Beta-adrenergic Agonist Research Articles

Investigation of the Interaction Mechanism between Salbutamol and Human Serum Albumin by Multispectroscopic and Molecular Docking.

Salbutamol (SBAL), a kind of short-acting beta 2-adrenergic agonist, has been mainly used to treat bronchial asthma and other allergic airway diseases clinically. In this study, the interaction mechanism between salbutamol and human serum albumin was researched by the multispectral method and molecular docking. The fluorescence intensity of HSA could be regularly enhanced with the increase of SBAL concentration. Both the results of the multispectral method and molecular docking showed that SBAL could bind HSA with van der Waals force and hydrogen bonds. The binding mechanism was further analysed by UV-Vis and synchronous fluorescence spectra. The contents of the secondary structure of free HSA and SBAL-HSA complex were evaluated using CD spectra.

Bioequivalence studies of inhaled indacaterol maleate in healthy Chinese volunteers under gastrointestinal non-blocking or blocking with concomitant charcoal administration

BackgroundIndacaterol is one of the long-acting beta2-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life. ObjectiveThe three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol. MethodsTwo BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 μg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of Cmax and AUC0-t fell within the limits of 0.8–1.25. ResultsIndacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean Cmax and AUC0-t was 109.9% (90% CI, 106.1–113.8%) and 104.8% (90% CI, 101.5–108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%–104.4%) for non-block subjects. No serious adverse events were reported. ConclusionsThe results showed that 150 μg indacaterol (+/− 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.

Evaluation of inhaled beta-2 agonist in management of transient tachypnea of the newborn

BackgroundTransient tachypnea of the newborn (TTN) is a common cause of early neonatal respiratory distress. It is due to delayed clearance of fetal lung fluid.AimTo evaluate the effect of inhaled salbutamol, a beta-2 adrenergic agonist (β2AA), in management of TTN and to detect any side effects as a result of using itMethodsA total of 100 infants with TTN were randomly divided into two groups to receive either inhaled salbutamol (treatment group) or an equal volume of normal saline solution (placebo group) at the time of diagnosis. At enrollment (by the 6th hour), complete blood count, blood glucose, serum potassium (K+), arterial blood gasses, respiratory rate, heart rate, blood oxygen saturation (O2 Sat), fraction of inspired oxygen (FiO2), and TTN clinical score were determined for all patients. At 0.5, 1, and 4 h after drug administration, respiratory rate, heart rate, O2 Sat, FiO2, and the clinical TTN score were recorded. At 4 h after treatment, arterial blood gasses, serum K+, and blood glucose levels were measured again. The duration of total respiratory support and the duration of hospitalization were recorded as well.ResultsNo statistically significant differences existed between both groups in terms of gestational age, birth weight, gender, mode of delivery, Apgar score, or maternal risk factors. The duration of respiratory support and duration of hospitalization were significantly shorter in the treatment (salbutamol) group (P < 0.0005, P < 0.0002, respectively). In the treatment (salbutamol) group; the respiratory rate, FiO2 and TTN score were significantly lower after treatment (P < 0.0001, P < 0.0000, P < 0.0000, respectively). Also the PaO2 significantly increased (P < 0.0000) with significant improvement in PH (P < 0.0001) and significant reduction in PaCO2 (P < 0.03). However, there were no statistically significant differences in heart rates, serum K+, or glucose levels after treatment.ConclusionInhaled salbutamol, a β2AA, was effective in reducing the duration of respiratory support and hospitalization in TTN, with no detected side effects.

