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Brain Research Apr 2020Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional...
Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional hyperthermia. Sympathetically-mediated brown adipose tissue (BAT) thermogenesis contributes substantially to this hyperthermic response. The systemic administration of α-adrenergic agonists is known to inhibit both febrile and shivering responses. In the present study, we investigated whether systemic administration of clonidine, a α-adrenoceptor agonist, attenuates the emotional hyperthermia evoked in conscious unrestrained rats suddenly confronted with a second (intruder) rat, itself confined to a small cage. Pre-implanted thermistors were used to measure BAT and body temperature in conscious, freely moving, male Sprague-Dawley rats. The rats were pre-treated with intraperitoneally administered vehicle (Ringer solution) or clonidine (1, 10 and 100 µg/kg). Clonidine, in a dose-dependent manner, reduced the intruder-elicited increases in BAT (log-dose linear regression F(1,16) = 9.52, R = 0.37, P < 0.01) and body temperature (F(1,16) = 6.48, R = 0.29, P < 0.05). We also investigated, in anesthetized rats, whether systemic clonidine administration inhibits BAT sympathetic nerve discharge evoked via activation of neurons in the lateral habenula (LHb) - a nucleus involved in the regulation of emotional hyperthermia. In anesthetized rats, clonidine abolished the BAT sympathetic nerve discharges elicited via bicuculline-mediated disinhibition of the LHb. These results suggest that activation of central α-adrenergic receptors attenuates the process of emotional hyperthermia by reduction of BAT thermogenesis.
Topics: Adipose Tissue, Brown; Adrenergic alpha-2 Receptor Agonists; Animals; Body Temperature; Clonidine; Emotions; Habenula; Hyperthermia; Male; Rats; Rats, Sprague-Dawley; Thermogenesis
PubMed: 31981679
DOI: 10.1016/j.brainres.2020.146678 -
Experimental Physiology May 2020What is the central question of this study? What is the role of β -adrenergic receptor (β AR) vasodilatation in older postmenopausal women as compared to premenopausal...
NEW FINDINGS
What is the central question of this study? What is the role of β -adrenergic receptor (β AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β AR-mediated vasodilatation in both groups of women? What is the main finding and its importance? β AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β AR-mediated vasodilatation in young premenopausal women.
ABSTRACT
β -Adrenergic receptor (β AR)-mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β AR-mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra-arterial infusions of terbutaline at 0.1-2.0 µg (100 ml tissue) min with and without the NO synthase inhibitor l-N -monomethylarginine (l-NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l-NMMA co-infusion vs. without l-NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l-NMMA co-infusion (P > 0.05 for all). These data suggest that β AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β AR-mediated vasodilatation in young premenopausal women.
Topics: Adrenergic Agonists; Adult; Arterial Pressure; Female; Forearm; Humans; Middle Aged; Nitric Oxide; Plethysmography; Postmenopause; Premenopause; Terbutaline; Vasodilation
PubMed: 32170888
DOI: 10.1113/EP088452 -
Current Opinion in Ophthalmology Mar 2015Prostaglandin analogs (PGAs) are the most widely used ocular hypotensive medications. Half of the patients with glaucoma and 40% of patients with ocular hypertension... (Review)
Review
PURPOSE OF REVIEW
Prostaglandin analogs (PGAs) are the most widely used ocular hypotensive medications. Half of the patients with glaucoma and 40% of patients with ocular hypertension require more than one medication to sufficiently lower their intraocular pressures (IOPs). Therefore, it is important to understand the varying efficacy of adjunctive therapies currently available for use in combination with PGAs.
RECENT FINDINGS
The IOP-lowering efficacy and safety profiles of various adjunctive treatments continue to be better elucidated, including the nocturnal IOP-lowering efficacy of various medication classes and laser trabeculoplasty.
SUMMARY
For patients already on a PGA, the mean diurnal IOP-lowering achieved with the addition of an alpha2 adrenergic agonist, a beta adrenergic antagonist, or a topical carbonic anhydrase inhibitor is similar, whereas the side-effect profiles, nocturnal IOP-lowering efficacy, and trough IOP-lowering effects vary. Laser trabeculoplasty is also an effective means of further lowering the IOP in patients on a PGA.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Drug Combinations; Glaucoma; Humans; Intraocular Pressure; Ocular Hypertension; Prostaglandins, Synthetic
PubMed: 25594765
DOI: 10.1097/ICU.0000000000000134 -
Biochemistry. Biokhimiia Jul 2022In this study, we conducted a comparative analysis of the structure of agonists and antagonists of transmembrane (TM) β-adrenoceptors (β-ARs) and their interactions...
