Safety and tolerability of ß-blockers: importance of cardioselectivity.

Cardioselective ß-blockade is generally well tolerated in practice and contraindications to this therapy are uncommon. ß-blockers are a diverse therapeutic class, and their individual tolerability profiles are influenced strongly by their pharmacodynamic effects across different adrenergic receptors. Bisoprolol, probably the ß-blocker with the highest selectivity for blockade of ß1- vs. ß2-adrenoceptors, does not block ß2-adrenoceptors to an appreciable extent at doses in therapeutic use. Side-effects often attributed to ß-blockers, such as erectile dysfunction and adverse metabolic effects are uncommon with bisoprolol and other ß-blockers used at doses which only block ß1-adrenoceptors. Cautious use of a cardioselective ß-blocker is not contraindicated in people with chronic obstructive pulmonary disease or asthma and the outcomes benefits of ß-blockers in patients with coronary heart disease or heart failure are also apparent in patients with concurrent COPD. Starting with a low dose and titrating upwards carefully is important for optimising the tolerability of a ß-blocker. Most people with hypertension will receive combination antihypertensive therapy in practice, and the low-dose combination therapy approach provides a useful strategy for optimising the efficacy and tolerability of a regimen that includes a ß-blocker, compared with up-titrating an existing monotherapy.

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α2A-adrenergic receptor.

BACKGROUND: The cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats. METHODS: We explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL. RESULTS: We found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H2O2-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α2A-AR. CONCLUSION: These results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through ß1 adrenergic receptor.

This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI-induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α-SMA). Combined with RNA-sequencing analysis and G protein-coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln-mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with ß1-adrenergic receptor (AR). Moreover, ß1-AR blocker treatment indeed extended the cardiac remodeling after PAGln-enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via ß1-AR.

Potential side effects of currently available pharmacotherapies in male lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

INTRODUCTION: The drug classes of α1-adrenoceptor antagonists, 5α-reductase inhibitors, and phosphodiesterase type 5 inhibitors are guideline-recommended treatments of lower urinary tract symptoms suggestive of benign prostatic hyperplasia; muscarinic receptor antagonists and ß3-adrenoceptor agonists are also recommended if storage symptoms are insufficiently addressed with one of the other three drug classes. AREAS COVERED: We provide a narrative review (no formalized literature searches performed) of the tolerability of these drug classes with emphasis on the more recently introduced medications, on combination treatment, and on more lately emerging risks. EXPERT OPINION/COMMENTARY: The tolerability profiles are distinct between drug classes but, with few exceptions, similar within a drug class. Within a drug, formulations with longer duration of action tend to have better tolerability. Efficacy gains using combination treatment at least partly come at a cost of lesser tolerability. Greater susceptibility to experience adverse events based on age, comorbidities, and comedications appears conceptually important but remains under-investigated in this therapeutic area.

Several classes of medicines are available to treat male lower urinary tract symptoms that are believed to result from an enlarged prostate. These include α₁-adrenoceptor antagonists (α-blockers), 5α-reductase inhibitors (ARI), and phosphodiesterase type 5 inhibitors (PDEI); muscarinic receptor antagonists and ß₃-adrenoceptor agonists are additionally used in men that have persisting storage symptoms upon treatment with the former three drug classes. Each drug class has a distinct tolerability profile. Within a drug class, medicines with a longer duration of action, either intrinsically or due to specific drug formulations, tend to have better tolerability. Men with greater age, comorbidities, and comedications may be at greater risk of experiencing side effects when medically treating their lower urinary tract symptoms. While combination of members of multiple drug classes may increase efficacy, this often comes at the price of experiencing more side effects. The relative benefit/risk ratio needs to be individually analyzed in each patient.

PHARMACOLOGY OF POST-TRAUMATIC STRESS DISORDER.