Beta2-adrenergic receptor agonist inhibits keratinocyte proliferation by mechanisms involving nitric oxide

IntroductionBeta2-adrenoceptors regulate proliferation of keratinocytes. Nitric oxide (NO) produced by keratinocytes through stimulation of nitric oxide synthase (NOS) mediates keratinocyte proliferation. Aim: In this study, the mechanism interaction β-ARs and NO production on keratinocyte will be explored, and the important for proliferation will be studied.Material and methodsTo understand the relationship among β2-adrenoceptors, NO production and proliferation in keratinocytes, the experiment is divided to two parts. In the first part of the experiment, keratinocytes are divided into five groups which are treated with 0 M, 10–7 M, 10–6 M, 5 × 10–6 M and 10–5 M isoproterenol, respectively. In the second part of the experiment, the keratinocytes are divided into five groups which are treated with 10–5 M isoproterenol and L-NMMA at doses of 0 M, 10–6 M, 5 × 10–6 M, 10–5 M and 5 × 10–5 M, respectively. We examine NOS expression, NO production, c-AMP level and proliferation in human keratinocytes.ResultsThe results show that isoproterenol results in iNOS and ncNOS protein raised and the elevation of nitric oxide. L-NMMA can block the increase of iNOS and ncNOS protein expression and the ability to inhibit proliferation caused by isoproterenol.ConclusionsBeta2-adrenergic receptor agonist mediates nitric oxide synthase to affect keratinocyte proliferation in skin. The physiological and pathological relationship of these discoveries remains to be defined. These results can provide new possibilities in the therapy of integumentary disease conditions linked with the dysfunction of β-AR-mediated NO production.

Ractopamine Hydrochloride and Estradiol + Trenbolone Acetate Implants Alter Myogenic mRNA, &amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt;-Adrenergic Receptors, and Blood Metabolites

Two commonly used growth promotants in the United States beef industry are β-agonists and anabolic steroid hormones. Each has been shown to increase lean muscle deposition in cattle provided treatments of each growth technology, but much is still unknown of how steroidal implants and β-agonists work in combination. It was our goal to determine the effect of implant strategy and β-agonist administration in beef feedlot heifers (n = 264). A 3 × 2 factorial randomized complete block design was used with 2 levels of OPT and 3 different durations of terminal implant (TI) windows for a total of 6 treatment groups with 9 replications. Terminal implants (20 mg estradiol/200 mg trenbolone acetate implant, Component TE-200) were provided to heifers 140 d from slaughter (TI140), 100 d from slaughter (TI100), or 60 d from slaughter (TI60). Animals receiving the later two TI being first implanted on day 0 (8 mg estradiol/80 mg trenbolone acetate implant, Component TE-IH). The second treatment of the cattle received was the orally active beta adrenergic agonist, ractopamine-hydrochloride (RH) in the form of Optaflexx®(OPT; 0 (NO) or 200 (YES) mg/hd·d-1) over the final 28 days of the trial. Thirty animals were subjected to longissimus muscle (LM) biopsies on d 0, 40, 80, 112, and at slaughter on d 140 to view mRNA levels of myogenic related genes and protein quantities of the β1-adrenergic receptor (β1 AR) and β2-adrenergic receptor (β2 AR). On the same days, blood samples were taken from 108 animals to assess changes in plasma blood urea nitrogen (BUN), non-esterified fatty acids (NEFA) and progesterone due to treatments. Relative mRNA levels of myosin heavy chain IIX (MHC IIX), AMPKα, and IGF-I were increased (P P = 0.09) due to OPT. An interaction between TI d and OPT administration caused an increase (P β2 AR was decreased (P β1 AR protein intensity tended to be lower (P P P β-adrenergic receptors, and blood metabolites in finishing beef heifers.

