Does nebivolol have renoprotective action in patients with chronic kidney disease conditions? An integrative review.

Systemic arterial hypertension (SAH) is a chronic disease of multifactorial origin and one of the main risk factors for major adverse cardiovascular events (MACE), which are the leading causes of morbidity and mortality worldwide. The pharmacological treatment of SAH involves five main classes of drugs, and Nebivolol (NEB) is one of those drugs, belonging to the class of third generation ß1-adrenoceptors selective blockers. NEB is composed of a racemic mixture of two enantiomers: d-nebivolol, which exerts antagonist effects on ß1-adrenoceptors, and l-nebivolol, a vascular ß3 receptor agonist. There are several studies that report different actions of NEB, not only for the treatment of SAH, but also as an antioxidant agent or even as a protector of renal damage. The aim of this systematic review was to investigate the available evidence regarding the effects of NEB on kidney diseases, evaluating its possible renoprotective action.

ß3-Adrenoreceptors as ROS Balancer in Hematopoietic Stem Cell Transplantation.

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of ß3-adrenoreceptors (ß3-ARs) in regulating HSCs redox homeostasis. ß3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that ß3-ARs agonism and antagonism could be exploited for clinical benefit.

Contemporary use of prescription medications for neurogenic lower urinary tract dysfunction.

OBJECTIVES: First-line treatment for patients with neurogenic detrusor overactivity (NDO) is anticholinergic or beta-3 agonist medication. The addition of a secondary medication in patients with NDO may avoid progression to third- and fourth-line therapies. We aim to identify patterns of medication use for patients with neurogenic lower urinary tract dysfunction (NLUTD) using a national database. METHODS: The National Ambulatory Medical Care Survey (NAMCS) database was queried for a sample of ambulatory patient visits from 2003 to 2015. Outpatient visits were included for all patients aged 18 years or older diagnosed with NLUTD. Dual therapy was defined as prescription of two anticholinergics or one anticholinergic + beta-3 agonist on the same visit. Visits in which medications were prescribed were analyzed with descriptive statistics. RESULTS: Out of a weighted sample of 5 391 680 patient visits with a primary diagnosis of NLUTD, 1 602 705 (30%) were prescribed medical therapy. Of included patients prescribed NDO medications, the majority were white (80%), located in the Northeast (71%), and of a mean age of 51 ± 3. Of these patients, at least 93% of patients were prescribed anticholinergics, and 37% were prescribed dual therapy. Patients 65 years and older were more likely to initiate a new NDO medication at their visit (43%) than patients under 65 (7%). CONCLUSIONS: This is the first study to analyze the use of medical therapy for NLUTD in a large outpatient setting. Further prospective evaluation of patient satisfaction and efficacy of both single anticholinergic medication and dual therapy is needed.

ß3-Adrenergic receptor blockade reduces mortality in endotoxin-induced heart failure by suppressing induced nitric oxide synthase and saving cardiac metabolism.

The ß3-adrenergic receptor (ß3AR) is related to myocardial fatty acid metabolism and its expression has been implicated in heart failure. In this study, we investigated the role of ß3AR in sepsis-related myocardial dysfunction using lipopolysaccharide (LPS)-induced endotoxemia as a model of cardiac dysfunction. We placed mice into three treatment groups and treated each with intraperitoneal injections of the ß3AR agonist CL316243 (CL group), the ß3AR antagonist SR59230A (SR group), or normal saline (NS group). Survival rates were significantly improved in the SR group compared with the other treatment groups. Echocardiography analyses revealed cardiac dysfunction within 6-12 h of LPS injections, but the outcome was significantly better for the SR group. Myocardial ATP was preserved in the SR group but was decreased in the CL-treated mice. Additionally, quantitative PCR analysis revealed that expression levels of genes associated with fatty acid oxidation and glucose metabolism were significantly higher in the SR group. Furthermore, the expression levels of mitochondrial membrane protein complexes were preserved in the SR group. Electron microscope studies showed significant accumulation of lipid droplets in the CL group. Moreover, inducible nitric oxide synthase (iNOS) protein expression and nitric oxide were significantly reduced in the SR group. The in vitro study demonstrated that ß3AR has an independent iNOS pathway that does not go through the nuclear factor-κB pathway. These results suggest that blockading ß3AR improves impaired energy metabolism in myocardial tissues by suppressing iNOS expression and recovers cardiac function in animals with endotoxin-induced heart failure.NEW & NOTEWORTHY Nitric oxide production through stimulation of ß3-adrenergic receptor (ß3AR) may improve cardiac function in cases of chronic heart failure. We demonstrated that the blockade of ß3AR improved mortality and cardiac function in endotoxin-induced heart failure. We also determined that LPS-induced inducible nitric oxide synthase has a pathway that is independent of nuclear factor-κB, which worsened cardiac metabolism and mortality in the acute phase of sepsis. Treatment with the ß3AR antagonist had a favorable effect. Thus, the blockade of ß3AR could offer a novel treatment for sepsis-related heart failure.