The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases PubMed, Ovid, EMBASE by keywords: "posttraumatic stress disorder", "treatment", and "medications". Search depth 2012-2022 years. From the general data (4877 articles) there were selected 14 articles with the highest degree of relevance. A content analysis of selected articles was carried out with the formation of recommendations for the use of pharmacotherapy in posttraumatic stress disorder. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Antidepressants (SSRI SNRIs) are primarily considered as first-line drugs, but only sertraline, paroxetine, and fluoxetine are approved by the FDA. But these drugs have a fairly wide range of side effects, including suicidal thoughts. The use of benzodiazepines should be limited as they increase the risk of developing posttraumatic stress disorder. Vortioxetine becomes a very promising option. The most significant benefits of vortioxetine are the significant positive effects of vortioxetine on attention, memory, and executive function. There is some evidence for the use of alpha-1 adrenoceptor antagonists and alpha-2 adrenoceptor agonists in therapy. In insomnia the use of prazosin and trazodone is recommended. Pharmacotherapy of posttraumatic stress disorder requires administration of medications with multimodal action. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Further randomized clinical trials are necessary for developing effective treatment of posttraumatic stress disorder.

Current optimal pharmacologic therapies for overactive bladder.

INTRODUCTION: Overactive bladder (OAB) is a common syndrome in adults. Current pharmacologic treatment includes antimuscarinic agents and ß-3 adrenoceptor agonists. For non-responders to oral medication, intravesical injection of botulinum toxin A (BoNT-A) is an effective option. However, these treatments have potential adverse events and should be cautiously selected for appropriate patients. This review presents the recently published results of clinical trials and studies for patients with OAB and the underlying pathophysiology of OAB. Appropriate medical therapy based on pathophysiology of OAB is also presented. AREAS COVERED: Literature search from Pubmed from 2001 to 2023 including clinical background, pharmacology, and clinical studies for OAB medications. EXPERT OPINION: Treatment of OAB syndrome with any antimuscarinic or ß-3 adrenoceptor agonist is feasible as a first-line approach. For patients with suboptimal therapeutic effect to full-dose antimuscarinics or mirabegron, combination with both drugs can improve efficacy. Intravesical BoNT-A 100-U injection provides therapeutic effects for refractory OAB. Patients who are refractory to initial pharmacotherapies should be investigated for the underlying pathophysiology; then an appropriate medication can be added, such as an α1-blocker or anti-inflammatory agents. Patient education about behavioral modification and therapies should always be provided with oral medication or BoNT-A injection for OAB patients.

Overactive bladder (OAB) causes urgency, frequency, and nocturia, and greatly impacts quality of life. Pharmacological treatment with antimuscarinics, beta-3 adrenoceptor agonists, or in combination can effective improve OAB symptoms. In cases of treatment failure, searching for underlying causes and switching to the other treatment modalities such as Botox injection are also feasible to relieve the bothersome bladder symptoms.

Effects of a new selective ß3 -adrenoceptor agonist, vibegron, on bladder and urethral function in a rat model of Parkinson's disease.

OBJECTIVES: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel ß3 -adrenoceptor agonist approved for the treatment of overactive bladder. However, how ß3 -adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease. METHODS: In a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity. RESULTS: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter-contraction interval (p < .05) and reduced voiding pressure (p < .01). However, no significant effects on urethral function were observed. CONCLUSIONS: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of ß3 -adrenoceptor agonists.

Role of DNA methylation during recovery from spinal cord injury with and without ß2-adrenergic receptor agonism.