Finishing Cattle in All-Natural and Conventional Production Systems

Beef cattle producers in the North America have a variety of production and marketing options and must choose the best production system for their situation. This review describes considerations involved in choosing between feeding cattle conventionally versus feeding them in programs that prohibit the use of certain technologies. Data from peer-reviewed journals, extension publications, nutritional consultants, governmental organizations, and feed companies were used to construct this review. Most cattle in North America are fed in conventional production systems. Conventional beef production systems typically use steroidal implants, ionophores, and beta-adrenergic agonists to improve animal productivity; as well as feed grade and injectable antimicrobials to control, treat or prevent disease and improve animal health. These technologies have been shown to lower the cost of production, allowing for beef to be competitive in the global protein market. Some consumers have expressed a preference for beef produced without these technologies. These “All-natural” (AN) cattle may bring a premium price in the market. The economic impact of differing productions systems can be described in relation to 1) cost of production, 2) operating costs of the feedlot, 3) price paid for feeder calves, and 4) price received for fed cattle. Conventional production provides the most favorable outcome for factors 1, 2, and 3, while AN production provides the most favorable outcome for item 4. There are also industry wide and societal aspects related to differing beef production systems related to health and safety of beef, land use, and cost of production allowing for a greater share of the global protein market. Technologies used in conventional production are critical tools to North American beef production. Differences in efficiencies between each type of non-conventional production systems must be re-captured in added premiums when cattle are marketed and sold. Premiums for AN cattle are enticing, but the true differences in the cost of production between the AN and conventional cattle must be evaluated in order for a producer to make the correct decision for their operation.

408 Effect of monensin intake during a stocker phase and subsequent finishing phase on rumen bacterial diversity of beef steers

Abstract Three monensin levels during a stocker phase (0, 800, 1600 g/ton fed in a free choice mineral) and two levels during finishing [0 (U) or 37.5 mg/kg diet DM (M)] were used to determine the effects of monensin supplementation during a stocker and subsequent finishing phase on rumen bacterial communities of beef steers. Thirty calves were fed pearl millet (Pennisetum glaucum) hay with soybean hull and corn gluten feed supplement (0.5% BW daily, AF basis) or grazed fall wheat pasture (Triticum aestivum) during a stocker phase and then transported 1,067 km to Canyon, TX, for finishing. Rumen fluid was collected on d 0, 28, and the end of the stocker phase (d 85). Samples were also obtained at feedlot d 0, 14, 28, 56, and immediately prior to a diet change to include a beta-adrenergic agonist and before shipping for harvest. Rumen microbiota were characterized by next generation sequencing the 16S v4 hypervariable region with the Illumina MiSeq platform. During the stocker phase, Prevotella and Bacteroidetes were the most dominant genus regardless of diet or treatment. Monensin decreased (P ≤ 0.01) alpha diversity (Shannon Index) for cattle consuming hay on d 28 of the stocker phase. In the feedlot, Prevotella, Lachnospiraceae, and Bacteroidetes were the most abundant genus. Steers that were previously on the 0 and 1600 treatments during the stocker phase and were fed monensin at the feedlot had decreased alpha diversity (P = 0.04) on feedlot d 14 compared to those that did not. Monensin at the feedlot tended to increase alpha diversity on d 28 for cattle previously on the 1600 treatment (P = 0.06), and on d 56 for cattle previously on the 0 treatment (P = 0.06). This experiment provides a better understanding of the effect of monensin on rumen bacterial communities throughout production.

Urinary Incontinence in Elderly Men: Update on Evaluation and Treatment

To provide an overview of the appropriate evaluation of elderly men with urinary incontinence and an updated review of treatment options available to these patients. Adding pelvic floor physical therapy to bladder training exercises is more effective for treating overactive bladder than bladder training alone. Beta-3 adrenergic agonists are a safe and effective alternative to anticholinergic therapy in older adults. Sacral neuromodulation is safe and effective in older adults and may benefit men with incomplete bladder emptying. A de-obstructing surgery may benefit men with both underactive bladder and bladder outlet obstruction, given that a majority will recover detrusor function following intervention. In post prostatectomy incontinence, the artificial urinary sphincter is more effective in men with moderate to severe incontinence, though it is associated with a higher rate of complications. Many options are available to the elderly male patient with urinary incontinence. Careful consideration of patient’s functional status, frailty, mental health status, and social support systems are needed to guide the appropriate treatment options.

Congenital myasthenic syndrome in Turkey: clinical and genetic features in the long-term follow-up of patients.