Beta-3 adrenoceptors: A potential therapeutic target for heart disease.

As heart failure (HF) is a growing public health problem worldwide, rapid therapeutic development is required to improve HF management. Decreased myocardial contractility in HF is associated with the persistent sympathetic activation of ß1/ß2-adrenoceptors (ß1/ß2-ARs). Although it is initially activated to compensate for a decline in myocardial contractility, it plays a pivotal role in organ damage and functional deterioration over time, resulting in the desensitization of receptors involved. The third ß-AR subtype, ß3-AR, is resistant to desensitization, and as a result, the expression of this subtype is enhanced in human failing myocardium. In addition, this upregulation and the stimulation of this subtype have been demonstrated to mediate cardioprotective effects such as antihypertrophic, antioxidant and antifibrotic effects via various signaling pathways in different cell types. However, the role of this attractive therapeutic intervention in heart diseases must be clarified through clinical trials.

The Relative Efficacy and Safety of Mirabegron and OnabotulinumtoxinA in Patients With Overactive Bladder who Have Previously Been Managed With an Antimuscarinic: A Network Meta-analysis.

OBJECTIVE: To compare the efficacy and safety of mirabegron and onabotulinumtoxinA in the management of treatment-experienced patients with overactive bladder. METHODS: The network meta-analysis was based on evidence from a systematic literature review of randomized controlled trials and a post-hoc analysis of treatment-experienced subpopulations from mirabegron studies. RESULTS: Nineteen trials described in 21 publications were included. CONCLUSION: Overall, compared to mirabegron, there was some evidence that onabotulinumtoxinA was associated with improved outcomes, including reductions in the number of micturitions in a 24-hour period, and the number of incontinence episodes. However, mirabegron was associated with a lower risk of urinary tract infections compared with onabotulinumtoxinA.

ß-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do ß3-Adrenoceptors Play a Role?

Infantile hemangiomas (IH) are frequent (4-5% of the childhood population) benign vascular tumors that involve accumulation, proliferation, and differentiation of aberrant vascular cells. Typically, IH are innocuous and spontaneously disappear, but they represent a potential risk for harmful effects in the body (e.g., permanent disfigurement) and health (e.g., ulcerations) in some patients. From a serendipitous discovery, the nonselective ß-adrenoceptor blocker propranolol (which blocks ß1-adrenoceptors, ß2-adrenoceptors, and ß3-adrenoceptors) emerged as an alternative therapy to treat this pathology and it quickly became a first-line treatment for IH. Nevertheless, its specific mechanisms of action remain thus far unknown. In this respect, several studies have suggested that ß1-adrenoceptors and ß2-adrenoceptors play a role in proliferative and angiogenic mechanisms. However, current basic research studies suggest that ß3-adrenoceptors could be also involved. Notably, ß3-adrenoceptors stimulate multiple intracellular pathways related to vascular function (e.g., blood flow, angiogenesis, etc.). This review compiles some lines of evidence suggesting that ß3-adrenoceptors may: (1) play a role in the pathophysiology of IH and (2) represent a potential therapeutic target for IH treatment. Hence, clinical evidence is mandatory to decide whether incorporation of ß3-adrenoceptor blockers into the therapeutic armamentarium may increase effectiveness in the treatment of IH and other vascular anomalies.

Medical management of urinary incontinence in women.