Daily treatment with the FDA-approved ß2-adrenergic receptor agonist formoterol beginning 8 h after severe spinal cord injury (SCI) induces mitochondrial biogenesis and improves recovery in mice. We observed decreased DNA methyltransferase (DNMT) expression, global DNA methylation and methylation of the mitochondrial genes PGC-1α and NDUFS1 in the injury site of formoterol-treated mice 1 DPI, but this effect was lost by 7 DPI. To investigate the role of DNA methylation on recovery post-SCI, injured mice were treated daily with formoterol or vehicle, plus the DNMT inhibitor decitabine (DAC) on days 7-9. While DAC had no apparent effect on formoterol-induced recovery, mice treated with vehicle plus DAC exhibited increased BMS scores compared to vehicle alone beginning 15 DPI, reaching a degree of functional recovery similar to that of formoterol-treated mice by 21 DPI. Furthermore, DAC treatment increased injury site mitochondrial protein expression in vehicle-treated mice to levels comparable to that of formoterol-treated mice. The effect of DNMT inhibition on pain response with and without formoterol was assessed following moderate SCI. While all injured mice not treated with DAC displayed thermal hyperalgesia by 21 DPI, mice treated with formoterol exhibited decreased thermal hyperalgesia compared to vehicle-treated mice by 35 DPI. Injured mice treated with DAC, regardless of formoterol treatment, did not demonstrate thermal hyperalgesia at any time point assessed. Although these data do not suggest enhanced formoterol-induced recovery with DNMT inhibition, our findings indicate the importance of DNA methylation post-SCI and support both DNMT inhibition and formoterol as potential therapeutic avenues.

Alpha-1 Adrenergic Antagonists Sensitize Neuroblastoma to Therapeutic Differentiation.

Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using α1/α1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacologic target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease. SIGNIFICANCE: Targeting α-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse.

Orally administered sodium nitrite prevents the increased α-1 adrenergic vasoconstriction induced by hypertension and promotes the S-nitrosylation of calcium/calmodulin-dependent protein kinase II.

The unsatisfactory rates of adequate blood pressure control among patients receiving antihypertensive treatment calls for new therapeutic strategies to treat hypertension. Several studies have shown that oral sodium nitrite exerts significant antihypertensive effects, but the mechanisms underlying these effects remain unclear. While these mechanisms may involve nitrite-derived S-nitrosothiols, their implication in important alterations associated with hypertension, such as aberrant α1-adrenergic vasoconstriction, has not yet been investigated. Here, we examined the effects of oral nitrite treatment on vascular responses to the α1-adrenergic agonist phenylephrine in two-kidney, one clip (2K1C) hypertensive rats and investigated the potential underlying mechanisms. Our results show that treatment with oral sodium nitrite decreases blood pressure and prevents the increased α1-adrenergic vasoconstriction in 2K1C hypertensive rats. Interestingly, we found that these effects require vascular protein S-nitrosylation, and to investigate the specific S-nitrosylated proteins we performed an unbiased nitrosoproteomic analysis of vascular smooth muscle cells (VSMCs) treated with the nitrosylating compound S-nitrosoglutathione (GSNO). This analysis revealed that GSNO markedly increases the nitrosylation of calcium/calmodulin-dependent protein kinase II γ (CaMKIIγ), a multifunctional protein that mediates the α1-adrenergic receptor signaling. This result was associated with reduced α1-adrenergic receptor-mediated CaMKIIγ activity in VSMCs. We further tested the relevance of these findings in vivo and found that treatment with oral nitrite increases CaMKIIγ S-nitrosylation and blunts the increased CaMKIIγ activity induced by phenylephrine in rat aortas. Collectively, these results are consistent with the idea that oral sodium nitrite treatment increases vascular protein S-nitrosylation, including CaMKIIγ as a target, which may ultimately prevent the increased α1-adrenergic vasoconstriction induced by hypertension. These mechanisms may help to explain the antihypertensive effects of oral nitrite and hold potential implications in the therapy of hypertension and other cardiovascular diseases associated with abnormal α1-adrenergic vasoconstriction.

Analysis of Urinary Retention Caused by Selective ß 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER).