Congenital Myasthenic Syndromes (CMS) are rare disorders that occur as a result of defects in the structure and in the function of neuromuscular junctions. Molecular genetic diagnosis is important to select the most suitable therapeutic option and treatment. Eight patients with congenital myasthenic syndromes who presented to the Çukurova University Pediatric Neurology Department Outpatient Clinic between June 2015 and May 2018 were reviewed. Mutations in the acetylcholine receptor (subunits in epsilon) (CHRNE) in three and mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) gene in five patients were identified; p.W148 mutation was detected to be homozygous in four, c.1169A > G novel mutation in COLQ gene was homozygous in one, c452_454delAGG mutation was homozygous in the other patient, IVS7 + 2T > C(c.802 + 2T > C) mutation was homozygous in a patient and compound heterozygous mutations of c.865C > T(p.Leu289Phe) and c.872C > G(p.A2916)(p.Arg291Gly) in the CHRNE gene in the last patient. The parents of all the evaluated patients were consanguineous. Ptosis, ophthalmoplegia, generalized hypotonia, bulbar weakness, and respiratory crisis were the main findings at the time of presentation. Pyridostigmine is the first-line drug therapy in primary AChR deficiency. Beta adrenergic agonists, ephedrine, and albuterol are the other treatment options for CMS subtypes caused by mutations in COLQ. This study points out the genetic and phenotypic features of CMS patients in the Turkish population and it also reports previously unreported mutations in the literature. CHRNE and COLQ gene mutations are common in the Turkish population. Patients can get serious benefits and recover after the treatment. The treatment should be planned according to genetic tests and clinical findings.

Classification of asthma.

Asthma is a chronic inflammatory disorder of the airways that results, physiologically, in hyperreactivity and, clinically, in recurrent episodes of wheezing, chest tightness, or coughing. Airway inflammation, smooth-muscle contraction, epithelial sloughing, mucous hypersecretion, bronchial hyperresponsiveness, and mucosal edema contribute to the underlying pathophysiology of asthma. Diagnostic tests such as methacholine or mannitol challenges or spirometry (pre- and postbronchodilator responses) help to identify such underlying pathophysiology via assessments of bronchial hyperreactivity and lung mechanics but are imperfect and, ultimately, must be viewed in the context of a patient's clinical presentation, including response to pharmacotherapy. Asthma can be classified into either intermittent or persistent, and the latter is either mild, moderate, or severe. Some patients change, in either direction, from intermittent to persistent asthma. In addition, patients with asthma may be classified as allergic (immunoglobulin E mediated), nonallergic (often triggered by viral upper respiratory tract infections or no apparent cause), occupational, aspirin-exacerbated respiratory disease, potentially fatal, exercise-induced, and cough variant asthma. In the latter, the patients have a nonproductive cough that responds to treatment for asthma but not with antibiotics, expectorants, mucolytics, antitussives, or beta₂-adrenergic agonists, and to treatment for acid reflux and rhinosinusitis. Thus, cough variant asthma is in the differential diagnosis of chronic cough.

PRS5 TREATMENT PERSISTENCE AND EXACERBATIONS IN PATIENTS WITH ASTHMA INITIATING TREATMENT WITH INHALED CORTICOSTEROIDS AND LONG-ACTING BETA-ADRENERGIC AGONISTS (ICS/LABA): REAL-LIFE STUDY

