Selective Β2-adrenergic Agonist Research Articles

Особенности влияния бета-адреномиметика гинипрала на радикальную активность нейтрофилов в крови женщин на разных этапах репродукции

In recent years, the idea about the physiological significance of neutrophils, including during pregnancy and childbirth, has evolved significantly. There is an opinion that in the course of pregnancy, the activity of non-specific cellular immunity increases, which, in addition to performing a protective function, forms a mode of contractile activity of the uterus that is optimal for child-bearing. In obstetric practice, in order to reduce uterine hypertonicity in the treatment of miscarriage, β-adrenergic agonists are widely used. However, many aspects of their influence on the mother and the foetus remain insufficiently studied. The aim of this paper was to study the effect of Gynipral (selective β2-adrenergic agonist) on the intensity of latex-induced respiratory burst of venous blood neutrophils in women at different stages of reproduction. Using the chemiluminescence method, we showed for the first time that Gynipral, depending on the stage of reproduction, has multidirectional effect on the latex-induced radical activity of neutrophils in the venous blood of women in vitro. At a low level of radical reaction of neutrophils to latex (in the follicular phase of the cycle, during pregnancy and, which is especially important, during childbirth), Gynipral enhances the oxidative activity of cells; at a high level of radical reaction of neutrophils (during the luteal phase of the cycle and after childbirth), Gynipral inhibits it. It can be assumed that in women, catecholamines (adrenaline) during pregnancy through β2- and/or β3-adrenergic receptors increase the ability of neutrophils to produce activated forms of oxygen, while after delivery they reduce this ability. Such changes in receptor activation may be associated with the phenomenon of switching of β-adrenergic receptor coupling from Gs protein to Gi protein, which is important for regulatory mechanisms. For citation: Polezhaeva T.V., Paturova I.G., Zaytseva O.O., Solomina O.N., Khudyakov A.N., Sergushkina M.I., Dmitrieva S.L., Tsirkin V.I. Effect of Beta-Adrenergic Agonist Gynipral on the Radical Activity of Neutrophils in the Blood of Women at Different Stages of Reproduction. Journal of Medical and Biological Research, 2021, vol. 9, no. 2, pp. 171–181. DOI: 10.37482/2687-1491-Z055

VAMS and StAGE as innovative tools for the enantioselective determination of clenbuterol in urine by LC-MS/MS

Clenbuterol is a chiral, selective β2-adrenergic agonist. It is administered as a racemic mixture for therapeutic purposes (as a bronchodilator or prospective neuroprotective agent), but also for non-therapeutic uses (athletic performance enhancement, cattle growth promotion). Aim of the present study is to develop an original, enantioselective workflow for the analysis of clenbuterol enantiomers in urine microsamples. An innovative miniaturised sampling procedure by volumetric absorptive microsampling (VAMS) and a microsample pretreatment strategy based on stop-and-go extraction (StAGE) tips were developed and coupled to an original, chiral analytical method, exploiting liquid chromatography with triple quadrupole detection (LC-MS/MS). The method was validated, with satisfactory results: good linearity (r2 ≥ 0.9995) and LOQ values (0.3 ng/mL) were found over suitable concentration ranges. Extraction yield (>87 %), precision (RSD < 4.3 %) and matrix effect (85–90 %) were all within acceptable levels of confidence. After validation, the method was applied to the determination of clenbuterol in dried urine sampled by VAMS from patients taking the drug for therapeutic reasons. Analyte content ranged from 0.8 to 2.5 ng/mL per single enantiomer, with substantial retention of the original drug racemic composition. The VAMS-StAGE-LC-MS/MS workflow seems to be suitable for future application to anti-doping testing of clenbuterol in urine.

Effects of salbutamol and phlorizin on acute pulmonary inflammation and disease severity in experimental sepsis.

Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes.

Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway.

Efficacy of a new intravenous β2-adrenergic agonist (bedoradrine, MN-221) for patients with an acute exacerbation of asthma

BackgroundMany patients with acute exacerbation of asthma are non-responders to inhaled β-adrenergic agonists. The goal of this study was to evaluate the safety and efficacy of intravenous bedoradrine (MN-221), a highly selective β2-adrenergic agonist, as adjunct to standard therapy in the management of patients with acute exacerbation of asthma who did not respond to standard therapy. MethodsPatients (N = 167) received standard therapy and were randomized to either bedoradrine (1200 μg) or placebo. Safety and efficacy parameters were monitored hourly for 3 h, followed by a 24-h follow-up visit and an 8-day follow-up phone call. Change in %FEV1 from baseline to Hour 3 was the primary outcome. Secondary outcome measures included change in %FEV1 at 1 and 2 h, change in dyspnea score at 1, 2, and 3 h, treatment failure rate, defined as a combination of hospitalization on the index visit or return to the emergency department within 1 week, and safety monitoring. ResultsThere was no significant difference in %FEV1 at 3 h between the 2 groups. The dyspnea scores were significantly improved for patients treated with bedoradrine compared to placebo (AUC0–2 hP < 0.005, AUC0–3 hP < 0.05). The safety profile for those treated with bedoradrine was consistent with the known mechanism of action of β-adrenergic agonists, and included both cardiovascular and metabolic effects. ConclusionsIntravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores. Trial registrationClinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov

Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac

It has been demonstrated that connexin 43 (Cx43) and microRNAs have significant roles in glioma. Cyclic adenosine monophosphate (cAMP) is suggested to be a regulator of connexins and microRNAs. However, it remains elusive whether cAMP and exchange protein directly activated by cAMP (Epac2), have a regulatory effect on Cx43 and microRNA-451 (miR-451) in astrocytoma cells. We treated 1321N1 astrocytoma cells with a selective β2 adrenergic agonist and a selective Epac activator with and without adenyl cyclase and protein kinase A inhibition. Cx43 and miR-451 expression were measured. Next, we evaluated the effect of miR-451 overexpression on Cx43 expression. Cell proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that cAMP-Epac2 increased Cx43 and miR-451 expression. However, the alteration of miR-451 expression required a higher dose of drugs. Overexpression of miR-451 had no significant effect on Cx43 expression. The MTT assay showed that cAMP-Epac stimulation and miR-451 overexpression had a synergic inhibitory effect on cell proliferation. These findings may expand our understanding of the molecular biology of glioma and provide new potential therapeutic targets.

Clenbuterol suppresses proteasomal and lysosomal proteolysis and atrophy-related genes in denervated rat soleus muscles independently of Akt

Although it is well known that administration of the selective β(2)-adrenergic agonist clenbuterol (CB) protects muscle following denervation (DEN), the underlying molecular mechanism remains unclear. We report that in vivo treatment with CB (3 mg/kg sc) for 3 days induces antiproteolytic effects in normal and denervated rat soleus muscle via distinct mechanisms. In normal soleus muscle, CB treatment stimulates protein synthesis, inhibits Ca(2+)-dependent proteolysis, and increases the levels of calpastatin protein. On the other hand, the administration of CB to DEN rats ameliorates the loss of muscle mass, enhances the rate of protein synthesis, attenuates hyperactivation of proteasomal and lysosomal proteolysis, and suppresses the transcription of the lysosomal protease cathepsin L and of atrogin-1/MAFbx and MuRF1, two ubiquitin (Ub) ligases involved in muscle atrophy. These effects were not associated with alterations in either IGF-I content or Akt phosphorylation levels. In isolated muscles, CB (10(-6) M) treatment significantly attenuated DEN-induced overall proteolysis and upregulation in the mRNA levels of the Ub ligases. Similar responses were observed in denervated muscles exposed to 6-BNZ-cAMP (500 μM), a PKA activator. The in vitro addition of triciribine (10 μM), a selective Akt inhibitor, did not block the inhibitory effects of CB on proteolysis and Ub ligase mRNA levels. These data indicate that short-term treatment with CB mitigates DEN-induced atrophy of the soleus muscle through the stimulation of protein synthesis, downregulation of cathepsin L and Ub ligases, and consequent inhibition of lysosomal and proteasomal activities and that these effects are independent of Akt and possibly mediated by the cAMP/PKA signaling pathway.

Vibrational spectroscopic study of salbutamol hemisulphate

Salbutamol hemisulphate is a relatively selective beta(2)-adrenergic agonist and is used as a bronchodilator. In this work, we present a detailed vibrational spectroscopic investigation of salbutamol hemisulphate using mid-infrared and near-infrared Fourier-transform (NIR-FT) Raman spectroscopies. These data are supported by quantum chemical calculations, which allow us to characterise the vibrational spectra of this compound reasonably. As such, this study could be viable for examining the way in which this drug interacts with its target molecules.

Beta1-Adrenergic Agonist Is a Potent Stimulator of Alveolar Fluid Clearance in Hyperoxic Rat Lungs

Because it was still uncertain whether a stimulation of β1-adrenoceptors accelerated alveolar fluid clearance in hyperoxic lung injury, the effect of denopamine, a selective β1-adrenergic agonist, on alveolar fluid clearance was determined in rats exposed to 93% oxygen for 48 and 56 h. Alveolar fluid clearance was measured by the progressive increase in the concentration of Evans blue labeled albumin instilled into the alveolar spaces over 1 h at 37°C in isolated rat lungs. The principle results were as follows: 1) Although lung water volume increased in rats exposed to hyperoxia for 48 and 56 h, basal alveolar fluid clearance did not change for up to 56 h; 2) Denopamine increased alveolar fluid clearance in rats exposed to hyperoxia as well as in rats without exposure to hyperoxia; 3) Denopamine primarily increased amiloride-insensitive alveolar fluid clearance in rats exposed to hyperoxia; 4) The potency of denopmaine was similar to that of terbutaline, a selective β2-adrenergic agonist. In summary, denopamine is a potent stimulator of alveolar fluid clearance in rats exposed to hyperoxia.

