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Current Medicinal Chemistry 2011The purine ribonucleoside adenosine (Ado) has been recognized for its regulatory functions in situations of cellular stress like ischemia, hypoxia and inflammation. The... (Review)
Review
The purine ribonucleoside adenosine (Ado) has been recognized for its regulatory functions in situations of cellular stress like ischemia, hypoxia and inflammation. The importance of extracellular Ado as a modulator in the immune system is a theme of great appreciation and the focus of recent increasing interest in the field of gastrointestinal inflammation. In this review, the different aspects of Ado signaling during inflammatory responses in the gut are discussed, considering the contribution of the four known Ado receptors (ARs; A(1), A(2A), A(2B), and A(3)), their mechanisms and expression patterns. Activation of these receptors in epithelial cells as well as in immune cells recruited to the inflamed intestinal mucosa determines the overall effect, ranging from a protective, anti-inflammatory modulation to a strong pro-inflammatory induction. Here we present the current advances in agonists and antagonists development and their potential therapeutic application studied in animal models of intestinal inflammation. In addition, alternative complementary approaches to manipulate such a complex signaling system are discussed, for example, the use of AR allosteric modulators or interference with Ado metabolism. Special features of the gut environment are taken into account: the contribution of diet components; the involvement of Ado in intestinal infections; the interactions with the gut microbiome, particularly, the recent exciting finding that an intestinal bacterium can directly produce extracellular Ado in response to host defense mechanisms in an inflammation scenario. Understanding each component of this dynamic system will broaden the possibilities for applying Ado signaling as a therapeutic target in gut inflammation.
Topics: Adenosine; Adrenergic Agonists; Adrenergic Antagonists; Animals; Humans; Inflammatory Bowel Diseases; Receptors, Purinergic P1; Structure-Activity Relationship
PubMed: 21649583
DOI: 10.2174/092986711796011274 -
Anesthesiology Feb 2009The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist...
BACKGROUND
The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects.
METHODS
Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays.
RESULTS
Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold.
CONCLUSIONS
Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.
Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics; Animals; Brimonidine Tartrate; Calcium; Clonidine; Dinoprostone; Drug Interactions; Excitatory Amino Acid Agonists; Exploratory Behavior; Hyperalgesia; Injections, Spinal; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Pain Measurement; Prazosin; Quinoxalines; Receptors, Adrenergic, alpha-2
PubMed: 19194166
DOI: 10.1097/ALN.0b013e3181943226 -
Computational and Mathematical Methods... 2022Electroconvulsive therapy (ECT) is a nonpharmacological treatment for depressive episodes and other psychiatric disorders. It is used to control the condition by causing...
Electroconvulsive therapy (ECT) is a nonpharmacological treatment for depressive episodes and other psychiatric disorders. It is used to control the condition by causing a transient loss of consciousness through electrical stimulation. Dexmedetomidine (DEX) is a novel and highly selective adrenergic agonist with sedative, sympathetic nerve activity inhibiting and stress-responsive effects. This study focused on the effect of DEX on cerebral protection after ECT treatment. 68 depression patients were enrolled and divided into control group and DEX group. The occurrence of delirium after ECT treatment in depression cases was recorded. In vivo, we constructed chronic mild and unpredictable stress (CUMS) rats to mimic depression model. Meanwhile, ECT treatment and DEX injection were administrated in CUMS rats. Learning and memory in rats were measured by Morris water maze test, open field test (OFT), and forced swimming test (FST). Finally, the expression of miR-146a-5p and NF-B was determined by RT-qPCR and western blot assay. The incidence of delirium after ECT treatment was prominently reduced in DEX group in relation to control group. In vivo, DEX injection had no effect on ECT treatment efficacy against depression conditions. After ECT treatment, the cognitive impairment was ameliorated in CUMS rats accomplished with decreased miR-146a-5p and increased NF-B level. Finally, compared with ECT treatment, DEX injection could protect against depression-like behaviors by increasing miR-146a-5p level and inactivated NF-B pathway. Overall, ECT-induced cognitive impairment in depression rats could be ameliorated by DEX injection via miR-146a-5p/NF-B axis.
