Beta3-adrenoreceptor Agonist Research Articles

Therapeutic Potential for Beta-3 Adrenoreceptor Agonists in Peripheral Arterial Disease and Diabetic Foot Ulcers.

Annually, peripheral arterial disease is estimated to cost over USD 21 billion and diabetic foot disease an estimated at USD 9-13 billion. Mirabegron is a TGA-approved beta-3 adrenoreceptor agonist, shown to be safe and effective in the treatment of overactive bladder syndrome by stimulating bladder smooth muscle relaxation. In this review, we discuss the potential use of beta-3 adrenoreceptor agonists as therapeutic agents repurposed for peripheral arterial disease and diabetic foot ulcers. The development of both conditions is underpinned by the upregulation of oxidative stress pathways and consequential inflammation and hypoxia. In oxidative stress, there is an imbalance of reactive oxygen species and nitric oxide. Endothelial nitric oxide synthase becomes uncoupled in disease states, producing superoxide and worsening oxidative stress. Agonist stimulation of the beta-3 adrenoreceptor recouples and activates endothelial nitric oxide synthase, increasing the production of nitric oxide. This reduces circulating reactive oxygen species, thus decreasing redox modification and dysregulation of cellular proteins, causing downstream smooth muscle relaxation, improved endothelial function and increased angiogenesis. These mechanisms lead to endothelial repair in peripheral arterial disease and an enhanced perfusion in hypoxic tissue, which will likely improve the healing of chronic ulcers.

Percutaneous Tibial Nerve Stimulation in the Treatment of Refractory Idiopathic Overactive Bladder Syndrome: A Retrospective Cohort Study.

Overactive bladder (OAB) is a syndrome defined as urinary urgency, accompanied by increased frequency and nocturia with or without urge incontinence, in the absence of urinary tract infection or other obvious pathology. The standard therapies are anticholinergic agents, selective beta-3 adrenoreceptor agonists, or intradetrusor injections of botulinum toxin (BTX-A). For patients with contraindications for BTX-A or drug therapies, percutaneous tibial nerve stimulation (PTNS) may be used. PTNS shows fewer side effects than anticholinergic drugs and costs less than BTX-A. The primary outcome of this study was to assess the efficacy of PTNS in women with refractory OAB. Women with refractory OAB undergoing PTNS at our tertiary referral center from 2017 to 2019 were included. The validated German Female Pelvic Floor Questionnaire and a micturition protocol were filled out before and after PTNS. PTNS was applied weekly for 12 weeks. Improvements in OAB symptoms were seen in daily micturition frequency, urgency, and urgency incontinence from pre- to post-PTNS (p < 0.006). Impairments to quality of daily life were significantly (p < 0.0002) less severe after PTNS. There was a significant reduction in daytime voiding frequency from a median of nine to five (p < 0.0001). Substantial reductions in OAB symptoms, daily micturition frequency, urgency, and urgency incontinence were found in patients with refractory OAB after PTNS.

1681-P: RNA Binding Protein HuR Is Essential for Adaptive Thermogenesis

Brown adipose tissue (BAT) plays a key role in the regulated production of heat in response to cold temperatures, known as adaptive thermogenesis. While the transcriptional mechanisms underlying the thermogenic function of BAT has been widely studied, the role of posttranscriptional processes in BAT thermogenesis remain largely unexplored. RNA binding proteins are central to the control multiple aspects of posttranscriptional RNA biology. Here, we identify brown fat HuR as a critical regulator of adaptive thermogenesis. Mice with adipocyte-specific HuR deletion (AKO) were unable to increase energy expenditure in response to a cold challenge, resulting in marked hypothermia. HuR AKO mice housed at thermoneutrality also failed to increase energy expenditure upon beta-3 adrenoreceptor agonist treatment, indicating a defect in thermogenic BAT. HuR-deleted brown adipocytes displayed impaired mitochondrial respiration under β-adrenergic stimulation. RNA sequencing data revealed that loss of HuR led to downregulation of genes associated with TCA cycle, β-oxidation, and mTORC1 signaling in BAT. Our findings reveal an essential role for RNA binding protein HuR in thermogenic programs of the brown adipocyte and highlight the importance of posttranscriptional processes in BAT thermogenesis. Disclosure K.Park: None. S.Choi: None. J.Suh: None.

