ABSTRACT
PURPOSE: The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects. METHODS: For the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining. RESULTS: HL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and α-smooth muscle actin expression induced by Dex treatment. CONCLUSIONS: HL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma. TRANSLATIONAL RELEVANCE: HL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.
Subject(s)
Glaucoma , Intraocular Pressure , Animals , Disease Models, Animal , Glaucoma/drug therapy , Humans , Latanoprost/adverse effects , Mice , Purinergic P1 Receptor Antagonists/adverse effects , Rabbits , Receptors, Purinergic P1/therapeutic useABSTRACT
BACKGROUND: Adenosine is used in stress perfusion cardiac imaging to reveal myocardial ischemia by its vasodilator effects. Caffeine is a competitive antagonist of adenosine. However, previous studies reported inconsistent results about the influence of caffeine on adenosine's vasodilator effect. This study assessed the impact of caffeine on the myocardial perfusion reserve index (MPRI) using adenosine stress cardiovascular magnetic resonance imaging (CMR). Moreover, we sought to evaluate if the splenic switch-off sign might be indicative of prior caffeine consumption. METHODS: Semiquantitative perfusion analysis was performed in 25 patients who underwent: 1) caffeine-naïve adenosine stress CMR demonstrating myocardial ischemia and, 2) repeat adenosine stress CMR after intake of caffeine. MPRI (global; remote and ischemic segments), and splenic perfusion ratio (SPR) were assessed and compared between both exams. RESULTS: Global MPRI after caffeine was lower vs. caffeine-naïve conditions (1.09 ± 0.19 vs. 1.24 ± 0.19; p < 0.01). MPRI in remote myocardium decreased by caffeine (1.24 ± 0.19 vs. 1.49 ± 0.19; p < 0.001) whereas MPRI in ischemic segments (0.89 ± 0.18 vs. 0.95 ± 0.23; p = 0.23) was similar, resulting in a lower MPRI ratio (=remote/ischemic segments) after caffeine consumption vs. caffeine-naïve conditions (1.41 ± 0.19 vs. 1.64 ± 0.35, p = 0.01). The SPR was unaffected by caffeine (SPR 0.38 ± 0.19 vs. 0.38 ± 0.18; p = 0.92). CONCLUSION: Caffeine consumption prior to adenosine stress CMR results in a lower global MPRI, which is driven by the decreased MPRI in remote myocardium and underlines the need of abstinence from caffeine. The splenic switch-off sign is not affected by prior caffeine intake.
Subject(s)
Adenosine/administration & dosage , Caffeine/administration & dosage , Coronary Circulation/drug effects , Magnetic Resonance Imaging, Cine , Myocardial Ischemia/diagnostic imaging , Myocardial Perfusion Imaging/methods , Purinergic P1 Receptor Antagonists/administration & dosage , Vasodilation/drug effects , Vasodilator Agents/administration & dosage , Aged , Caffeine/adverse effects , Female , Humans , Hyperemia , Male , Middle Aged , Myocardial Ischemia/physiopathology , Predictive Value of Tests , Prospective Studies , Purinergic P1 Receptor Antagonists/adverse effects , Reproducibility of ResultsABSTRACT
BACKGROUND: Caffeine is one of the most widely consumed stimulants worldwide. It is a well-recognized antagonist of adenosine and a potential cause of false-negative functional measurements during vasodilator myocardial perfusion. The aim of this systematic review is to summarize the evidence regarding the effects of caffeine intake on functional measurements of myocardial perfusion in patients with suspected coronary artery disease. Pubmed, Web of Science, and Embase were searched using a predefined electronic search strategy. Participants-healthy subjects or patients with known or suspected CAD. Comparisons-recent caffeine intake versus no caffeine intake. Outcomes-measurements of functional myocardial perfusion. Study design-observational. Fourteen studies were deemed eligible for this systematic review. There was a wide range of variability in study design with varying imaging modalities, vasodilator agents, serum concentrations of caffeine, and primary outcome measurements. The available data indicate a significant influence of recent caffeine intake on cardiac perfusion measurements during adenosine and dipyridamole induced hyperemia. These effects have the potential to affect the clinical decision making by re-classification to different risk-categories.
