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Circulation Research Jan 2021Changing activity of cardiac Ca1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and...
RATIONALE
Changing activity of cardiac Ca1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and pathophysiology. Although cardiac Ca1.2 channels are prominently upregulated via activation of PKA (protein kinase A), essential molecular details remained stubbornly enigmatic.
OBJECTIVE
The primary goal of this study was to determine how various factors converging at the Ca1.2 I-II loop interact to regulate channel activity under basal conditions, during β-adrenergic stimulation, and in heart failure.
METHODS AND RESULTS
We generated transgenic mice with expression of Ca1.2 α subunits with (1) mutations ablating interaction between α and β-subunits, (2) flexibility-inducing polyglycine substitutions in the I-II loop (GGG-α), or (3) introduction of the alternatively spliced 25-amino acid exon 9* mimicking a splice variant of α upregulated in the hypertrophied heart. Introducing 3 glycine residues that disrupt a rigid IS6-α-interaction domain helix markedly reduced basal open probability despite intact binding of Caβ to α I-II loop and eliminated β-adrenergic agonist stimulation of Ca1.2 current. In contrast, introduction of the exon 9* splice variant in the α I-II loop, which is increased in ventricles of patients with end-stage heart failure, increased basal open probability but did not attenuate stimulatory response to β-adrenergic agonists when reconstituted heterologously with β and Rad or transgenically expressed in cardiomyocytes.
CONCLUSIONS
Ca channel activity is dynamically modulated under basal conditions, during β-adrenergic stimulation, and in heart failure by mechanisms converging at the α I-II loop. Caβ binding to α stabilizes an increased channel open probability gating mode by a mechanism that requires an intact rigid linker between the β-subunit binding site in the I-II loop and the channel pore. Release of Rad-mediated inhibition of Ca channel activity by β-adrenergic agonists/PKA also requires this rigid linker and β-binding to α.
Topics: Adrenergic beta-Agonists; Animals; Calcium Channels, L-Type; HEK293 Cells; Heart Failure; Humans; Ion Channel Gating; Membrane Potentials; Mice, Transgenic; Mutation; Myocytes, Cardiac; Phosphorylation; Protein Conformation; Rabbits; Structure-Activity Relationship; ras Proteins
PubMed: 33086983
DOI: 10.1161/CIRCRESAHA.120.317839 -
Brazilian Journal of Anesthesiology... 2022Dexmedetomidine is a potent adrenergic alpha-2 agonist, and analgesic, sedative, anxiolytic and sympatholytic. Given there have been reports of dexmedetomidine... (Observational Study)
Observational Study
INTRODUCTION AND OBJECTIVE
Dexmedetomidine is a potent adrenergic alpha-2 agonist, and analgesic, sedative, anxiolytic and sympatholytic. Given there have been reports of dexmedetomidine associated temperature changes, in which these events have been associated with complications, our objective was to describe both temperature increase and decrease, during the intra and postoperative period (initial 24 hours), and factors associated, in patients who received dexmedetomidine for anesthesia/sedation in the surgical suite.
METHOD
Retrospective observational study, analyzing charts of patients ≥ 18 years submitted to anesthesia/sedation with dexmedetomidine, between 1/1/2017 and 31/12/2017. Upper temperature threshold was considered ≥ 37.8 °C, and lower, < 35 °C. The association with dexmedetomidine was assessed by the OMS/UMC causality system and by the Naranjo algorithm.
RESULTS
The sample included 42 patients who received dexmedetomidine and whose temperature data were available, with predominance of men 26 (62%), 49.4/16.5 years old (mean/standard deviation), and weight 65/35.8 kg. None of the patients presented intraoperative temperature equal to or above 37.8 °C or below 35 °C. During the postoperative period, one patient presented an increase ≥ 37.8 °C (2.4%) and three, temperature decrease < 35 °C (7%). Surgery/anesthesia time and exposure time to dexmedetomidine were not appropriate linear predictors of maximum temperature. Older age (p < 0.01), longer exposure to dexmedetomidine (p < 0.05) and shorter surgery time (p < 0.01) were significant linear predictors for lower minimum temperature.
CONCLUSIONS
Increase ≥ 37.8 °C/decrease < 35 °C of temperature possibly associated with dexmedetomidine did not occur in the intraoperative period and had a low frequency during the postoperative period.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia; Dexmedetomidine; Humans; Hypnotics and Sedatives; Male; Middle Aged; Temperature
PubMed: 34214520
DOI: 10.1016/j.bjane.2021.02.062 -
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 -
Chronic Respiratory Disease 2023This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment... (Review)
Review
This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.