Topics: Adrenergic Agonists; Animals; Cognitive Dysfunction; Delirium; Dexmedetomidine; Electroconvulsive Therapy; Hypnotics and Sedatives; MicroRNAs; NF-kappa B; Rats
PubMed: 36238484
DOI: 10.1155/2022/8371492 -
Investigative Ophthalmology & Visual... Jul 2021To determine the effect of the new β3-agonist (mirabegron), which is used for overactive bladder (OAB) treatment, on central retinal thickness (CRT) and choroidal...
PURPOSE
To determine the effect of the new β3-agonist (mirabegron), which is used for overactive bladder (OAB) treatment, on central retinal thickness (CRT) and choroidal vascularity.
MATERIAL AND METHODS
The 26 eyes of 26 cases using 50 mg tablet mirabegron once per day for OAB were included in this prospective case control study. The CRT, choroidal thickness (ChT), and choroidal vascularity were measured at baseline, week 1 (W1), month 1 (M1), month 2 (M2), and month 3 (M3). Subfoveal ChT measurement included the total subfoveal choroidal thickness (SFCT), and the small and large choroidal vessel layer (SCVL and LCVL) thickness. The total choroidal area (TCA), lumen area (LA), stromal area (SA), stroma/lumen ratio, and choroidal vascularity index (CVI) were measured with the Image-J software.
RESULTS
The largest SFCT increase compared to baseline was at M1 (26.8 ± 40.8 µm, P = 0.001). The subfoveal SCVL thickness showed a significant decrease at M2 and M3 (-6.0 ± 8.9 µm, P = 0.002; -7.8 ± 13.4 µm, P = 0.046, respectively). LCVL thickness showed a significant increase at W1, M1, and M2, with the largest at M1. CVI showed a significant increase at M1, M2, and M3 (P < 0.05 for all). The TCA, LA, and SA showed a significant increasing trend at all follow-up periods. LA/SA decreased at W1 because of stromal expansion but increased at M3 with more prominent vascular dilatation. CRT values showed no significant change.
CONCLUSIONS
Mirabegron had a significant effect on choroidal thickness. Choroidal vascular response is in the form of narrowing in the choriocapillaris and enlargement in the Haller's layer.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Choroid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Retinal Vessels; Thiazoles; Tomography, Optical Coherence; Visual Acuity
PubMed: 34241623
DOI: 10.1167/iovs.62.9.17 -
European Journal of Heart Failure Mar 2023
Topics: Humans; Hypertension, Pulmonary; Heart Failure; Adrenergic beta-3 Receptor Agonists; Acetanilides
PubMed: 36691743
DOI: 10.1002/ejhf.2780 -
International Journal of Molecular... Sep 2022This study was designed to connect aortic stiffness to vascular contraction in young male and female Wistar rats. We hypothesized that female animals display reduced...
This study was designed to connect aortic stiffness to vascular contraction in young male and female Wistar rats. We hypothesized that female animals display reduced intrinsic media-layer stiffness, which associates with improved vascular function. Atomic force microscopy (AFM)-based nanoindentation analysis was used to derive stiffness (Young's modulus) in biaxially (i.e., longitudinal and circumferential) unloaded aortic rings. Reactivity studies compatible with uniaxial loading (i.e., circumferential) were used to assess vascular responses to a selective α1 adrenergic receptor agonist in the presence or absence of extracellular calcium. Elastin and collagen levels were indirectly evaluated with fluorescence microscopy and a picrosirius red staining kit, respectively. We report that male and female Wistar rats display similar AFM-derived aortic media-layer stiffness, even though female animals withstand higher aortic intima-media thickness-to-diameter ratio than males. Female animals also present reduced phenylephrine-induced aortic force development in concentration-response and time-force curves. Specifically, we observed impaired force displacement in both parts of the contraction curve (Aphasic and Atonic) in experiments conducted with and without extracellular calcium. Additionally, collagen levels were lower in female animals without significant elastin content and fragmentation changes. In summary, sex-related functional differences in isolated aortas appear to be related to dissimilarities in the dynamics of vascular reactivity and extracellular matrix composition rather than a direct response to a shift in intrinsic media-layer stiffness.
Topics: Adrenergic Agonists; Animals; Calcium; Carotid Intima-Media Thickness; Collagen; Elastin; Female; Male; Phenylephrine; Rats; Rats, Wistar; Vascular Stiffness
PubMed: 36232616
DOI: 10.3390/ijms231911314 -
British Journal of Pharmacology Nov 19881. Experiments were done to characterize a putative adrenoceptor which functions to inhibit longitudinal muscle tension development in the guinea-pig ileum. Several...