Subject(s)
Caffeine/adverse effects , Coronary Artery Disease/diagnostic imaging , Coronary Circulation/drug effects , Myocardial Perfusion Imaging/methods , Purinergic P1 Receptor Antagonists/adverse effects , Adult , Aged , Clinical Decision-Making , Coronary Artery Disease/physiopathology , Coronary Artery Disease/therapy , Female , Humans , Hyperemia/physiopathology , Male , Middle Aged , Observational Studies as Topic , Predictive Value of Tests , Prognosis , Reproducibility of Results , Vasodilation/drug effects , Vasodilator Agents/administration & dosageABSTRACT
OBJECTIVES: Adenosine concentration significantly increases in tumour microenvironment contributing to tumorigenic processes including cell proliferation, survival, invasion and of special interest in this review angiogenesis. KEY FINDINGS: This review summarizes the role of pharmacological adenosine receptor agonist and antagonist in regulating angiogenesis for a better understanding and hence a better management of angiogenesis-associated disorders. SUMMARY: Depending upon the pharmacological characteristics of adenosine receptor subtypes, adenosine elicits anti- or pro-angiogenic responses in stimulated cells. Inhibition of the stimulatory effect of adenosine signalling on angiogenesis using specific pharmacological adenosine receptor agonist, and antagonist is a potentially novel strategy to suppress angiogenesis in tumours.
Subject(s)
Angiogenesis Inducing Agents/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Neoplasms/drug therapy , Neovascularization, Pathologic , Purinergic P1 Receptor Agonists/therapeutic use , Purinergic P1 Receptor Antagonists/therapeutic use , Receptors, Purinergic P1/drug effects , Angiogenesis Inducing Agents/adverse effects , Angiogenesis Inhibitors/adverse effects , Animals , Humans , Neoplasms/metabolism , Neoplasms/pathology , Purinergic P1 Receptor Agonists/adverse effects , Purinergic P1 Receptor Antagonists/adverse effects , Receptors, Purinergic P1/metabolism , Signal Transduction/drug effectsABSTRACT
Caffeine is an adenosine receptor antagonist and a possible cause of inadequate stress perfusion. Splenic switch-off (SSO) and splenic rest-stress T1-mapping have been proposed as indicators of stress adequacy during perfusion cardiac magnetic resonance (CMR). We compared myocardial rest-stress T1-mapping with SSO and splenic rest-stress T1-mapping in patients with and without recent coffee intake. We analyzed 344 consecutive patients suspected of myocardial ischemia with adenosine perfusion CMR. All 146 normal CMR studies with a normal T1-rest of the myocardium, used as standard of reference, were included and divided in two groups. 22 patients accidentally ingested coffee < 4 h before CMR, compared to control group of 124 patients without self-reported coffee intake. Two independent readers graded SSO visually. T1-reactivity (ΔT1) was defined as percentual difference in T1-rest and T1-stress. Follow-up data were extracted from electronic patients records. In patients with recent coffee intake SSO was identified in 96%, which showed no significant difference with SSO in controls (94%, p = 0.835), however event rates were significantly different (13.6 and 0.8%, respectively (p < 0.001), median FU 17 months). Myocardial ΔT1 in the coffee group (- 5.2%) was significantly lower compared to control (+ 4.0%, p < 0.001), in contrast to the splenic ΔT1 (- 3.7 and - 4.0%, p = 0.789). The splenic T1-mapping results failed to predict false negative results. SSO and splenic rest-stress T1-mapping are not reliable indicators of stress adequacy in patients with recent coffee intake. Therefore, the dark spleen sign does not indicate adequate myocardial stress in patients with recent caffeine intake. Myocardial rest-stress T1-mapping is an excellent indicator of stress adequacy during adenosine perfusion CMR.
