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Scientific Reports Nov 2016Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting...
Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.
Topics: Adrenergic beta-3 Receptor Agonists; Animals; Dioxoles; Gene Expression Regulation; Hypertrophy; Male; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle Strength; Muscle, Skeletal; Nitric Oxide Synthase Type I; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 27874066
DOI: 10.1038/srep37504 -
Anesthesiology Sep 2016Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and... (Review)
Review
Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Dexmedetomidine; Dogs; Humans; Rats
PubMed: 27348818
DOI: 10.1097/ALN.0000000000001214 -
Scandinavian Journal of Trauma,... Dec 2016Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiac dysfunction, calling for immediate pharmacologic intervention. Studies show... (Review)
Review
Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiac dysfunction, calling for immediate pharmacologic intervention. Studies show that although cardiac pharmacologic support is applied when rewarming these patients, a lack of updated treatment recommendations exist. Mainly due to lack of clinical and experimental data, neither of the international guidelines includes information about pharmacologic cardiac support at temperatures below 30 °C. However, core temperature of accidental hypothermia patients is often reduced below 30 °C. Few human studies exploring effects of adrenergic drugs during hypothermia have been published, and therefore prevailing information is collected from pre-clinical studies. The most prominent finding in these studies is an apparent depressive effect of adrenaline on cardiac function when used in doses which elevate cardiac output during normothermia. Also noradrenaline and isoprenaline largely lacked positive cardiac effects during hypothermia, while dopamine is a more promising drug for supporting cardiac function during rewarming. Data and information from these studies are in support of the prevailing notion; not to use adrenergic drugs at core temperatures below 30 °C.
Topics: Adrenergic Agonists; Body Temperature; Hemodynamics; Humans; Hypothermia; Rewarming
PubMed: 27919274
DOI: 10.1186/s13049-016-0339-8 -
The Western Journal of Emergency... May 2015
Topics: Adrenergic Agonists; Anaphylaxis; Community Medicine; Epinephrine; First Aid; Humans; Injections, Intramuscular; Schools; Severity of Illness Index; Time Factors
PubMed: 25987911
DOI: 10.5811/westjem.2015.3.25337 -
American Family Physician Jul 2011Asthma exacerbations can be classified as mild, moderate, severe, or life threatening. Criteria for exacerbation severity are based on symptoms and physical examination... (Review)
Review
Asthma exacerbations can be classified as mild, moderate, severe, or life threatening. Criteria for exacerbation severity are based on symptoms and physical examination parameters, as well as lung function and oxygen saturation. In patients with a peak expiratory flow of 50 to 79 percent of their personal best, up to two treatments of two to six inhalations of short-acting beta2 agonists 20 minutes apart followed by a reassessment of peak expiratory flow and symptoms may be safely employed at home. Administration using a hand-held metered-dose inhaler with a spacer device is at least equivalent to nebulized beta2 agonist therapy in children and adults. In the ambulatory and emergency department settings, the goals of treatment are correction of severe hypoxemia, rapid reversal of airflow obstruction, and reduction of the risk of relapse. Multiple doses of inhaled anticholinergic medication combined with beta2 agonists improve lung function and decrease hospitalization in school-age children with severe asthma exacerbations. Intravenous magnesium sulfate has been shown to significantly increase lung function and decrease the necessity of hospitalization in children. The administration of systemic corticosteroids within one hour of emergency department presentation decreases the need for hospitalization, with the most pronounced effect in patients with severe exacerbations. Airway inflammation can persist for days to weeks after an acute attack; therefore, more intensive treatment should be continued after discharge until symptoms and peak expiratory flow return to baseline.
Topics: Acute Disease; Adrenergic Agonists; Anti-Asthmatic Agents; Asthma; Cholinergic Antagonists; Drug Administration Routes; Emergency Medicine; Glucocorticoids; Humans; Oxygen Inhalation Therapy; Recurrence; Survival Rate; Treatment Outcome; United States
PubMed: 21766754
DOI: No ID Found -
Urologia Internationalis 2008This article reviews the mechanisms affecting contraction and relaxation of the urethra in order to establish a basis for current and future treatments for urinary... (Review)
Review
INTRODUCTION
This article reviews the mechanisms affecting contraction and relaxation of the urethra in order to establish a basis for current and future treatments for urinary incontinence in women.