In this study, we conducted a comparative analysis of the structure of agonists and antagonists of transmembrane (TM) β-adrenoceptors (β-ARs) and their interactions with the β-ARs and proposed the mechanism of receptor activation. A characteristic feature of agonist and antagonist molecules is the presence of a hydrophobic head (most often, one or two aromatic rings) and a tail with a positively charged amino group. All β-adrenergic agonists have two carbon atoms between the aromatic ring of the head and the nitrogen atom of the amino group. In antagonist molecules, this fragment can be either reduced or increased to four atoms due to the additional carbon and oxygen atoms. The agonist head, as a rule, has two H-bond donors or acceptors in the para- and meta-positions of the aromatic rings, while in the antagonist heads, these donors/acceptors are absent or located in other positions. Analysis of known three-dimensional structures of β-AR complexes with agonists showed that the agonist head forms two H-bonds with the TM5 helix, and the tail forms an ionic bond with the D3.32 residue of the TM3 helix and one or two H-bonds with the TM7 helix. The tail of the antagonist can form similar bonds, but the interaction between the head and the TM5 helix is much weaker. As a result of these interactions, the agonist molecule acquires an extended "strained string" conformation, in contrast to the antagonist molecule, which has a longer, bended, and flexible tail. The "strained string" of the agonist interacts with the TM6 helix (primarily with the W6.48 residue) and turns it, which leads to the opening of the G protein-binding site on the intracellular side of the receptor, while flexible and larger antagonist molecules do not have the same effect on the receptor.
Topics: Adrenergic beta-Agonists; Carbon; Models, Molecular; Nitrogen; Oxygen; Protein Conformation; Protein Structure, Secondary; Receptors, Adrenergic
PubMed: 36154885
DOI: 10.1134/S0006297922070057 -
European Journal of Heart Failure Mar 2023Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis,... (Randomized Controlled Trial)
Randomized Controlled Trial
β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.
AIMS
Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH).
METHODS AND RESULTS
The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre-specified secondary outcomes.
CONCLUSIONS
SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.
Topics: Humans; Hypertension, Pulmonary; Heart Failure; Quality of Life; Stroke Volume; Adrenergic Agonists; Double-Blind Method; Treatment Outcome
PubMed: 36404400
DOI: 10.1002/ejhf.2745 -
Expert Opinion on Drug Safety May 2018Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay... (Comparative Study)
Comparative Study Review
INTRODUCTION
Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay pharmaceutical treatment of OAB whereas β3-adrenoceptor agonists, such as mirabegron, represent a good alternative. Owing to the important role of muscarinic and β3 receptors in cardiovascular (CV) tissue and to the fact that OAB patients often have CV comorbidities, the safety-profile of these drugs constitute an important challenge.
AREAS COVERED
The aim of this review is to evaluate the CV effects of AMs and mirabegron in OAB. A systematic literature search from inception until December 2017 was performed on PubMed and Medline.
EXPERT OPINION
AMs are generally considered to have good CV safety profile but, however, they may cause undesirable adverse events, such as dry mouth, constipation. CV AEs are rare but noteworthy, the most common CV consequences related to the use of these drugs are constituted by an increase in HR and QT interval. Mirabegron has similar efficacy and tolerability to AMs but causes less adverse events, with either modest hypertension and modest increase in HR (<5 bpm) being the most commonly reported.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Cardiovascular Diseases; Heart Rate; Humans; Hypertension; Muscarinic Antagonists; Thiazoles; Urinary Bladder, Overactive
PubMed: 29542337
DOI: 10.1080/14740338.2018.1453496 -
Current Neurovascular Research 2021Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial...
BACKGROUND
Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial growth factor (anti-VEGF)-drugs are used to treat AMD patients; however, some patients are resistant to these therapies.
OBJECTIVE
The purpose of this study was to investigate the anti-angiogenic effects of α2-adrenergic agonists, including guanabenz and clonidine.
METHODS
We evaluated the anti-angiogenic effects of α2-adrenergic agonists in human retinal microvascular endothelial cells (HRMECs). A proliferation assay was conducted, and the migration ratio was evaluated. In a laser-induced CNV model, guanabenz and clonidine were delivered via intraperitoneal injection or implantation of an osmotic pump device. Fourteen days following CNV induction, CNV lesion size and fundus fluorescein angiography (FFA) were evaluated.