Effect of Pharmacotherapy for Overactive Bladder on the Incidence of and Factors Related to Urinary Tract Infection: A Systematic Review and Meta-analysis.

The aim of this meta-analysis was to investigate the effect of pharmacotherapy for overactive bladder on the pathogenesis of urinary tract infection. A comprehensive search was performed in MEDLINE and the Cochrane Library using terms for overactive bladder, antimuscarinic agents, and beta 3-adrenoceptor agonists. The primary end point was the emergence of urinary tract infection after pharmacotherapy for overactive bladder. The secondary end point was the emergence of urinary retention, dysuria, and/or increased residual urine volume after overactive bladder treatment. Meta-analyses were conducted using random-effects models. A total of 35,939 patients in 33 trials (29 trials of antimuscarinic agents vs placebo, and 9 trials of beta 3-adrenoceptor agonists vs placebo) that included patients with overactive bladder were identified. At 1-3 months after treatment, the incidence of urinary tract infections was statistically significantly higher in the patients treated with antimuscarinic agents (RR: 1.23, 95% CI: 1.04, 1.45; P = .013) than in the placebo control group. The incidence of urinary tract infections was not increased in the patients treated with beta 3-adrenoceptor agonists (RR: 1.04, 95% CI: 0.76, 1.42; P = .796). Antimuscarinic agents also statistically significantly increased the risks of urinary retention, dysuria, and/or increased residual urine volume (RR: 2.88, 95% CI: 1.79, 4.63; P < .001), whereas beta 3-adrenoceptor agonists did not (RR: 1.26, 95% CI: 0.38, 4.14; P = .708). This meta-analysis showed that antimuscarinic agents statistically significantly increased the incidences of urinary tract infection and lower urinary tract symptoms and dysfunction, but beta 3-adrenoceptor agonists did not. To prevent urinary tract infection emergence, beta 3-adrenoceptor agonists might be safer than antimuscarinic agents.

Yearly Trends of Overactive Bladder Medication Usage.

Anticholinergics are associated with cognitive side effects and dementia. Agents such as trospium, fesoterodine and darifenacin have been shown to be less likely to cross the blood-brain barrier. Furthermore, in 2012, mirabegron was approved by the U.S. Food and Drug Administration as the first beta-3 adrenoreceptor agonist to treat overactive bladder (OAB). This study aims to examine prescribing patterns of OAB medications in the United States over time. The 2013-2017 Medicare Part D Public Use File was used to identify prescribers of OAB medications including oxybutynin, tolterodine, trospium, darifenacin, solifenacin, fesoterodine and mirabegron. The number of claims and total annual expenditure for each medication for all prescribers, nonurologists and urologists were analyzed from 2013 to 2017. Oxybutynin was consistently the most prescribed OAB medication each year, comprising 53.9% of all OAB medication prescriptions in 2017. From 2013 to 2017, mirabegron claims increased from 140,401 to 1,617,439, making it the second most prescribed OAB medication. Solifenacin usage decreased each year. Trospium, darifenacin and fesoterodine were the least prescribed agents each year. These trends were similar for those ≥65 years old. Total annual expenditure for mirabegron increased yearly, and it had the highest total expenditure of OAB medications, with $658.6 million in 2017. Oxybutynin was consistently the most prescribed OAB medication every year. Mirabegron utilization steadily increased each year. Anticholinergic medications associated with fewer cognitive adverse effects, such as trospium, darifenacin and fesoterodine, were among the least prescribed.

Urodynamic effectiveness of a beta-3 adrenoreceptor agonist (vibegron) for a pediatric patient with anticholinergic-resistant neurogenic detrusor overactivity: a case report