Subject(s)
Adenosine/administration & dosage , Caffeine/adverse effects , Coffee/adverse effects , Coronary Circulation/drug effects , Hemodynamics/drug effects , Myocardial Ischemia/diagnostic imaging , Myocardial Perfusion Imaging/methods , Purinergic P1 Receptor Antagonists/adverse effects , Spleen/blood supply , Vasodilator Agents/administration & dosage , Aged , Caffeine/administration & dosage , Case-Control Studies , Female , Humans , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Middle Aged , Myocardial Ischemia/physiopathology , Observer Variation , Predictive Value of Tests , Purinergic P1 Receptor Antagonists/administration & dosage , Reproducibility of ResultsABSTRACT
OBJECTIVES: Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. KEY FINDINGS: Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. SUMMARY: Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.
Subject(s)
Adenosine/metabolism , Drug Design , Receptors, Purinergic P1/drug effects , Adenosine/chemistry , Animals , Drug-Related Side Effects and Adverse Reactions/epidemiology , Humans , Ligands , Purinergic P1 Receptor Agonists/adverse effects , Purinergic P1 Receptor Agonists/pharmacology , Purinergic P1 Receptor Antagonists/adverse effects , Purinergic P1 Receptor Antagonists/pharmacology , Receptors, Purinergic P1/metabolism , Signal Transduction/drug effectsABSTRACT
Chronic obstructive pulmonary disease (COPD) is independently associated with atrial fibrillation (AF). Decreased oxygenation, hypercapnia, pulmonary hypertension, diastolic dysfunction, oxidative stress, inflammation, changes in atrial size by altered respiratory physiology, increased arrhythmogenicity from nonpulmonary vein foci commonly located in the right atrium, and respiratory drugs have been implicated in the pathogenesis of AF in COPD. The understanding of the relationship between COPD and AF is of particular importance, as the presence of the arrhythmia has significant impact on mortality, especially in COPD exacerbations. On the other hand, COPD in AF is associated with AF progression, success of cardioversion, recurrence of AF after catheter ablation, and increased cardiovascular and all-cause mortality. Treatment of the underlying pulmonary disease and correction of hypoxia and acid-base imbalance represents first-line therapy for COPD patients who develop AF. Cardioselective ß-blockers are safe and can be routinely used in COPD. In addition, AF ablation was proved to be efficient and safe, and improves quality of life in these patients. This review presents the association between COPD and AF, describes the pathophysiological mechanisms implicated in AF development in COPD, underlines the prognostic significance of AF in COPD patients and vice versa, and highlights emerging therapeutic approaches in this setting.
Subject(s)
Atrial Fibrillation/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Adrenergic beta-2 Receptor Agonists/administration & dosage , Adrenergic beta-2 Receptor Agonists/adverse effects , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/therapy , Calcium Channel Blockers/therapeutic use , Cardiac Pacing, Artificial , Catheter Ablation/adverse effects , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Humans , Prognosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Purinergic P1 Receptor Antagonists/administration & dosage , Purinergic P1 Receptor Antagonists/adverse effectsABSTRACT
This study investigated the effects of caffeine in the behavioral and inflammatory alterations caused by copper in zebrafish larvae, attempting to correlate these changes with the modulation of adenosine receptors. To perform a survival curve, 7dpf larvae were exposed to 10µM CuSO4, combined to different concentrations of caffeine (100µM, 500µM and 1mM) for up to 24h. The treatment with copper showed lower survival rates only when combined with 500µM and 1mM of caffeine. We selected 4 and 24h as treatment time-points. The behavior evaluation was done by analyzing the traveled distance, the number of entries in the center, and the length of permanence in the center and the periphery of the well. The exposure to 10µM CuSO4 plus 500µM caffeine at 4 and 24h changed the behavioral parameters. To study the inflammatory effects of caffeine, we assessed the PGE2 levels by using UHPLC-MS/MS, and TNF, COX-2, IL-6 and IL-10 gene expression by RT-qPCR. The expression of adenosine receptors was also evaluated with RT-qPCR. When combined to copper, caffeine altered inflammatory markers depending on the time of exposure. Adenosine receptors expression was significantly increased, especially after 4h exposure to copper and caffeine together or separately. Our results demonstrated that caffeine enhances the inflammation induced by copper by decreasing animal survival, altering inflammatory markers and promoting behavioral changes in zebrafish larvae. We also conclude that alterations in adenosine receptors are related to those effects.