1. Experiments were done to characterize a putative adrenoceptor which functions to inhibit longitudinal muscle tension development in the guinea-pig ileum. Several phenylethylamine based agonists were investigated: BRL 37344, (-)-isoprenaline, (+)-isoprenaline, noradrenaline, adrenaline, and fenoterol. Propranolol and nadolol were tested as antagonists. Agonist-induced inhibition of the contractile response to histamine was measured under equilibrium conditions with alpha-adrenoceptors and muscarinic cholinoceptors inhibited. 2. Inhibitory responses were obtained to (-)-isoprenaline and BRL 37344 that were resistant to beta-adrenoceptor blockage with propranolol (5 microM) and nadolol (10 microM). These resistant responses were antagonized by much higher concentrations of nadolol (30 to 1000 microM) yielding apparent pA2 values for nadolol of 4.31 with (-)-isoprenaline as the agonist, and 4.68 with BRL 37344 as the agonist. Similar apparent pA2 values for nadolol at the putative adrenoceptor were obtained with noradrenaline (4.79), adrenaline (4.68), and fenoterol (4.38). 3. The order and relative potency of agonists at the putative adrenoceptor was: BRL 37344 (20) greater than (-)-isoprenaline (8) greater than noradrenaline (1) greater than adrenaline (0.5) greater than fenoterol (0.35) greater than (+)-isoprenaline (0.27). 4. The resistance to blockade by propranolol (5 microM), the low affinity of nadolol, and the order and relative potency of agonists, suggest the presence of an adrenoceptor with distinct pharmacological characteristics from currently defined alpha- and beta-adrenoceptors.
Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Guinea Pigs; Ileum; Male; Muscle Contraction; Receptors, Adrenergic
PubMed: 2905184
DOI: 10.1111/j.1476-5381.1988.tb11698.x -
Journal of Investigational Allergology... Apr 2023To determine the relationship between short-acting ß-adrenergic agonist (SABA) overuse and health care resource use and costs in asthma patients in routine clinical...
BACKGROUND AND OBJECTIVE
To determine the relationship between short-acting ß-adrenergic agonist (SABA) overuse and health care resource use and costs in asthma patients in routine clinical practice.
METHODS
A longitudinal retrospective study was conducted in Spanish primary and specialized care centers using the BIG-PAC medical records database. The study population comprised asthma patients ≥12 years of age who attended ≥2 consultations during 2017 and had 1-year follow-up data available. The main outcomes were demographics, comorbidities, medication, and clinical and health care resource use and costs. The relationship between SABA overuse and health care costs and between asthma severity and health care costs was determined.
RESULTS
The SABA use IN Asthma (SABINA) study included 39 555 patients, with a mean (SD) age of 49.8 (20.7) years (64.2% female). The Charlson comorbidity index was 0.7 (1.0). SABA overuse (≥3 canisters/y) was 28.7% (95%CI, 27.7-29.7), with a mean of 3.3 (3.6) canisters/y. Overall, 5.1% of patients were prescribed ≥12 canisters/y. SABA overuse was correlated with health care costs (ρ=0.621; P<.001). The adjusted mean annual cost/patient according to the Global Initiative for Asthma (GINA 2019) classification of asthma severity was €2231, €2345, €2735, €3473, and €4243 for steps 1-5, respectively (P<.001). Regardless of asthma severity, SABA overuse yielded a significant increase in health care costs per patient and year (€5702 vs €1917, P<.001) compared with recommended use (<2 canisters/y).
CONCLUSION
SABA overuse yields high costs for the Spanish National Health System. Costs increased with severity of asthma.
Topics: Humans; Female; Middle Aged; Male; Retrospective Studies; Spain; Asthma; Comorbidity; Adrenergic Agonists; Anti-Asthmatic Agents; Administration, Inhalation
PubMed: 34825651
DOI: 10.18176/jiaci.0767 -
PloS One 2022Previous observational studies assessing β2-agonist/-antagonist use on PD risk have yielded conflicting results. We evaluated the relationship between β2-agonist use...
