of the pathophysiology behind obstructive airway diseases in general and asthma in particular; this knowledge, however, has not translated to major breakthroughs in the treatment of these disorders. Current therapeutic options are less than optimal and frequently are associated with systemic adverse effects. Recent studies indicate that endogenous purine nucleotides, adenosine 5'-triphosphate (ATP) in particular, could play a mechanistic role in obstructive airway diseases through their actions on multiple cell types relevant to these disorders, including mast cells, eosinophils, dendritic cells, and neurons.