Topics: Humans; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Clinical Trials as Topic
PubMed: 37800633
DOI: 10.1177/14799731231202257 -
Bulletin of Experimental Biology and... Dec 2021The concentration dependenies of the chronotropic response and changes in blood supply to the isolated heart of 7-day-old newborn rats induced by application of...
The concentration dependenies of the chronotropic response and changes in blood supply to the isolated heart of 7-day-old newborn rats induced by application of α2-adrenergic receptor agonist clonidine hydrochloride in concentrations of 10-10 M were revealed. The minimum concentration of α2-adrenergic receptor agonist caused tachycardia, while higher concentrations led to bradycardia. The maximum effect manifesting in a decrease in coronary flow was recorded at the minimum concentration of the agonist, while the highest concentration had no effect on the coronary flow. When comparing these results with those obtained in control adult rats, we found that the most pronounced differences in the chronotropic effects were observed after addition of the minimum concentration of the α2-adrenergic receptor agonist: bradycardia in adult rats and tachycardia in newborns. The maximum differences in coronary flow parameters were observed after addition of α2-adrenergic receptor agonist in the maximum concentration that induced a two-phase response in adult rats and had no effect on the blood supply in newborns.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Animals, Newborn; Animals, Outbred Strains; Cells, Cultured; Clonidine; Heart; Heart Rate; Organ Culture Techniques; Perfusion; Rats; Receptors, Adrenergic, alpha-2
PubMed: 34855077
DOI: 10.1007/s10517-021-05347-5 -
International Immunopharmacology Apr 2023Dexmedetomidine (Dex) is a highly selective α-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, which plays a...
OBJECTIVE
Dexmedetomidine (Dex) is a highly selective α-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, which plays a neuroprotective role in diabetic peripheral neuropathy (DPN) and diabetes-induced nerve damage. However, the related molecular mechanisms are not fully understood. Therefore, our study explored the mechanism of Dex in DPN using rat and RSC96 cell models.
METHODS
Sciatic nerve sections were observed under an optical microscope and the ultrastructure of the sciatic nerves was observed under a transmission electron microscope. Oxidative stress was assessed by detecting MDA, SOD, GSH-Px, and ROS levels. The motor nerve conduction velocity (MNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) of rats were measured. Cell viability, apoptosis, and the changes in the expression of related genes and proteins were examined. Furthermore, the relationship between microRNA (miR)-34a and SIRT2 or SIRT2 and S1PR1 was analyzed.
RESULTS
Dex reversed DPN-induced decreases in MNCV, MWT, and TWL. Dex alleviated oxidative stress, mitochondrial damage, and apoptosis in both the rat and RSC96 cell models of DPN. Mechanistically, miR-34a negatively targeted SIRT2, and SIRT2 inhibited S1PR1 transcription. The overexpression of miR-34a or S1PR1 or the inhibition of SIRT2 counteracted the neuroprotective effects of Dex in DPN in vivo and in vitro.
CONCLUSION
Dex alleviates oxidative stress and mitochondrial dysfunction associated with DPN by downregulating miR-34a to regulate the SIRT2/S1PR1 axis.
Topics: Rats; Animals; Dexmedetomidine; Diabetic Neuropathies; Sirtuin 2; Oxidative Stress; Adrenergic alpha-2 Receptor Agonists; MicroRNAs; Mitochondria; Apoptosis; Diabetes Mellitus; Sphingosine-1-Phosphate Receptors
PubMed: 37012886
DOI: 10.1016/j.intimp.2023.109910 -
Anesthesia and Analgesia Dec 2023The hypothesis "General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal" was... (Review)
Review
The hypothesis "General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal" was used as a basis for the review of published data on general anesthetic interactions with antinociceptive agents: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. This review is focused on a specific type of anesthetic interaction-the transformation of antinociceptive agents into general anesthetic adjuncts. The primary aim is to answer 2 questions. First, how does an antinociceptive agent transform the effect of an anesthetic in providing a certain component of anesthesia-hypnosis, immobility, or hemodynamic response to noxious stimulation? Second, does a combination of an anesthetic with an adjunct result in a simple summation of their respective effects or in a supra-additive or infra-additive interaction? The Medline database was searched for data describing the interactions of antinociceptive agents and general anesthetics. The following classes of antinociceptive agents were considered: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. Drugs used in combination with antinociceptive agents were general anesthetics and benzodiazepines. The following terms related to drug interactions were used: anesthetic interactions, synergy, antagonism, isobolographic analysis, response surface analysis, and fractional analysis. The interactions of antinociceptive agents with general anesthetics result in a decrease of general anesthetic requirements, which differ for each of the components of general anesthesia: hypnosis, immobility, and hemodynamic response to noxious stimulation. Most studies of the nature of anesthetic interactions are related to opioid-general anesthetic combinations, and their conclusions usually confirm supra-additivity.