Urinary incontinence is common, underreported, and undertreated. Primary care physicians should be comfortable discussing urinary incontinence with their female patients and managing it with conservative treatment.

Chronic Pelvic Ischemia: Contribution to the Pathogenesis of Lower Urinary Tract Symptoms (LUTS): A New Target for Pharmacological Treatment?

The incidence of lower urinary tract symptoms, including overactive bladder (OAB), is continuing to rise, and is associated with a negative impact on quality of life and a heavy economic burden. A major risk factor for OAB is advancing age. The etiology of OAB is multifactorial and appears to involve myogenic, neurogenic, and urotheliogenic factors. In this article, we review the strengthening preclinical evidence supporting the contribution of chronic pelvic ischemia to the pathogenesis of OAB. In animal models, chronic ischemia induced by arterial injury and a high-fat diet upregulates markers of oxidative stress and proinflammatory cytokines in the urothelium and lamina propria, and leads to increased expression of nerve growth factor. These processes result in increased afferent activity and an increased frequency of micturition, reflecting a state of bladder hyperactivity. In severe, prolonged cases, bladder overactivity may develop into underactivity. Antimuscarinic therapies are the mainstay of OAB treatment, but their usefulness is limited by modest efficacy and troublesome side-effects. Our increasing understanding of the contribution of chronic ischemia to OAB is leading toward novel therapeutic options targeting chronic pelvic ischemia and its morphological, functional, and oxidative consequences. Preclinical trials have demonstrated encouraging results with α1 -adrenoreceptor blockade, phosphodiesterase type 5 inhibition, ß3 -adrenoreceptor agonism, free radical scavenging, and stem cell therapy, in preventing morphological, biochemical and functional changes induced by chronic bladder ischemia.

[The new era in the pharmacological treatment of overactive bladder (OAB): mirabegron--a new selective beta3agonist]. / Nowa era w farmakologicznym leczeniu pecherza nadreaktywnego (OAB): mirabegron--selektywny agonista receptora beta3.

Overactive bladder is defined by ICS as urgency frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection, or other obvious causative pathology Lower urinary tract symptoms (LUTS) are highly prevalent, especially in aging populations. Epidemiological studies reported LUTS in 62% of men and 67% of women, rising to 81% and 79%, respectively in adults over 60 years old. However the actual burden of LUTS remains relatively unrecognized. LUTS, mainly due to considerable distress including almost all aspects of social functioning, impact on sleep and mental health, may significantly affect quality of life. Management of LUTS including OAB has undergone dramatic changes since 1972, when the first antimuscarinic drug-oxybutynin, was introduced into clinical practice. In the last two decades, six new antimuscarinic drugs entered OAB field and this was accompanied by introduction of botulinum toxin into clinical practice in patients resistant to or not compliant with antimuscarinics. Nowadays, it is recognized that OAB is progressive, age-related and non sex-specific condition with most patients experiencing a combination of storage, voiding and post-micturition symptoms. In 2013, the next step was taken, with new therapeutic options for OAB, enabling an even more patient-tailored approach. This was possible for both, male and female OAB sufferers with new class of oral 3 adrenoreceptor agonist (mirabegron). This drug, by stimulation of 3-adrenoceptors, couples via Gs proteins to adenylyl cyclase, what results in an increase of intracellular cAMP levels and a subsequent activation of cAMP-dependent protein kinase A, which then phosphorylates myosin light chain kinase responsible for inhibition of calcium-calmodulin dependent interaction of myosin with actin. Moreover the cAMP increase also leads to the reduction of cytoplasmic Ca2+ concentration by removal of calcium ions from cytoplasm. These both actions result in a significant increase in the storage bladder capacity and by this interval between micturitions is prolonged. Mirabegron was evaluated in three 12-week, double blind, randomized, placebo controlled, parallel-group, multicenter clinical trials in OAB patients with symptoms of urge urinary incontinence, urgency and frequency - study 046, 047 and 074. It should be pointed out that efficacy of mirabegron was maintained through the entire 12-month period in phase Ill long-term study Discoveries on the physiology of the normal bladder and on the pathophysiology underlying OAB have led to the development of new treatment options for OAB. Pharmacological management of OAB should be tailored to patient's characteristics. New and recent options of pharmacological treatment have undoubtedly expanded treatment possibilities, what should allow physicians to select the optimal treatment for each patient.