Asthma, a chronic inflammatory disease of the respiratory tract, presents with bronchial hyperresponsiveness and variable airflow obstruction. The objective of the study was to determine treatment persistence and exacerbations in patients initiating asthma treatment with various fixed-dose inhaled corticosteroid/long-acting beta-adrenergic agonist (ICS/LABA) combinations. An observational study was conducted by reviewing medical records. Patients aged ≥18 years were included who initiated treatment with ICS/LABA and met the inclusion/exclusion criteria. Patients were followed for one year. Study groups: fluticasone propionate/salmeterol (FP/SAL), beclomethasone/formoterol (BDP/FORM), budesonide/formoterol (BUD/FORM), fluticasone furoate/vilanterol (FF/VI) and fluticasone propionate/formoterol (FP/FORM). The main measurements were: treatment persistence, medication possession ratio (MPR) and exacerbations. Statistical significance was p <0.05. 3,203 patients were recruited, of which 31.1% were on FP/SAL, 28.6% BDP/FORM, 25.0% BUD/FORM, 8.2% FF/VI and 7.0% FP/FORM. The mean age was 52.2 years and 60.8% were female: 44.9% had moderate asthma. Treatment persistence was 61.7% (95% CI: 60.0-63.4%), and by study groups was: FP/SAL: 60.7%, BDP/FORM: 61.2 %, BUD/FORM: 60.3%, FF/VI: 66.7% and FP/FORM: 67.6% (p = 0.046). The MPR was: FP/SAL: 74.3%, BDP/FORM: 73.8%, BUD/FORM: 74.6%, FF/VI: 79.4% and FP/FORM: 80.6% (p = 0.028). The mortality rate was 2.9% and the percentage of exacerbations was: FP/SAL: 21.9%, BDP/FORM: 22.2%, BUD/FORM: 22.8%, FF/VI: 17.9% and FP/FORM: 16.0% (p = 0.036). Patients receiving FP/FORM and FF/VI had significantly greater treatment adherence (persistence, MPR) and lower rates of exacerbations. These differences could be due to the pharmacological properties of the drugs or other, unmeasured, factors.

Pediatric asthma: Principles and treatment.

Approximately one-half of children with asthma present with symptoms before 3 years of age. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection (URI), activity, or changes in weather. When symptoms occur after a viral URI, children with asthma often take longer than the usual week to fully recover from their respiratory symptoms. Wheezing and coughing during exercise or during laughing or crying, and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers identified by a history, such as second-hand cigarette smoke exposure, and allergens identified by skin-prick testing can significantly reduce symptoms. According to the 2007 National Asthma Education and Prevention Program (NAEPP) report, if impairment symptoms are present for >2 days/week or 2 nights/month, then the disease process is characterized as persistent, and, in all age groups, inhaled corticosteroids (ICS) are recommended as the preferred daily controller therapy. Montelukast is approved for children ages ≥ 12 months and is often used for its ease of daily oral dosing. Long-acting beta-2 adrenergic agonists should only be used in combination with an ICS. For more-severe or difficult-to-control phenotypes, biologic therapy has been developed, which targets the type of inflammation present.

Bronchodilator test in extreme old age: Adverse effects of short-acting beta-2 adrenergic agonists with clinical repercussion and bronchodilator response.

To evaluate chronological age as a limiting factor to perform the bronchodilator test, determine significant adverse effects of short-acting beta 2 agonists with clinical repercussions, and assess bronchodilator response in extreme-old-age patients who undergo the spirometry test. This is a cross-sectional and retrospective study. The sample was extracted from the database (spirometer and respiratory questionnaire) of a pulmonary function service. Patients over 90 years old were included in the research, and we evaluated their bronchodilator response and its significant adverse effects that may have clinical repercussions related to the bronchodilator. A sample of 25 patients aged 92.12 ± 2.22 years (95% CI, 91.20 - 93.04), with a minimum age of 90 years and a maximum of 97 years and a predominance of females with 72% (18/25). The bronchodilator test was performed in 84% (21/25) of the patients. The bronchodilator response was evaluated in 19 of the 21 patients (90.47%) who underwent the bronchodilator test. Two tests did not meet the criteria of acceptability and reproducibility. No clinical adverse effects were observed with the bronchodilator medication (salbutamol) during or after the exam. Chronological age is not a limiting factor for the bronchodilator test, short-acting beta-2 agonists did not present adverse effects with significant clinical repercussion and were useful in the diagnosis and therapeutic guidance of extreme-old-age patients.