Subject(s)
Caffeine/adverse effects , Copper/toxicity , Larva/drug effects , Purinergic P1 Receptor Antagonists/adverse effects , Receptors, Purinergic P1/metabolism , Water Pollutants, Chemical/toxicity , Zebrafish/physiology , Animals , Behavior, Animal/drug effects , Biomarkers/metabolism , Caffeine/agonists , Caffeine/antagonists & inhibitors , Copper/agonists , Copper/chemistry , Copper Sulfate/administration & dosage , Dinoprostone/agonists , Dinoprostone/antagonists & inhibitors , Dinoprostone/metabolism , Gene Expression Regulation, Developmental/drug effects , Inflammation Mediators/agonists , Inflammation Mediators/metabolism , Larva/growth & development , Larva/immunology , Larva/metabolism , Osmolar Concentration , Purinergic P1 Receptor Agonists/chemistry , Purinergic P1 Receptor Agonists/toxicity , Purinergic P1 Receptor Antagonists/chemistry , Receptors, Purinergic P1/chemistry , Receptors, Purinergic P1/genetics , Survival Analysis , Water Pollutants, Chemical/agonists , Water Pollutants, Chemical/antagonists & inhibitors , Zebrafish/growth & development , Zebrafish/immunology , Zebrafish Proteins/agonists , Zebrafish Proteins/antagonists & inhibitors , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention. METHODS: We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI. We examined patient-reported reasons for switching, GUSTO moderate or severe bleeding, major adverse cardiovascular events (MACEs), and definite stent thrombosis events around the time of the switch. RESULTS: Among patients still on ADPri therapy 1 year post-MI, 663 (7.6%) switched ADPri during that year. Switching occurred at a median of 50 days postdischarge and most frequently in patients discharged on ticagrelor (64/226; 28.3%), followed by prasugrel (383/2,489; 15.4%) and clopidogrel (216/5,957; 3.6%) (P < .001). Among patients discharged on prasugrel, 97.3% of switches were to clopidogrel and 87.5% of ticagrelor switches were to clopidogrel; both of these groups most often cited cost as a reason for switching (43.6% and 39.1%, respectively), whereas 60.7% who switched from clopidogrel cited physician decision as a reason. In the 7 days preceding the switch from clopidogrel, 40 (18.5%) had a MACE and 12 (5.6%) had a definite stent thrombosis event, whereas that from prasugrel or ticagrelor, a GUSTO moderate or severe bleeding event occurred in 1 (0.3%) and 0 patients, respectively. CONCLUSIONS: Postdischarge ADPri switching occurred infrequently within the first year post-MI and uncommonly was associated with MACEs or bleeding events.