Safety and tolerability of the ß3 -adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III trial.

AIMS: To evaluate the safety and tolerability of the ß3 -adrenoceptor agonist, mirabegron, in patients with overactive bladder (OAB). METHODS: Tolerability and safety data from three 12-week, randomised, placebo-controlled, double-blind, Phase III trials (Studies 046, 047 and 074) were pooled by treatment group. The three studies were of a similar design, although the assessed doses of mirabegron [25, 50 or 100 mg once daily (qd)] varied, and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study 046 only. Tolerability and safety data from a 1-year, randomised, double-blind, Phase III trial (Study 049) are also presented. Safety variables included the incidence and severity of treatment-emergent adverse events (TEAEs), vital signs and electrocardiogram data. RESULTS: Mirabegron (25, 50 or 100 mg qd) was safe and well-tolerated in patients with OAB over 12-week (n = 2736) and 1-year (n = 1632) periods. The incidence of TEAEs and treatment discontinuations as a result of TEAEs was low; the majority were mild in severity and few were serious. Hypertension, nasopharyngitis and urinary tract infection were the most common TEAEs with mirabegron. The mirabegron tolerability profile was similar to that seen with placebo and tolterodine ER 4 mg, except for dry mouth, which occurred, on average, five times less frequently with mirabegron than tolterodine ER 4 mg. In the pooled 12-week analysis, mirabegron 50 mg was associated with placebo-adjusted mean increases of 0.4-0.6 mmHg in blood pressure and approximately one beat per minute in pulse rate, both reversible upon treatment discontinuation. The incidence of Major Adverse Cardiovascular Events as adjudicated by an independent cardiovascular committee was low and similar across treatment groups. CONCLUSION: The favourable tolerability profile of mirabegron in patients with OAB may allow improved treatment compliance compared with antimuscarinics, with important implications for patient outcomes.

ß3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of ß3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. ß3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac ß3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 µg/kg iv), a selective ß3-adrenergic receptor antagonist (ß3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after ß3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, ß3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.

Brown adipose tissue thermogenesis: ß3-adrenoreceptors as a potential target for the treatment of obesity in humans.

It has been shown in rodents and newborn babies that brown adipose tissue (BAT) plays an important role in the generation of heat for maintenance of core body temperature. BAT is responsible for the process of adaptive thermogenesis, which involves heat generation in response to a drop in the environment's temperature or to high energy intake from diet. In rodents, the process of BAT thermogenesis is controlled by activation of the ß3-adrenergic receptor (ß3-AR), which has a protective effect against development of obesity. Previously, it was generally thought that in humans, BAT dissipated after childhood and adopted an insignificant role in human physiology. However, over the past few years, it has been discovered that adult humans still possess fully functional BAT. Through imaging with F-fluorodeoxyglucose positron emission tomography-computed tomography scans, it has been determined that not only does human BAT exist, but also it is still responsive to stimuli, such as a drop in the environment's temperature. Although some evidence exists for ß3-AR control of BAT thermogenesis in humans, this fact remains unclear due to a lack of highly selective ß3-AR agonists and antagonists which have an effect on the human body. With further investigation on thermogenesis receptor control and effect of BAT metabolism on whole body energy expenditure, BAT may serve as a potential target for the treatment and prevention of obesity and other metabolic conditions in humans.

ß(3)-Adrenoceptor ligand development history through patent review.

INTRODUCTION: Stimulation of the ß(3)-adrenoceptor (ß(3)-AR) is thought to be a valuable approach for the treatment of obesity, type 2 diabetes, heart failure, frequent urination, preterm labor, anxiety and depression. Therefore, the ß(3)-AR is recognized as an attractive target for drug discovery. Simultaneous activation of the ß(1)- and ß(2)-AR can cause undesirable side effects such as increased heart rate and muscle tremors. Consequently, much effort has been directed towards the design and development of selective ß(3)-AR agonists through original synthetic chemistry, extensive in vitro tests and detailed preclinical investigations to various phases of clinical trials. AREAS COVERED: SciFinder Scholar, PubMed, ISI web of Knowledge(SM), Espacenet, ClinicalTrials and Google have been used as the main sources for retrieving literature and patents filed since the discovery of ß(3)-AR through to June 2010. This review discusses the enormous efforts made by private and public research laboratories to uncover ß(3)-AR ligands and to prove their usefulness as drugs. EXPERT OPINION: Remarkable knowledge has been gained about the physio-pathological role of the ß(3)-AR to date. Many highly potent and selective ß(3)-AR ligands (agonists, antagonists and inverse agonists) have been discovered; however, further investigations are still needed to identify novel compounds acting as ß(3)-AR ligands in order to adequately treat the diseases in which ß(3)-AR is involved.