Pharmaceutical Options for Stress Urinary Incontinence

We review the currently available pharmaceutical options for SUI. Pharmaceutical options for SUI are either drugs that manipulate hormones or those that impact neurotransmitter levels. Local estrogen replenishment has been associated with improved OAB symptoms in postmenopausal women, but its impact on SUI is unclear. Subjective improvement may be noted, while objective outcome indices are typically unchanged. There is weak evidence to suggest that any adrenergic agonist is better than placebo in improving objective incontinence measures. Both alpha- and beta-adrenergic agonists are associated with significant side effects. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has been shown to improve both objective and subjective outcome indices, but it is associated with significant side effects and is not FDA-approved. Evidence for the use of TAS-303, a norepinephrine reuptake inhibitor, is currently in the early stages and its clinically significant improvement and durability are unknown at this time. Finally, selective androgen receptor modulators (SARM) have shown promise in both animal and early human studies; however, a preliminary report from a large, multi-institutional, placebo-controlled trial of one of these agents (enobosarm reported that this drug did not achieve statistical significance in its primary endpoint compared to placebo. Overall, the drug was well tolerated. The majority of drugs available for SUI treatment are associated with limited improvement, unknown durability, and potential for significant side effects. There is some evidence for efficacy of both SNRIs and SARMs; however, more research is needed. At present, any use of medications for SUI is off-label in the USA.

β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure.

Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice.

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.

Congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are a group of genetically heterogeneous disorders of the neuromuscular transmission, clinically characterized by muscle weakness and fatigability. Mutations in several proteins affecting structure, development and function of the neuromuscular junction result in CMS by compromising the safety margin of neuromuscular transmission through a variety of mechanisms. Defects in postsynaptic proteins are the most frequent cause of CMS, but presynaptic proteins have been increasingly recognized as causative of these disorders. In addition, it has become evident that myasthenia can be a part of a more complex phenotype featured also by central nervous system involvement. Disease-onset ranges from prenatal life to adulthood while the clinical phenotype spans from severe generalized weakness to mild predominant cranial muscle weakness. Low frequency repetitive nerve stimulation often demonstrates a decremental response. Single-fiber EMG or conditioning with exercise or high frequency nerve stimulation may be needed to unmask the neuromuscular synaptic defect in some cases. Only some presynaptic CMS show facilitation (hallmark of the autoimmune presynaptic defect of neuromuscular transmission), depending on the characteristics of the underlying quantal release defect. The molecular diagnosis and the understanding of the disease mechanism of a specific CMS are crucial to individualize patient care. Cholinergic drugs (such as pyridostigmine or 3,4-diamynopyridine) improve the myasthenic symptoms in certain CMS subtypes patients but worsen the symptoms in others, who respond positively to beta-adrenergic agonists (such as salbutamol) or long-lived acetylcholine receptor channel blockers (such as fluoxetine). The combination of a cholinergic drug and a beta-adrenergic agonist can further optimize the pharmacological treatment of certain CMS subtypes.

The practice of meditation is not associated with improved interoceptive awareness of the heartbeat.

Meditation is commonly assumed to be associated with enhanced interoceptive accuracy. We previously found that experienced meditators did not exhibit a greater ability than nonmeditators to detect heartbeat sensations at rest, despite the meditators' reported subjective ratings of higher accuracy and lower difficulty. Here, attempting to overcome previous methodological limitations, we assessed interoceptive awareness of heartbeat and breathing sensations across physiological arousal levels using infusions of isoproterenol, a beta-adrenergic agonist similar to adrenaline. We hypothesized that meditators would display greater interoceptive awareness than nonmeditators, as evidenced by higher interoceptive detection rates, increased interoceptive accuracy, and differences in localization of heartbeat sensations. We studied 15 meditators and 15 nonmeditators, individually matched on age, gender, and body mass index, using randomized, double-blinded, and placebo-controlled bolus infusions of isoproterenol. Participants reported their experience of heartbeat and breathing sensations using a dial during infusions and the location of heartbeat sensations on a two-dimensional manikin afterward. There was no evidence of higher detection rates or increased accuracy across any dose, although meditators showed a tendency to report cardiorespiratory sensation changes sooner at higher doses. Relative to nonmeditators, meditators exhibited prominent geographical differences in heartbeat localization, disproportionally reporting sensations throughout central regions of the chest, abdomen, neck, back, and head. To further assess indications of potential differences in cardiac interoceptive accuracy between meditators and nonmeditators, we conducted a meta-analysis including 724 participants and found little evidence for such differences. We conclude that the practice of meditation is not associated with improved cardiac interoceptive awareness.