BackgroundMyelomeningocele, which causes a neurogenic bladder, is usually treated with anticholinergics in children with neurogenic detrusor overactivity (NDO); however, anticholinergics cause side effects such as dry mouth, constipation, attention deficit, and inadequate reduction in detrusor leak point pressure. Vibegron, a novel selective beta-3 adrenoreceptor agonist, is a well-established alternative to anticholinergics in adults with an overactive bladder. It remains unknown whether this agent can be used for pediatric patients. We report the case of a girl with anticholinergic-resistant NDO due to tethered cord syndrome after myelomeningocele repair, who was treated with vibegron.Case presentationA 4-year-old Filipino girl had increased frequency of daytime urinary incontinence and foul-smelling urine since the age of 3. Clinical examination revealed constipation, and urinalysis revealed bacteriuria. Voiding cystourethrography revealed an enlarged and trabeculated bladder without vesicoureteral reflux. On the urodynamic study (UDS), she was found to have detrusor overactivity (DO) and low bladder compliance. She could not void and was diagnosed with overflow incontinence. Clean intermittent catheterization (CIC) and orally administered propiverine (0.8 mg/kg/day) were initiated, and urinary incontinence was resolved. She underwent a UDS annually; the UDS at 6 years of age still revealed DO and low bladder compliance in spite of receiving propiverine. The treatment was switched from propiverine to vibegron (1.4 mg/kg/day). On the UDS after a 5-week treatment schedule of vibegron, the DO disappeared and the bladder compliance improved. CIC and orally administered vibegron have been continued for 7 months so far, and she has had no urinary tract infection with no drug-related adverse events.Conclusions Vibegron was effective and well tolerated in the treatment of a pediatric patient with NDO. Vibegron improved the urodynamic parameters for anticholinergic-resistant neurogenic bladder. This agent can be a beneficial and preferable alternative therapeutic agent to anticholinergics in patients with anticholinergic-resistant NDO.

Current role of treatment in men with lower urinary tract symptoms combined with overactive bladder.

Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in older men. The storage subcategory of LUTS is synonymous with overactive bladder (OAB) syndrome, which is an empirical diagnosis. Traditionally, alpha-blockers are widely prescribed to manage the LUTS of BPH, although storage symptoms may persist in many men despite treatment. Therefore, because therapies that target the prostate often fail to alleviate storage symptoms, they may not be the appropriate therapy for OAB. In past years, most physicians appeared to give more weight in elderly men to voiding symptoms than to storage symptoms and to be more concerned with initial treatment with anticholinergics for males with storage symptoms. Considering the recent increase in data on the efficacy and safety of combination treatment with alpha receptor antagonists and antimuscarinic agents, the standard pharmacologic treatment of patients with LUTS combined with OAB should be an alpha receptor antagonist and an antimuscarinic agent. Beta-3 adrenoreceptor agonists may also potentially be useful for the treatment of male LUTS combined with OAB.

Mirabegron - a selective β3-adrenoreceptor agonist for the treatment of overactive bladder.

Overactive bladder is a common condition that significantly impacts overall quality of life. Antimuscarinics are the current main pharmacological option for treatment; however, many patients fail to adhere to therapy due to troublesome side effects. Mirabegron is a new beta-3 adrenoreceptor agonist which causes detrusor smooth muscle relaxation and has been proposed to be effective for treating overactive bladder symptoms. Mirabegron has been shown to be superior to placebo for reducing the mean number of incontinence episodes per 24 hours and the mean number of micturitions per 24 hours. Side effects such as dry mouth were observed at similar or lower rates than those seen for placebo and antimuscarinics. Higher doses of mirabegron were associated with minor increases in pulse rate and mean blood pressure. Mirabegron offers a new alternative for treating overactive bladder in patients for which antimuscarinics are either not tolerated or not appropriate.

Chronic CNS administration of Agouti-related protein (Agrp) reduces energy expenditure.

To investigate whether the Agouti-related protein (Agrp), the melanocortin receptor antagonist, alters oxygen consumption, as a measure of energy expenditure. A 7-day intracerebroventricular administration of Agrp (1 nmol/day) in rats. Oxygen consumption was determined in closed-circuit respirometers on days 1 and 8. BRL-35135, a beta3-adrenoreceptor agonist known to activate the brown adipose tissue (BAT) thermogenesis directly and increase core temperature, was administered i.p. (40 microg/kg) on day 9 to challenge functionally the BAT. Agrp treatment caused a 54% increase in daily food intake and a 12% increase in body weight. An 8% decrease in VO(2) measurements was observed following ICV Agrp treatment on day 1. A similar decrease (7%) was observed on day 8. BRL-35135 stimulated colonic temperature in control rats. However, in the rats that had previously been treated with Agrp this effect was significantly blunted. Chronic CNS administration of Agrp decreases oxygen consumption and decreases the capacity of BAT to expend energy. The obesity observed following CNS administration of Agrp is the result of decreased energy expenditure and increased food intake.

Nebivolol induces calcium-independent signaling in endothelial cells by a possible beta-adrenergic pathway.