ß(3)-Adrenoceptor agonists and (antagonists as) inverse agonists history, perspective, constitutive activity, and stereospecific binding.

ß(3)-Adrenergic receptor (ß(3)-AR) is expressed in several tissues and is considered a drug target for the treatment of several pathologies such as obesity, type 2 diabetes, cachexia, metabolic syndrome, heart failure, anxiety and depressive disorders, preterm labor, overactive bladder, control colon motility, and of coadjuvants in colon cancer therapy. It is a seven-transmembrane domain (7TD) G-protein coupled receptor and is usually coupled to a Gs-protein (Gi-protein in very few cases), and its stimulation increases the production of cAMP. A lot of ß(3)-AR agonists have been uncovered and extensively characterized. Conversely, very little is known about ß(3)-AR inverse agonists that would suppress the agonist-independent activity (constitutive activity) of the receptor by stabilizing it in its inactive state. This chapter attempts to outline (a) the importance of the ß(3)-AR as a therapeutic target through the disquisition of its role in human health (physiology) and disease (pathology); (b) the description of ß(3)-AR structure [amino acid sequence and 7TD organization]; (c) the medicinal chemistry of ß(3)-AR: 7TD amino acid-ligand specific interactions, ß-adrenoreceptor subtype selectivity, stereospecific interactions and biological activity relationships, inverse agonism and blockage of ß(3)-adrenoceptor constitutive activity; and (d) ß(3)-AR inverse agonists. The detailed procedure to prepare and assess the biological activity/selectivity of the more potent and selective ß(3)-AR inverse agonists (SP-1e and SP-1g) up to now known is also described.

Pharmacological evidence for the presence of functional beta(3)-adrenoceptors in rat retinal blood vessels.

The aim of this study was to examine whether stimulation of beta(3)-adrenoceptors dilates rat retinal blood vessels and how diabetes affects the vasodilator responses. Images of ocular fundus were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate (HR) were continuously recorded. The beta(3)-adrenoceptor agonist CL316243 (0.3-10 microg/kg/min, i.v.) increased diameter of retinal arterioles (at 10 microg/kg/min, a 31% increase) and decreased mean blood pressure (at 10 microg/kg/min, a 21% decrease) in a dose-dependent manner. CL316243 produced a small but significant increase in HR (at 10 microg/kg/min, a 9% increase). Both SR59230A (1 mg/kg, i.v.) and L-748337 (50 microg/kg, i.v.), beta(3)-adrenoceptor antagonists, significantly prevented CL316243-induced retinal vasodilator responses. Similar observations were made with another beta(3)-adrenoceptor agonist, BRL37344. The beta(2)-adrenoceptor agonist salbutamol also increased diameter of retinal arterioles (at 10 microg/kg/min, a 43% increase), whereas the drug produced greater decrease in blood pressure (at 10 microg/kg/min, a 46% decrease) and increase in HR (at 10 microg/kg/min, a 16% increase), compared with beta(3)-adrenoceptor agonists. The retinal vasodilator responses to CL316243 and BRL37344 observed under blockade of beta(1)/beta(2)-adrenoceptors with propranolol (2 mg/kg, i.v. bolus followed by 100 microg/kg/min infusion) were unaffected 2 weeks after induction of diabetes by the combination of streptozotocin treatment and D: -glucose feeding. On the other hand, the vasodilator responses to salbutamol of retinal arterioles were significantly reduced in diabetic rats. These results suggest that stimulation of beta(3)-adrenoceptors causes the vasodilation of retinal arterioles in vivo and the vasodilator responses are unaffected at the early stage of diabetes.