INTRODUCTION
Previous observational studies assessing β2-agonist/-antagonist use on PD risk have yielded conflicting results. We evaluated the relationship between β2-agonist use and the incidence of Parkinson's disease in patients with chronic lung disease.
METHODS
We performed a retrospective cohort analysis on a 20% random sample abstracted from a traditional (fee-for-service) Medicare program in the United States. Inclusion criteria were individuals over 65 years old diagnosed with asthma, COPD, and/or bronchiectasis who were enrolled in a prescription drug (standalone Part D) plan over 2007-2010 and alive through 2014. The main outcome measure was a diagnosis of Parkinson's disease over the period 2011-2014, in relation to the number of 30-day-equivalent drug claims over 2007-2010. Logistic regression analysis was performed on a sample including 236,201 Medicare beneficiaries.
RESULTS
The sample was 68% female, 80% white, and on average 77 years old as of 2010. Compared to non-users, β2-agonist users were more likely to be younger (76.3y versus 78.0y), smokers (40.4% versus 31.1%) and asthmatic (62.4% versus 28.3%). The odds ratio for a β2-agonist claim on PD development was 0.986 (95% CI 0.977-0.995) after adjusting for demographics, smoking history, respiratory exacerbations, comorbidities, and other drug use. Risk reductions were larger for males than females (0.974 versus 0.994, P = 0.032), and for individuals with COPD compared to those with asthma (0.968 versus 0.998, P = 0.049). Reverse causality was addressed with a Cox analysis that allowed β2-agonist use to vary from medication initiation to disease onset. By the end of the follow-up period, β2-agonist use was shown to be associated with a true protective effect against PD onset.
DISCUSSION
β2-agonist use is associated with decreased risk of PD incidence. Further investigation, possibly including clinical trials, is warranted to strengthen the evidence base supporting clinical decision-makers looking to repurpose pharmaceuticals to prevent neurodegenerative disease onset.
Topics: Male; Humans; Aged; Female; United States; Retrospective Studies; Incidence; Adrenergic Agonists; Parkinson Disease; Neurodegenerative Diseases; Medicare; Asthma; Pulmonary Disease, Chronic Obstructive
PubMed: 36441791
DOI: 10.1371/journal.pone.0276368 -
Climacteric : the Journal of the... Aug 2012ABSTRACT Background Seventy percent of postmenopausal women suffer from hot flushes but the pathophysiology is poorly understood. Proposed mechanisms include altered...
ABSTRACT Background Seventy percent of postmenopausal women suffer from hot flushes but the pathophysiology is poorly understood. Proposed mechanisms include altered peripheral vascular reactivity and a narrowed thermoneutral zone. A trigger has not yet been identified; however, the α-adrenergic system, and specifically noradrenaline, has been implicated. Aim To assess the role of the α-adrenergic system by studying the effect of clonidine (α-adrenergic agonist) on flushes and cutaneous microvascular perfusion. Methods Thirty-two postmenopausal women with severe flushing and 14 non-flushing postmenopausal women were recruited. Cutaneous microvascular perfusion was measured using laser Doppler imaging and endothelial function was assessed by iontophoresis (administration of vasoactive agents through the skin by an electric current) of acetylcholine (ACh - endothelium-dependent) and sodium nitroprusside (SNP - endothelium-independent). In a double-blind, longitudinal, cross-over study, clonidine (an α-adrenergic agonist) was compared to placebo in its ability to modulate this response in the flushing group of women. Results The response of the subcutaneous vessels was greater in women who flushed than those who did not (ACh, p < 0.001 and SNP, p = 0.001). However, even though the intensity and number of flushes were decreased by clonidine, there was no difference compared to placebo (p = 0.21) and this 'placebo effect' was also noted in perfusion responses (ACh, p = 0.98; SNP, p = 0.50). Conclusion There was a significant 'placebo effect' for both clinical response and the reactivity of the subcutaneous vessels, making conclusions regarding the role of the α-adrenergic nervous system in hot flushing difficult to determine at a peripheral level. The mechanism for the change in vascular reactivity remains unclear.
Topics: Adrenergic alpha-Agonists; Aged; Analysis of Variance; Clonidine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Hot Flashes; Humans; Iontophoresis; Longitudinal Studies; Middle Aged; Placebo Effect; Postmenopause; Vasodilation; Vasodilator Agents
PubMed: 22208784
DOI: 10.3109/13697137.2011.636847