Nebivolol is a highly selective beta1-adrenoreceptor-blocking agent with a peculiar pharmacodynamic profile. It has peripheral acute vasodilating properties that are mediated by modulation of the endogenous production of nitric oxide. In this study we analyzed the different signaling pathways implicated in the response of human umbilical vein endothelial cells to nebivolol. Its effect on endothelial transduction pathways was determined by assaying phospholipase C and A2 activities and cyclic adenosine monophosphate (AMP) production. Variations in intracellular calcium concentration were also measured. Our results showed that nebivolol activates a calcium-independent transduction pathway that implicates an increase in adenylate cyclase and phospholipase A2 activity. Beta1- or beta2-Adrenoreceptor antagonists do not inhibit the action of nebivolol. However, its action on cyclic AMP production is inhibited by bupranolol, a beta1-3-adrenoreceptor antagonist, and S-(-)-cyanopindolol, a selective beta3-adrenoreceptor antagonist. Nebivolol also dose-dependently increased nitrite production. This effect was inhibited by bupranolol, suggesting that the possible action of nebivolol on beta3-adrenoreceptor is involved in its vasodilating properties. This study suggests that nebivolol could behave as a beta3-adrenoreceptor agonist and induce some calcium-independent pathways implicating phospholipase A2 and adenylate cyclase. This agonistic activity of nebivolol seems to be responsible for its endothelium-dependent vasodilating activity.

Beta-3 versus beta-2 adrenergic agonists and preterm labour: in vitro uterine relaxation effects

Objective 1. To investigate the effects of the selective beta-3 adrenoreceptor agonist, BRL 37344, on human pregnant myometrial contractility in vitro. 2. to compare these effects with those of the beta-2 adrenoreceptor agonist, ritodrine. Methods Isometric tension recording was performed under physiological conditions in isolated myometrial strips from biopsies obtained at elective caesarean section. Following pre-incubation with oxytocin (10 -9 M), the effects of cumulative additions of BRL 37344 or ritodrine (10 -8–10 -3.5 M) on myometrial contractility were investigated. Results were expressed as -log EC 50 (pD 2) and mean maximal inhibition achieved for both drug compounds. Results BRL 37344 exerted a concentration dependant relaxant effect on myometrial contractions in all strips exposed [pD 2, 7.26 (0.48) (SEM); mean maximal inhibition 61.98 (4.89%); n= 6]. Similarly, ritodrine exerted a concentration dependant inhibition of myometrial contractility in all strips exposed [pD 2 = 7.40 (0.28); mean maximal inhibition 59.49 (3.97%); n = 6]. There was no significant difference between calculated pD 2 values ( P = 0.65) or mean maximal inhibition achieved ( P = 0.79). Conclusions The beta-3 adrenoreceptor agonist BRL 37344 induced relaxation of human myometrial contractions with similar potency to that of the most commonly used tocolytic agent ritodrine. This raises the possibility that the novel beta-3 adrenoreceptor agonists may have potential as therapeutic agents for human preterm labour. In view of their reported reduced cardiovascular side effects their potential clinical use requires further evaluation.

Management of irritable bowel syndrome: novel approaches to the pharmacology of gut motility.