Subject(s)
Drug Substitution/statistics & numerical data , Myocardial Infarction/drug therapy , Purinergic P1 Receptor Antagonists/therapeutic use , Adenosine/analogs & derivatives , Adenosine/therapeutic use , Adenosine Diphosphate , Aged , Cardiovascular Diseases/epidemiology , Clopidogrel , Female , Hemorrhage/chemically induced , Humans , Longitudinal Studies , Male , Middle Aged , Patient Discharge , Patient Preference , Platelet Aggregation Inhibitors/therapeutic use , Prasugrel Hydrochloride/therapeutic use , Purinergic P1 Receptor Antagonists/adverse effects , Purinergic P1 Receptor Antagonists/economics , Ticagrelor , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic useABSTRACT
BACKGROUND & AIMS: Chest pain is a common and frightening symptom. Once cardiac disease has been excluded, an esophageal source is most likely. Pathophysiologically, gastroesophageal reflux disease, esophageal dysmotility, esophageal hypersensitivity, and anxiety disorders have been implicated. However, treatment remains a challenge. Here we examined the efficacy and safety of various commonly used modalities for treatment of esophageal (noncardiac) chest pain (ECP) and provided evidence-based recommendations. METHODS: We reviewed the English language literature for drug trials evaluating treatment of ECP in PubMed, Cochrane, and MEDLINE databases from 1968-2012. Standard forms were used to abstract data regarding study design, duration, outcome measures and adverse events, and study quality. RESULTS: Thirty-five studies comprising various treatments were included and grouped under 5 broad categories. Patient inclusion criteria were extremely variable, and studies were generally small with methodological concerns. There was good evidence to support the use of omeprazole and fair evidence for lansoprazole, rabeprazole, theophylline, sertraline, trazodone, venlafaxine, imipramine, and cognitive behavioral therapy. There was poor evidence for nifedipine, diltiazem, paroxetine, biofeedback therapy, ranitidine, nitrates, botulinum toxin, esophageal myotomy, and hypnotherapy. CONCLUSIONS: Ideally, treatment of ECP should be aimed at correcting the underlying mechanism(s) and relieving symptoms. Proton pump inhibitors, antidepressants, theophylline, and cognitive behavioral therapy appear to be useful for the treatment of ECP. However, there is urgent and unmet need for effective treatments and for rigorous, randomized controlled trials.
Subject(s)
Antidepressive Agents/therapeutic use , Chest Pain/etiology , Chest Pain/therapy , Cognitive Behavioral Therapy/methods , Esophageal Diseases/therapy , Proton Pump Inhibitors/therapeutic use , Theophylline/therapeutic use , Antidepressive Agents/adverse effects , Humans , Proton Pump Inhibitors/adverse effects , Purinergic P1 Receptor Antagonists/adverse effects , Purinergic P1 Receptor Antagonists/therapeutic use , Theophylline/adverse effects , Treatment OutcomeABSTRACT
OBJECTIVES: To assess the impact of ß1 -adrenoceptor blockers (ß1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. METHODS: From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. ß1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. RESULTS: Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 ± 4.6%) to (2.8 ± 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 ± 9.7%) during ß1 -blocker administration (P < 0.05), then quickly reduced to (1.6 ± 1.0%) during subsequent isoprenaline infusion. Repeated ß1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 ± 2.4%) from (1.6 ± 1.0%; P < 0.05). Isoprenaline and ß1 -blocker showed similar effects on the arrhythmias in catheter lab. CONCLUSIONS: In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of ß1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia.
Subject(s)
Adrenergic beta-1 Receptor Antagonists/adverse effects , Adrenergic beta-1 Receptor Antagonists/therapeutic use , Tachycardia, Ventricular/chemically induced , Tachycardia, Ventricular/prevention & control , Ventricular Premature Complexes/chemically induced , Ventricular Premature Complexes/prevention & control , Adrenergic beta-Agonists/adverse effects , Adrenergic beta-Agonists/therapeutic use , Adult , Aminophylline/adverse effects , Aminophylline/therapeutic use , Female , Humans , Isoproterenol/adverse effects , Isoproterenol/therapeutic use , Male , Middle Aged , Purinergic P1 Receptor Antagonists/adverse effects , Purinergic P1 Receptor Antagonists/therapeutic use , Tachycardia, Ventricular/diagnosis , Treatment Outcome , Ventricular Premature Complexes/diagnosisABSTRACT
OBJECTIVES: To establish whether aminophylline, administered at usual doses for rodents in pharmacological studies, induces brain injury in systemic hypoxaemia in guinea-pigs. METHODS: A hypoxaemia (partial oxygen tension of arterial blood (PaO2) = 40-60 mmHg) model was developed by low tidal volume mechanical ventilation in guinea-pigs. KEY FINDINGS: Under hypoxic conditions, aminophylline significantly increased the concentration of brain-specific creatine kinase in the serum in a dose- and time-dependent manner. A reduced number of hippocampal neuronal cells in the CA1 region, an increase in the concentration of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF), an increase in lipid hydroperoxides and a decrease in the ratio of glutathione to glutathione disulfide in the brain tissues were also observed. These effects were not observed when aminophylline at the same doses was administered under normoxic conditions (PaO2 = 80-100 mmHg). There was no difference in either serum or CSF concentrations of theophylline between normoxic and hypoxic conditions. Another methylxanthine, caffeine, did not increase the concentration of NSE in CSF. CONCLUSIONS: Aminophylline potentially induces brain damage under hypoxic conditions. We suggest that aminophylline treatment has adverse effects in patients with hypoxaemia subsequent to respiratory disorders such as asthma.