RESULTS
Guanabenz and clonidine inhibited VEGF-induced retinal endothelial cell growth and migration. In the CNV model mice, CNV lesion sizes were reduced by intraperitoneal administration of guanabenz or clonidine. Data, including body weight, systolic blood pressure, and heart rate showed that guanabenz (0.5 and 2.0 mg/kg/day) had little effect on these parameters; conversely, a high dose of clonidine (1.0 mg/kg/day) did affect these parameters. Additionally, clonidine did not affect CNV size, but continuous administration of guanabenz attenuated both CNV size and leakage from neovessels.
CONCLUSION
Our study suggests a key role for α2-adrenergic receptors during CNV formation. Therefore, we suggest that α2-adrenergic receptor agonists may represent novel therapeutic drugs for patients with neovascular AMD.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Cell Movement; Cell Proliferation; Choroidal Neovascularization; Clonidine; Disease Models, Animal; Endothelial Cells; Guanabenz; Humans; Male; Mice; Retina; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 34011258
DOI: 10.2174/1567202618666210518133634 -
Journal of Ocular Pharmacology and... Oct 2016Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are... (Review)
Review
Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A, A, and A. An AAR agonist is in clinical trials for glaucoma, AAR reduces neuroinflammation, AAR protects retinal ganglion cells from apoptosis, and both AAR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y and P2Y, lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.
Topics: Adrenergic Agonists; Dry Eye Syndromes; Glaucoma; Humans; Ligands; Molecular Structure; Receptors, Purinergic; Retinal Ganglion Cells; Structure-Activity Relationship
PubMed: 27574786
DOI: 10.1089/jop.2016.0090 -
Expert Opinion on Drug Safety May 2016Overactive Bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency... (Review)
Review
INTRODUCTION
Overactive Bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Antimuscarinics are currently the most widely prescribed drugs for OAB although persistence with medication is often limited due to lack of efficacy or intolerable adverse effects. Mirabegron is β3 adrenoreceptor agonist that is the first new drug licensed for the management of overactive bladder (OAB) in over 30 years.
AREAS COVERED
This review provides a comprehensive overview of the mirabegron clinical trials programme, including Phase II, III and IV studies with a particular focus on tolerability and safety. A literature search was performed in Pubmed using the key words 'mirabegron', 'overactive bladder', 'β3 adrenoceptor agonist' and 'detrusor overactivity' with no restriction on dates.
EXPERT OPINION
The extensive clinical trial programme has shown mirabegron to be safe and efficacious in the treatment of OAB symptoms and the evidence would suggest that it offers an effective alternative to antimuscarinic therapy.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Humans; Muscarinic Antagonists; Thiazoles; Urinary Bladder, Overactive
PubMed: 26980445
DOI: 10.1517/14740338.2016.1165663 -
Journal of Population Therapeutics and... Aug 2017Midodrine is an oral, peripherally acting alpha-adrenergic agonist. After gaining Food and Drug Administration (FDA) approval in 1996 for orthostatic hypotension, its... (Review)
Review
Midodrine is an oral, peripherally acting alpha-adrenergic agonist. After gaining Food and Drug Administration (FDA) approval in 1996 for orthostatic hypotension, its use has evolved to target vasoplegic conditions such as intradialytic hypotension in the end-stage renal disease population, refractory ascites in cirrhotic patients to support diuresis, and in hepatorenal syndrome. Upon oral ingestion, the drug undergoes enzymatic hydrolysis to an active metabolite, desglymidodrine. Its use has been well tolerated at 2.5 mg, 5 mg, and 10 mg oral doses. The most frequently occurring side effects relate directly to its sympathomimetic profile and include piloerection, scalp pruritis, generalized paresthesias, and urinary retention. The vasoplegic profile of sepsis would be a potential target for midodrine therapy. While its use to mediate recovery from septic shock has been suggested, there is a paucity of clinical data supporting its use. Such therapy may be uniquely appropriate in septic patients who are not candidates for intensive care unit (ICU) level of care.
Topics: Adrenergic alpha-Agonists; Humans; Hypotension; Intensive Care Units; Midodrine; Prodrugs; Pruritus
PubMed: 28873293
DOI: 10.22374/1710-6222.24.3.4