MATERIAL AND METHODS
A review of the English literature using MEDLINE was performed between 1970 and 2008 on female urethra pharmacology, urinary incontinence, and mechanisms involved in contraction and relaxation of the female human urethra.
RESULTS
alpha-Adrenoceptors (ARs) cause contraction and beta-ARs cause relaxation. Use of selective alpha-agonist and beta-AR blocker agents might have potential for the treatment of stress urinary incontinence. Tolerable doses of cholinergic agonists did not have significant effects on intraurethral pressure. Nitric oxide seems to be the major nonadrenergic-noncholinergic inhibitory transmitter causing relaxation. c-kit-positive interstitial cells seem to regulate urethral tone. The roles of adenosine triphosphate and carbon monoxide have not been fully investigated in humans. Neuropeptides function similarly to the urinary bladder. Prostanoids cause urethral contraction and relaxation depending on their subtypes. Serotonin enhances the strength of urethral sphincteric contractions. The Rho-kinase pathway also appears to be modulating smooth muscle contraction in the urethra.
CONCLUSIONS
Understanding of the urethral function and pharmacology may lead to the development of promising new agents which might be useful in the management of urinary incontinence in women.
Topics: Adrenergic Agonists; Adult; Age Factors; Aged; Female; Humans; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Neurotransmitter; Risk Factors; Sensitivity and Specificity; Treatment Outcome; Urethra; Urinary Incontinence; Urinary Incontinence, Stress
PubMed: 18587243
DOI: 10.1159/000132690 -
Anesthesiology Nov 1999alpha2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural...
BACKGROUND
alpha2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep.
METHODS
Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of MPV-2426.
RESULTS
MPV-2426 produced antinociception with greater potency intrathecally (ED50 = 49 microg) than epidurally (ED50 = 202 microg), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED95, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intravenous administration. Intrathecal MPV-2426, in an ED95 dose and three times this dose, produced a dose-independent reduction in thoracic and lumbar spinal cord blood flow.
CONCLUSIONS
MPV-2426 shares many characteristics of other alpha2-adrenergic agonists examined in sheep, but differs from clonidine and dexmedetomidine by lack of antinociception and minimal reduction in oxygen partial pressure after large intravenous and epidural injections. No hemodynamic depression was observed after intrathecal injection at antinociceptive doses. These results suggest this compound may be an effective spinal analgesic in humans with less hypotension than clonidine, although its relative potency to cause sedation was not tested in this study.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Algorithms; Analgesics; Animals; Blood Gas Analysis; Female; Hemodynamics; Imidazoles; Indans; Injections, Spinal; Regional Blood Flow; Sheep; Spinal Cord
PubMed: 10551595
DOI: 10.1097/00000542-199911000-00036 -
Biochemical and Biophysical Research... Jun 2022The β-adrenergic receptor (βAR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and...
The β-adrenergic receptor (βAR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and obesity. Here, we report the cryo-electron microscopy structures of the βAR-G signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound βAR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, βAR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why βAR prefers mirabegron and solabegron, as the narrow exosite is suitable for binding with agonists with elongated shapes. Our study deepens the understanding of the binding characteristics of βAR agonists and may pave the way for developing βAR-selective drugs.