Overactive bladder (OAB) is a frequent chronic disorder which impairs quality of life by frequent, uncontrollable urination. Newly developed selectiveß 3-adrenoceptor agonists (sß 3-agonists) have the same efficacy in treating OAB but significantly fewer side effects than the traditionally used anti-muscarinics. However, safety data on these compounds are scarce. In this study, we analysed the occurrence of adverse effects in patients taking sß 3-agonists and their characteristics using the JADER database. The most frequently reported adverse effect associated with the use of sß 3-agonists was urinary retention [mirabegron; crude reporting odds ratios (ROR): 62.1, 95% confidence interval (CI): 52.0-73.6, P<0.001, vibegron; crude ROR: 250, 95% CI : 134-483, P<0.001]. Data from patients with urinary retention were stratified by sex. In both men and women, the rate of urinary retention was higher when using the mirabegron/anti-muscarinic drug when compared to mirabegron monotherapy; its occurrence was higher in men with a history of benign prostatic hypertrophy than in those without. Weibull analysis showed that approximately 50% of sß 3 agonist-induced urinary retention occurred within 15 days after initiation of treatment, and then gradually decreased. Although sß 3-agonists are useful against OAB, they may induce several side effects, especially urinary retention, which can further evolve into more severe conditions. Urinary retention occurs more frequently in patients concomitantly taking medication that either increases urethral resistance or has organic factors that block the urethra. When using sß 3-agonists, the concomitantly used medications and underlying diseases should be thoroughly reviewed, and safety monitoring should be instituted early during the treatment.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

A novel vaccine targeting ß1-adrenergic receptor.

Beta-blockers are widely used in the treatment of hypertension, heart failure and ischemic heart disease. However, unstandardized medication results in diverse clinical outcomes in patients. The main causes are unattained optimal doses, insufficient follow-up and patients' poor adherence. To improve the medication inadequacy, our team developed a novel therapeutic vaccine targeting ß1-adrenergic receptor (ß1-AR). The ß1-AR vaccine named ABRQß-006 was prepared by chemical conjugation of a screened ß1-AR peptide with Qß virus like particle (VLP). The antihypertensive, anti-remodeling and cardio-protective effects of ß1-AR vaccine were evaluated in different animal models. The ABRQß-006 vaccine was immunogenic that induced high titers of antibodies against ß1-AR epitope peptide. In the NG-nitro-L-arginine methyl ester (L-NAME) + Sprague Dawley (SD) hypertension model, ABRQß-006 lowered systolic blood pressure about 10 mmHg and attenuated vascular remodeling, myocardial hypertrophy and perivascular fibrosis. In the pressure-overload transverse aortic constriction (TAC) model, ABRQß-006 significantly improved cardiac function, decreased myocardial hypertrophy, perivascular fibrosis and vascular remodeling. In the myocardial infarction (MI) model, ABRQß-006 effectively improved cardiac remodeling, reduced cardiac fibrosis and inflammatory infiltration, which was superior to metoprolol. Moreover, no significant immune-mediated damage was observed in immunized animals. The ABRQß-006 vaccine targeting ß1-AR showed the effects on hypertension and heart rate control, myocardial remodeling inhibition and cardiac function protection. These effects could be differentiated in different types of diseases with diverse pathogenesis. ABRQß-006 could be a novel and promising method for the treatment of hypertension and heart failure with different etiologies.

The effectiveness and safety of oral medications, onabotulinumtoxinA (three doses) and transcutaneous tibial nerve stimulation as non or minimally invasive treatment for the management of neurogenic detrusor overactivity in adults: a systematic review and network meta-analysis.

BACKGROUND: Oral medications, onabotulinumtoxinA injections, and transcutaneous tibial nerve stimulation (TTNS) are recommended by the American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction guidelines as non or minimally invasive treatments for patients with neurogenic detrusor overactivity (NDO) without treatment hierarchy. OBJECTIVE: The objective was to compare and rank the effectiveness and safety of oral medications, three doses of onabotulinumtoxinA, and TTNS on improving urodynamic outcomes in patient-reported outcomes and safety outcomes in patients with NDO. METHODS: The authors searched PubMed, EMBASE, MEDLINE, Cochrane Library, Medicine, and clinicaltrials.gov, from their inception to October 2022 and included randomized controlled studies on the drug, onabotulinumtoxinA, and TTNS for the treatment of patients with NDO. Outcomes included urodynamic parameters, voiding diary, quality of life changes, adverse event rate and postvoid residual. RESULTS: A total of 26 articles and 2938 patients were included in the statistics. Regarding effectiveness, all interventions except TTNS and α-blockers were statistically different for the placebo group. The urodynamic outcome and patient-reported outcome suggested that onabotulinumtoxinA injection (urodynamic outcome: onabotulinumtoxinA 200 U, the mean surface under the cumulative ranking curve (SUCRA): 87.4; patient-reported outcome: onabotulinumtoxinA 100 U, mean SUCRA: 89.8) was the most effective treatment, and the safety outcome suggested that TTNS (SUCRA: 83.3) was the safest. Cluster analysis found that antimuscarinics and ß3-adrenoceptor-agonists possessed good effectiveness and safety. CONCLUSION: OnabotulinumtoxinA injection is probably the most effective way to treat patients with NDO, with increasing effectiveness but decreasing safety as the dose rises. The effectiveness of α-blockers and TTNS was not statistically different from the placebo group. Antimuscarinics and ß3-adrenoceptor-agonists have good effectiveness and safety.

Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis.

This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model - experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through ß-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective ß-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.

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

PURPOSE: The aim of this meta-analysis was to investigate the effect of pharmacotherapy for overactive bladder on the pathogenesis of urinary tract infection. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy.

Chronic stimulation of cardiac α1A-adrenergic receptors (α1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic α1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experimental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with α1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24 h. Separate control experiments determined the effects of EHT age (3-5 wk) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared with vehicle treatment (n = 7/group, P = 0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the α1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by α1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the α1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

Cold stress-induced bladder overactivity in type 2 diabetic mellitus rats is mitigated by the combination of a M3 -muscarinic antagonist and a ß3 -adrenergic agonist.

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 M3 -muscarinic receptor antagonist and a ß3 -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 M3 -muscarinic receptor antagonist solifenacin, the ß3 -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 M3 -muscarinic and ß3 -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 M3 -muscarinic and ß3 -adrenergic receptors were detected, the expression of M3 -muscarinic receptor mRNA was significantly higher than that of ß3 -adrenergic receptor mRNA. CONCLUSIONS: The cold stress-induced bladder overactivity was not improved by either the M3 -muscarinic receptor antagonist or the ß3 -adrenergic receptor agonist alone. However, the combined treatment mitigated the cold stress responses. Combined therapy with M3 -muscarinic antagonists and ß3 -adrenergic agonists could reduce side effects and improve the quality of life for diabetic patients with bladder overactivity.

Drugs Showing Real-world Efficacy for Nocturia in Patients With Bladder Storage Symptoms.

BACKGROUND/AIM: Nocturia is defined as the symptom that an individual has to disrupt their sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces a patient's quality of life. The aim of the study was to elucidate which drugs, prescribed to reduce nocturia, show real-world efficacy in patients with bladder storage symptoms. PATIENTS AND METHODS: One hundred consecutive patients who visited the Fukuoka University Medical Center were evaluated between May and July 2022. Anticholinergic drugs, ß3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines were prescribed for relieving nocturia. Desmopressin was used as second-line treatment of nocturia only in males with nocturnal polyuria. The association between each drug and actual decrease in nocturia was investigated using multivariate analysis. RESULTS: The number of nocturia episodes was reduced in patients using anticholinergic drugs, ß3 adrenoceptor agonists, and desmopressin (-1.4±0.9, -1.3±0.9, -2.0 ±0.8 episodes/night, respectively). Multivariate analysis for the entire cohort showed that anticholinergic drugs and ß3 adrenoceptor agonists were associated with significantly decreased nocturia episodes (p=0.01 and p=0.04, respectively). In males, only desmopressin was associated with a significant decrease in nocturia (p=0.03), and combination therapy significantly decreased the number of nocturia episodes compared to monotherapy (p=0.001). CONCLUSION: In a real-world clinical setting, anticholinergic drugs and ß3 adrenoceptor agonists were similarly effective in reducing nocturia. Administration of desmopressin combined with anticholinergic drugs and/or ß3 adrenoceptor agonists is the most effective method for reducing nocturia in male patients with both storage symptoms and nocturnal polyuria.