Efficacy of Salmeterol Xinafoate Powder in Children With ChronicPersistent Asthma

1. Weinstein SF, 2. Pearlman DS, 3. Bronsky EA, 4. et al. (1998) Ann Allergy Asthma Immunol. 81:51–58. [OpenUrl][1][PubMed][2][Web of Science][3] #### Purpose Salmeterol xinafoate is a long-acting, highly selective β2-adrenergic agonist providing bronchodilatation for a median duration of 12 hours and protecting against a variety of bronchoconstrictory stimuli for a similar time interval. Salmeterol is available as an aerosol and a dry powder inhaler approved down to the age of 4 years. Because younger children have difficulty in properly using a metered dose inhaler, a powder inhaler, which is breath-activated, would be an advantage particularly in this population. The purpose of this study was to evaluate the efficacy and safety of salmeterol powder versus placebo in children 4 to 11 years of age with chronic, persistent asthma. ##### Population Male and female patients ages 4 to 11 years with asthma as defined by American Thoracic … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2Ballergy%252C%2Basthma%2B%2526%2Bimmunology%2B%253A%2B%2Bofficial%2Bpublication%2Bof%2Bthe%2BAmerican%2BCollege%2Bof%2BAllergy%252C%2BAsthma%252C%2B%2526%2BImmunology%26rft.stitle%253DAnn%2BAllergy%2BAsthma%2BImmunol%26rft.aulast%253DWeinstein%26rft.auinit1%253DS.%2BF.%26rft.volume%253D81%26rft.issue%253D1%26rft.spage%253D51%26rft.epage%253D58%26rft.atitle%253DEfficacy%2Bof%2Bsalmeterol%2Bxinafoate%2Bpowder%2Bin%2Bchildren%2Bwith%2Bchronic%2Bpersistent%2Basthma.%26rft_id%253Dinfo%253Apmid%252F9690573%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=9690573&link_type=MED&atom=%2Fpediatrics%2F104%2FSupplement_2%2F383.atom [3]: /lookup/external-ref?access_num=000075016700006&link_type=ISI

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Response of failing canine and human heart cells to beta 2-adrenergic stimulation.

Failing human hearts lose beta 1- but not beta 2-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of beta 2- to beta 1-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to beta 2-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional beta 2-adrenergic receptors. Myocytes from healthy dogs, dogs with tachypacing failure, and human transplant recipients were loaded with fura 2-AM and subjected to electric field stimulation in the presence of zinterol, a highly selective beta 2-adrenergic agonist. Zinterol significantly increased [Ca2+]i transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to beta 2-adrenergic stimulation. We also measured isotonic twitches, indo-1 fluorescence transients, and L-type Ca2+ currents in healthy canine myocytes. Zinterol (10(-5) mol/L) elicited large increases in the amplitudes of simultaneously recorded twitches and [Ca2+]i transients. Zinterol also increased L-type Ca2+ currents in the normal canine myocytes; this augmentation was abolished by 10(-7) mol/L ICI 118,551. cAMP production by suspensions of healthy and failing canine myocytes was not increased by zinterol (10(-9) to 10(-5) mol/L), nor did 10(-5) mol/L zinterol elicit phospholamban phosphorylation. Failing human ventricular cardiomyocytes contain functional beta 2-adrenergic receptors. Canine myocytes also contain functional beta 2-adrenergic receptors. The canine ventricular response to beta 2-agonists is increased in tachypacing failure. Positive inotropic responses to beta 2-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.

Differential effects of β-adrenergic agonists on insulin secretion from pancreatic islets isolated from rat and man

The selective beta 2-adrenergic agonist clenbuterol was ineffective as a stimulus for insulin secretion when isolated rat pancreatic islets were incubated with glucose at concentrations between 4 and 20 mM. Inclusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine led to potentiation of glucose-induced insulin secretion, but did not facilitate stimulation by clenbuterol. Furthermore, maintenance of isolated rat islets for up to 3 days in tissue culture also failed to result in the appearance of a secretory response to beta-agonists. By contrast, clenbuterol induced a dose-dependent increase in insulin release from isolated human islets incubated with 20 mM glucose. Clenbuterol did not increase the basal rate of insulin secretion (4 mM glucose) in human islets. Under perifusion conditions, the secretory response of human islets to clenbuterol was rapid, of similar magnitude to that seen under static incubation conditions and could be sustained for at least 30 min. The increase in insulin secretion induced by clenbuterol was inhibited by propranolol, indicating that the response was mediated by activation of beta-receptors. In support of this, a similar enhancement of glucose-induced insulin secretion was elicited by a different beta 2-agonist, salbutamol, in human islets. The results indicate that the B cells of isolated rat islets are unresponsive to beta-agonists, whereas those of human islets are equipped with functional beta-receptors which can directly influence the rate of insulin secretion.