Topics: Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Cryoelectron Microscopy; Diabetes Mellitus, Type 2; Humans; Isoproterenol; Receptors, Adrenergic, beta-3
PubMed: 35489202
DOI: 10.1016/j.bbrc.2022.04.065 -
British Journal of Pharmacology Jul 2019β -Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration... (Review)
Review
β -Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration may be limited by receptor-induced desensitisation. Whereas the β -adrenoceptor has phosphorylation sites that are important for desensitisation, the β -adrenoceptor lacks these; therefore, it had been assumed that β -adrenoceptors are largely resistant to agonist-induced desensitisation. While all direct comparative studies demonstrate that β -adrenoceptors are less susceptible to desensitisation than β -adrenoceptors, desensitisation of β -adrenoceptors has been observed in many models and treatment settings. Chimeric β - and β -adrenoceptors have demonstrated that the C-terminal tail of the receptor plays an important role in the relative resistance to desensitisation but is not the only relevant factor. While the evidence from some models, such as transfected CHO cells, is inconsistent, it appears that desensitisation is observed more often after long-term (hours to days) than short-term (minutes to hours) agonist exposure. When it occurs, desensitisation of β -adrenoceptors can involve multiple levels including down-regulation of its mRNA and the receptor protein and alterations in post-receptor signalling events. The relative contributions of these mechanistic factors apparently depend on the cell type under investigation. Which if any of these factors is applicable to the human urinary bladder remains to be determined. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
Topics: Adrenergic beta-3 Receptor Agonists; Animals; Humans; Receptors, Adrenergic, beta-3
PubMed: 30809805
DOI: 10.1111/bph.14633 -
JAMA Network Open Oct 2023Corticosteroids and β2-adrenergic agonists are commonly used during pregnancy to treat asthma. However, offspring neurodevelopmental outcomes following in utero...
IMPORTANCE
Corticosteroids and β2-adrenergic agonists are commonly used during pregnancy to treat asthma. However, offspring neurodevelopmental outcomes following in utero exposure to these medications remain unclear.
OBJECTIVE
To investigate the association between timing of in utero exposure to corticosteroids and β2-adrenergic agonists and offspring neurodevelopmental milestones during the first 3 years of life.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study obtained data from the Japan Environment and Children's Study, an ongoing birth cohort study conducted in collaboration with 15 Regional Centers across Japan. Participants were mother-offspring pairs who were recruited between January 1, 2011, and March 31, 2014. Data were analyzed between January and February 2023.
EXPOSURE
Corticosteroids and β2-adrenergic agonists were the exposure of interest. Timing of corticosteroid and β2-adrenergic agonist exposure included early pregnancy (weeks 0-12), mid- to late pregnancy (weeks >12), and both stages of pregnancy.
MAIN OUTCOMES AND MEASURES
Offspring neurodevelopmental milestones (communication, gross motor, fine motor, problem-solving, and personal-social skills) were assessed using the Japanese version of the Ages and Stages Questionnaires, 3rd edition, at 6, 12, 18, 24, 30, and 36 months.
RESULTS
In total, 91 460 mother-offspring pairs were analyzed. Among mothers, the mean (SD) age at delivery was 31.20 (5.05) years. Among offspring, 46 596 (50.9%) were males and 44 864 (49.1%) were females, of whom 66.4% had a gestational age of 39 to 41 weeks. During early, mid- to late, and both stages of pregnancy, 401 (0.4%), 935 (1.0%), and 568 (0.6%) offspring, respectively, were exposed to corticosteroids, whereas 170 (0.2%), 394 (0.4%), and 184 (0.2%), respectively, were exposed to β2-adrenergic agonists. No association of corticosteroid exposure during early, mid- to late, and both stages of pregnancy with all 5 neurodevelopmental milestones was found. Similarly, no association between β2-adrenergic agonist use during early pregnancy and all 5 neurodevelopmental milestones was observed. An association was found between β2-adrenergic agonist exposure during mid- to late pregnancy and delayed personal-social skills (adjusted odds ratio, 1.48; 95% CI, 1.01-2.32; P = .045).
CONCLUSIONS AND RELEVANCE
Results of this study found no association between in utero corticosteroid and β2-adrenergic agonist exposure and offspring neurodevelopmental outcomes, regardless of the timing of exposure. Despite the limitations and low power of the study, the findings suggest that corticosteroids and β2-adrenergic agonists are safe for pregnant individuals with asthma and the neurodevelopment of their offspring.
Topics: Male; Child; Female; Humans; Pregnancy; Adult; Infant; Cohort Studies; Adrenergic Agonists; Prenatal Exposure Delayed Effects; Asthma; Adrenal Cortex Hormones
PubMed: 37874567
DOI: 10.1001/jamanetworkopen.2023.39347