Although it is unclear to what extent irritable bowel syndrome (IBS) symptoms represent a normal perception of abnormal function or an abnormal perception of normal function, many believe that IBS constitutes the clinical expression of an underlying motility disorder, affecting primarily the mid- and lower gut. Indeed, transit and contractile abnormalities have been demonstrated with sophisticated techniques in a subset of patients with IBS. As a consequence, drugs affecting gastrointestinal (GI) motility have been widely employed with the aim of correcting the major IBS manifestations, ie, pain and altered bowel function. Unfortunately, no single drug has proven to be effective in treating IBS symptom complex. In addition, the use of some medications has often been associated with unpleasant side effects. Therefore, the search for a truly effective and safe drug to control motility disturbances in IBS continues. Several classes of drugs look promising and are under evaluation. Among the motor-inhibiting drugs, gut selective muscarinic antagonists (such as zamifenacin and darifenacin), neurokinin2 antagonists (such as MEN-10627 and MEN-11420), beta3-adrenoreceptor agonists (eg, SR-58611A) and GI-selective calcium channel blockers (eg, pinaverium bromide and octylonium) are able to decrease painful contractile activity in the gut (antispasmodic effect), without significantly affecting other body functions. Novel mechanisms to stimulate GI motility and transit include blockade of cholecystokinin (CCK)A receptors and stimulation of motilin receptors. Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically. This drug accelerates gastric emptying and colonic transit, thereby increasing the number of bowel movements in patients with chronic constipation. It is also able to reduce visceral perception. Erythromycin and related 14-member macrolide compounds inhibit the binding of motilin to its receptors on GI smooth muscle and, therefore, act as motilin agonists. This antibiotic accelerates gastric emptying and shortens orocecal transit time. In the large bowel a significant decrease in transit is observed only in the right colon, which suggests a shift in fecal distribution. Several 'motilinomimetics' have been synthesized. Their development depends on the lack of antimicrobial activity and the absence of fading of the prokinetic effect during prolonged administration. 5-hydroxytryptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are available for human use. These 'enterokinetic' compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that may make them suitable for treatment of IBS. Besides decreasing colonic sensitivity to distension, these drugs prolong intestinal transit and may be particularly useful in diarrhea-predominant IBS. Finally, when administered in small pulsed doses, octreotide, besides reducing the perception of rectal distension, accelerates intestinal transit, although other evidence disputes such an effect.

Characterization of a Novel Iodocyanopindolol and SM-11044 Binding Protein, Which May Mediate Relaxation of Depolarized Rat Colon Tonus

Studies under blockade of alpha-, beta1-, and beta2-adrenoreceptors revealed a good correlation between the responses of rat colon relaxation of depolarized tonus and of rat adipocyte lipolysis elicited by catecholamines or BRL-37344, a selective beta3-adrenoreceptor agonist, suggesting beta3-adrenoreceptor stimulation. In contrast, SM-11044, a nonselective beta-adrenoreceptor agonist, stimulated colon relaxation more efficiently than lipolysis; its effects were differently antagonized by cyanopindolol with pA2 values of 8.31 in colon and of 7.32 in adipocytes. Binding studies in rat colon smooth muscle membranes using [125I]iodocyanopindolol under blockade of adrenaline and serotonin receptors revealed the existence of a single class of sites (Kd = 11.0 nM, Bmax = 716.7 fmol/mg protein). The specific binding was saturable and reversible and was displaced by SM-11044 but not by BRL-37344, isoproterenol, noradrenaline, adrenaline, serotonin, nor dopamine. This binding site was photoaffinity labeled using [125I]iodocyanopindolol-diazirine. The labeling was prevented by SM-11044 but not by BRL-37344. The amino-terminal amino acid sequences of the high performance liquid chromatography-purified peptides generated by enzymatic and chemical cleavages of the affinity labeled 34-kDa protein confirmed that the novel iodocyanopindolol or SM-11044 binding protein of rat colon smooth muscle membranes is different from known adrenaline, serotonin, or dopamine receptors. Its functional role might include the relaxation of depolarized colon.

Essential cis-Acting Elements in Rat Uncoupling Protein Gene Are in an Enhancer Containing a Complex Retinoic Acid Response Domain

Transgenic mice were generated with a transgene containing the 211-base pair (bp) enhancer and 0.4 kilobase pairs of 5'-flanking DNA of the uncoupling protein (ucp) gene. Expression of this transgene was restricted to brown adipose tissue and was inducible by cold exposure or treatment of transgenic mice by norepinephrine, retinoic acid (RA), or CL-316,243 beta3-adrenoreceptor agonist. A search for retinoic acid response elements in the ucp gene enhancer was undertaken using mutagenesis and transfection of cultured cells with chloramphenicol acetyltransferase constructs. Deletion or mutations of several putative retinoic acid response elements were ineffective. Mutations of a TGAATCA region dramatically decreased the transcriptional activity in the presence of RA. In vitro this region was able to bind a complex containing proteins recognized by antibodies against Jun or Fos. Mutations of an adjacent region related to an inverted repeat of type 2 also markedly decreased RA effect. This region was able to bind in vitro retinoid X receptor alpha and retinoic acid receptor beta. The two regions form an activating region between bp -2421 and -2402 (referred to as the ucp gene-activating region), which has an enhancer activity but cannot confer RA response to a promoter. This response was obtained with a larger DNA fragment (bp -2489 to -2398) constituting a complex RA response domain.