Topics: Analgesics; Analgesics, Opioid; Drug Interactions; Anesthetics, General; Sodium Channel Blockers; Adrenergic Agonists; Dose-Response Relationship, Drug
PubMed: 37851902
DOI: 10.1213/ANE.0000000000006737 -
AANA Journal Dec 2021Enhanced Recovery After Surgery (ERAS) protocols have been implemented in many institutions to attenuate the stress of surgery and facilitate early recovery. Careful...
Enhanced Recovery After Surgery (ERAS) protocols have been implemented in many institutions to attenuate the stress of surgery and facilitate early recovery. Careful selection of multimodal analgesic medication plays an essential role in achieving the goals of ERAS protocols. Clonidine and dexmedetomidine are α-adrenergic receptor (α-AR) agonists that can greatly enhance various ERAS components owing to their unique pharmacologic properties: antinociception, anxiolysis, anti-inflammation, and renal protection. The α-AR agonists exert supraspinal and spinal antinociceptive effects by potentiating descending pain modulatory pathways and inhibiting peripheral C fibers. These antinociceptive effects of α-AR agonists are independent of opioid receptors and result in analgesic synergy with opioid agonists. Several meta-analyses and systematic reviews have reported that α-AR agonists decrease opioid consumption and side effects in adult and pediatric surgical patients. Given the wide distribution of α-ARs in the body, α-AR agonists have been associated with a reduction in anxiety, perioperative stress, inflammation, postoperative nausea and vomiting, shivering, and cognitive dysfunction. This course describes the basic and applied pharmacology of the α-AR agonists and provides emerging evidence to support their utility in acute pain management and ERAS protocols. Perioperative administration of α-AR agonists can enhance pain management, decrease adverse effects, and promote surgical recovery.
Topics: Adrenergic alpha-2 Receptor Agonists; Adult; Analgesics, Opioid; Child; Clonidine; Enhanced Recovery After Surgery; Humans; Treatment Outcome
PubMed: 34809759
DOI: No ID Found -
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 -
Lower Urinary Tract Symptoms Mar 2023Goto-Kakizaki (GK) rats with type 2 diabetes mellitus respond to low temperature (LT) environments with bladder overactivity, including increased voiding frequency and...
OBJECTIVES
Goto-Kakizaki (GK) rats with type 2 diabetes mellitus respond to low temperature (LT) environments with bladder overactivity, including increased voiding frequency and decreased voiding interval and micturition volume. We determined if bladder overactivity could be inhibited by treatment with the combination of a M -muscarinic receptor antagonist and a β -adrenergic receptor agonist.
METHODS
Ten-week-old female GK rats were fed a high-fat diet for 4 weeks. Cystometric investigations were conducted at room temperature (RT, 27 ± 2°C). The rats were then intraperitoneally administered the vehicle, the M -muscarinic receptor antagonist solifenacin, the β -adrenergic agonist mirabegron, or a combination of solifenacin and mirabegron. Ten minutes after the administrations, the rats were transferred to the LT environment (4 ± 2°C), where the cystometric measurements were continued. The expressions of both M -muscarinic and β -adrenergic receptors were investigated.
RESULTS
After transfer from RT to LT, both voiding interval and bladder capacity of the vehicle-, solifenacin-, or mirabegron-treated rats were significantly decreased. However, the combination of solifenacin and mirabegron significantly mitigated the bladder overactivity. While both M -muscarinic and β -adrenergic receptors were detected, the expression of M -muscarinic receptor mRNA was significantly higher than that of β -adrenergic receptor mRNA.
CONCLUSIONS
The cold stress-induced bladder overactivity was not improved by either the M -muscarinic receptor antagonist or the β -adrenergic receptor agonist alone. However, the combined treatment mitigated the cold stress responses. Combined therapy with M -muscarinic antagonists and β -adrenergic agonists could reduce side effects and improve the quality of life for diabetic patients with bladder overactivity.
Topics: Rats; Female; Animals; Urinary Bladder; Muscarinic Antagonists; Solifenacin Succinate; Urinary Bladder, Overactive; Cold-Shock Response; Diabetes Mellitus, Type 2; Adrenergic Agonists; Quality of Life; Receptors, Muscarinic; RNA, Messenger; Receptors, Adrenergic; Adrenergic beta-3 Receptor Agonists
PubMed: 36543093
DOI: 10.1111/luts.12472