P6279Mitochondria targeted catalase overexpression protects against beta-adrenergic receptor mediated cardiac remodeling in mice

Abstract Background Beta-adrenergic receptor signaling is widely recognized as a fundamental component in the pathogenesis of chronic heart failure. However, the mechanisms behind beta-adrenergic receptor-mediated remodeling in cardiomyocytes and the myocardium are not fully understood. Oxidative stress has been proposed as a central pathophysiological mediator in cardiovascular disease and heart failure. The triggers and sources of oxidative stress in heart failure remain unclear. In this study we use mice with mitochondria-targeted overexpression of the antioxidant enzyme catalase (mCAT) to link beta-adrenergic receptor-mediated stress to mitochondrial reactive oxidative species (ROS) and the progression of heart failure. Hypothesis Mitochondrial ROS, induced by beta-adrenergic receptor-activation, is a mediator in the progression of the heart failure phenotype. Methods mCAT and wild type mice (n=10) were administered the non-selective beta-adrenergic agonist Isoprotenerol (Iso; 50mg/kg/day) through subcutaneous osmotic pumps for 3 weeks. Hearts were taken for biochemistry (western blotting, qPCR). Cardiomyocytes were isolated and loaded with Fluo-3 AM to study intracellular Ca2+ transients and fractional shortening using confocal line scan microscopy. All experiments were performed in accordance with the Stockholm ethical committee for animal research. Results and conclusions The WT mice displayed an increased heart/body weight ratio following chronic Iso administration. In contrast, mCAT mice displayed resistance to Iso-induced cardiac hypertrophy (p&lt;0.05). Furthermore, chronic Iso exposure in WT mice induced increased ROS-dependent post-translational protein modifications, impaired cardiomyocyte Ca2+ handling and reduced contractility in isolated cardiomyocytes (p&lt;0.05). Cardiomyocytes from mCAT mice did not display the deleterious effects of chronic Iso exposure on cardiomyocyte Ca2+ and contractility. Our study demonstrates that beta-adrenergic receptor stimulation-induced remodeling of the heart, which is similar to what is seen in heart failure, can be prevented by overexpressing catalase in the mitochondria. This indicates an important role of mitochondrial ROS in the link between adrenergic signaling and the development of cardiomyopathy and heart failure. Acknowledgement/Funding Hjärtlungfonden

Uptake and Effects of the Beta-Adrenergic Agonist Salbutamol in Fish: Supporting Evidence for the Fish Plasma Model.

The fish plasma model (FPM) predicts the fish blood plasma concentration of a pharmaceutical from the water concentration to which the fish is exposed and compares it with the human therapeutic plasma concentration (Hther PC) with the postulate that no adverse toxic effects occur below the Hther PC. The present study provides several lines of evidence supporting the FPM for the beta-adrenergic agonist salbutamol, a small cationic molecule at ambient pH. Salbutamol exhibited very low acute toxicity to early and adult life stages of fish. Biomass reduction in fish early life stages was the most sensitive apical endpoint, with no-observed-effect concentrations (NOECs) in the low mg/L range after continuous exposure for up to 120 d. Given that predicted and measured environmental concentrations are at least 1000-fold lower, the risk of salbutamol in freshwater is deemed very low. Increase in heart beat rate and decrease in total triglyceride content in fish also occurred at the low mg/L range and resembled effects known from humans. This finding supports the FPM assumption of conserved targets in fish with similar functionality. Plasma concentrations measured in adult and juvenile fish exposed to water concentrations at approximately the NOECs exceeded Hther PC and even approached plasma concentrations toxic to humans. This result confirms for salbutamol the FPM hypothesis that no adverse (i.e., population-relevant) toxic effects occur in fish below the Hther PC. Environ Toxicol Chem 2019;38:2509-2519. © 2019 SETAC.