Subject(s)
Aminophylline/adverse effects , CA1 Region, Hippocampal/drug effects , Hypoxia, Brain/physiopathology , Neurons/drug effects , Neurotoxicity Syndromes/etiology , Phosphodiesterase Inhibitors/adverse effects , Purinergic P1 Receptor Antagonists/adverse effects , Aminophylline/administration & dosage , Aminophylline/metabolism , Aminophylline/pharmacokinetics , Animals , Antipyrine/administration & dosage , Antipyrine/analogs & derivatives , Antipyrine/therapeutic use , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/pathology , Creatine Kinase, BB Form/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Edaravone , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/therapeutic use , Glutathione/metabolism , Guinea Pigs , Infusions, Intravenous , Lipid Peroxides/metabolism , Male , Nerve Tissue Proteins/blood , Nerve Tissue Proteins/cerebrospinal fluid , Neurons/metabolism , Neurons/pathology , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/pathology , Neurotoxicity Syndromes/prevention & control , Oxidative Stress/drug effects , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphopyruvate Hydratase/cerebrospinal fluid , Purinergic P1 Receptor Antagonists/administration & dosage , Purinergic P1 Receptor Antagonists/metabolism , Purinergic P1 Receptor Antagonists/pharmacokinetics , Theophylline/blood , Theophylline/cerebrospinal fluidABSTRACT
AIMS: Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A(2A) receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period. MATERIAL AND METHODS: Gestational-day-11.5 pregnant mice were exposed to hypoxia (45 s duration followed by 10 min of recovery and repeated 3 times) while simultaneously monitoring maternal and fetal CO using high-resolution echocardiography. RESULTS: Following maternal hypoxia exposure, maternal CO transiently decreased and then returned to pre-hypoxia baseline values. In contrast to a uniform maternal cardiac response to each exposure to hypoxia, the fetal CO recovery time to the baseline decreased, and CO rebounded above baseline following the second and third episodes of maternal hypoxia. Maternal caffeine treatment inhibited the fetal CO recovery to maternal hypoxia by lengthening the time to CO recovery and eliminating the CO rebound post-recovery. Selective treatment with an adenosine A(2A) receptor antagonist, but not an adenosine A(1) receptor antagonist, reproduced the altered fetal CO response to maternal hypoxia created by caffeine exposure. CONCLUSIONS: Results suggest an additive negative effect of maternal caffeine on the fetal CV response to acute maternal hypoxia, potentially mediated via adenosine A(2A) receptor inhibition during primary cardiovascular morphogenesis.
Subject(s)
Caffeine/adverse effects , Fetal Heart/drug effects , Hypoxia , Pregnancy Complications , Purinergic P1 Receptor Antagonists/adverse effects , Animals , Female , Heart Rate, Fetal/drug effects , Hemodynamics/drug effects , Male , Mice , Organogenesis , Pregnancy , Stroke Volume/drug effectsSubject(s)
Caffeine/pharmacology , Child Development Disorders, Pervasive/drug therapy , Child Development Disorders, Pervasive/epidemiology , Purinergic P1 Receptor Antagonists/pharmacology , Adenosine A1 Receptor Agonists/pharmacology , Adenosine A2 Receptor Agonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacology , Animals , Caffeine/adverse effects , Child , Humans , Purinergic P1 Receptor Antagonists/adverse effects , Stereotypic Movement Disorder/drug therapyABSTRACT
OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC-2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma.