B1 Receptor Agonist Research Articles

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer's Disease Pathological Characteristics in a Transgenic Mouse Model.

Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein–kinin system (KKS) in Alzheimer’s disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer’s disease. Aim: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aβ peptide deposition. Methods: To assess the effects of B2, we used transgenic Alzheimer’s disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurotrophin BDNF, activated astrocyte marker S100B, and cell death were analyzed after treatments. Results: Treatment with the B2R agonist preserved the spatial memory of transgenic mice and decreased amyloid plaque deposition. In organotypic hippocampal culture, treatment with B2R agonist decreased cell death, neuroinflammation, and S100B levels, and increased BDNF release. Conclusions: Our results indicate that the kallikrein–kinin system plays a beneficial role in Alzheimer’s disease through B2R activation. The use of B2R agonists could, therefore, be a possible therapeutic option for patients diagnosed with Alzheimer’s disease.

PRS8 The Cost Effectiveness Analysis of SIX COPD Treatment Strategies in China

This study evaluated the cost-effectiveness of 6 recommended treatment strategies for the patients with Chronic obstructive pulmonary disease (COPD) in China. A Markov model was developed to simulate the progression of COPD under different treatment strategies during lifetime by 3-month cycle. Key treatment adverse events were also modeled, including death, acute hospital exacerbation, acute complications and chronic complications. Model was stratified by COPD severity (mild, moderately severe and very severe). The transition probabilities, clinical inputs and the utility values were extracted from the updated information of UK NICE COPD guideline (NG115). The cost data of Chinese COPD patients were extracted from a proprietary Chinese hospital database which contains both outpatient and inpatient data from more than 3000 major hospitals in China (ADEN). During the simulation, both costs and utilities were annually depreciated at the rate of 3.5%. The model was also validated against the observed values from ADEN to assure validity. Consistently with other countries, O5 strategy [LABA(Long acting β2 receptor agonist)+ICS(Inhaled corticosteroid) followed by Triple treatment] is shown as the most effective treatment strategy, offering the most quality adjusted life years among all tested strategies for most people. Due to the lower costs associated with LABA + ICS in China, O2 strategy [LAMA(Long acting anticholinergic antagonist) followed by LABA+ICS followed by Triple treatment] could be more cost effective for young and mild patients. The key model results predicted on the population level were close to the averages of respective observed values of COPD patients (N=14,162,347) on ADEN: 5-year death rate (21.51% vs. 19.68%), annual hospital exacerbation rate (16.10% vs. 16.59%), and annual inpatient costs (RMB 10,697.59 vs. 9,384.04). O5 strategy is the most effective treatment strategy for most Chinese COPD patients, while O2 strategy could be more cost effective for young and mild patients.

Preclinical support for the therapeutic potential of zolmitriptan as a treatment for cocaine use disorders

Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration but attenuate cocaine intake after prolonged abstinence. Here we investigated whether the less selective but clinically available 5-HT1D/1BR agonist, zolmitriptan, produces similar effects. Male and free-cycling female Sprague-Dawley rats were trained to lever press for cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg pellet) reinforcement until performance rates stabilized. Rats then received zolmitriptan (3.0, 5.6, and 10 mg/kg, s.c.) prior to testing for its effects on response and reinforcement rates. Under cocaine testing conditions, rats had access to the training dose for the first hour followed by a lower cocaine dose (0.075 mg/kg, i.v.) for the second hour. Zolmitriptan decreased cocaine intake at both cocaine doses and in both sexes even without a period of abstinence and without altering sucrose intake. A separate group of rats underwent identical training procedures and were tested for effects of the selective 5-HT1B and 5-HT1D receptor antagonists, SB224289 (3.2, 5.6, and 10 mg/kg, s.c.) and BRL15572 (0.3, 1.0, and 3.0 mg/kg, i.p.), respectively, alone or in combination with zolmitriptan (5.6 mg/kg, s.c.) under identical cocaine testing procedures as above. The zolmitriptan-induced decrease in cocaine intake was reversed by SB224289 and to a lesser extent by BRL15572, suggesting that the effects of zolmitriptan involve both 5-HT1B and 5-HT1D receptors. Neither zolmitriptan, SB224289, or BRL15572 altered locomotor activity at the doses effective for modulating cocaine intake. These findings suggest that zolmitriptan has potential for repurposing as a treatment for cocaine use disorders.

Angiotensin-Converting Enzyme Inhibitor Protects Against Cisplatin Nephrotoxicity by Modulating Kinin B1 Receptor Expression and Aminopeptidase P Activity in Mice.

Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 μM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 μM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 μM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice.

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.

PD36-12 DOES MIRABEGRON HAVE A POSITIVE IMPACT ON SEXUAL FUNCTION IN FEMALES WITH OVERACTIVE BLADDER?

You have accessJournal of UrologySexual Function/Dysfunction: Female (PD36)1 Apr 2020PD36-12 DOES MIRABEGRON HAVE A POSITIVE IMPACT ON SEXUAL FUNCTION IN FEMALES WITH OVERACTIVE BLADDER? Samer Morsy, Hussein Hussein*, Dalia Abdel Azim, Sarah Hassan, and Eman Hussein Samer MorsySamer Morsy More articles by this author , Hussein Hussein*Hussein Hussein* More articles by this author , Dalia Abdel AzimDalia Abdel Azim More articles by this author , Sarah HassanSarah Hassan More articles by this author , and Eman HusseinEman Hussein More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000907.012AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Overactive bladder (OAB) may be associated with unpleasent effect on female sexual function. Mirabegron, a β3 receptor agonist, improves OAB symptoms, but there is limited information about its role on female sexual dysfunction (FSD). Aim of the study was to assess the impact of Mirabegron on FSD in women affected by idiopathic OAB. METHODS: One hundred sexually active women suffering from idiopathic OAB were included in the study. Patients were assessed by means of a urogynecologic physical examination and were asked to complete the 3-day voiding diary, the International Consultation on Incontinence Questionnaire- Short Form (ICIQ-SF), the Female Sexual Function Index (FSFI) questionnaire and VAS, before and 12 weeks after treatment with Mirabegron 50 mg once daily dose. In addition, at the same time points, patients underwent uroflowmetry with the measurement of post- void residual volume (PVR). RESULTS: At baseline all patients were affected by OAB symptoms, with 98/100 patients (98%) presenting with FSD. At 12- weeks follow- up, OAB symptoms improved significantly in all patients, with 59.5% of subjects achieving a complete urinary continence. FSFI Total Score significantly improved in 84/100 patients (84%) from 18.9 ± 4.3 to 21.8 ± 4.5 (p < 0.0001). Thirty two cases (32%) presented with no FSD. Also mean ± SD scores of ICIQ-SF and VAS significantly improved (from 17.1 ± 5 to 7.9 ± 4.8 and from 3.9 ± 1.2 to 6.9 ± 1.2 respectively, p < 0.000). CONCLUSIONS: Mirabegron 50 mg control urinary symptoms in women with OAB, and also induces a significant improvement in their sexual life. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e727-e727 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Samer Morsy More articles by this author Hussein Hussein* More articles by this author Dalia Abdel Azim More articles by this author Sarah Hassan More articles by this author Eman Hussein More articles by this author Expand All Advertisement PDF downloadLoading ...

Kinin B1 Receptor Blockade Attenuates Hypertension via Angiotensin II Mediated Signaling in Neurons

Interaction between renin‐angiotensin system (RAS) and kallikrein‐kinin system (KKS) has been shown to play an important role in the regulation of blood pressure. We previously reported that kinin B1 receptor (B1R) expression is increased in the neurons of hypertensive mice with elevated angiotensin II (Ang II) levels in the brain. However, the role of B1R in neurogenic hypertension and its interaction with Ang II type 1 receptor (AT1R), the major receptor of Ang II, have not been studied. Ang II treatment (1 μg/kg/min, SC, 2 weeks) significantly increased blood pressure (radiotelemetry) in male wild‐type (WT) mice (145 ±13 mmHg, n=6, p&lt;0.01) compared to control mice (103 ±6 mmHg, n=6). This increase in blood pressure was attenuated in B1R knockout (B1RKO) mice with Ang II infusion (118 ±12 mmHg, n=6, p&lt;0.01). In addition, B1R knockdown significantly reduced Ang II‐induced AT1R expression and vasopressin levels. In order to further confirm the causative role of B1R on inducing hypertension, we used a specific B1R agonist Lys‐des‐Arg9‐BK (LDABK) to activate central B1R and measured blood pressure response using telemetry transmitters. A single bolus intracerebroventricular injection of 50 ng of LDABK, significantly increased blood pressure compared to artificial cerebrospinal fluid (18 ±5 mmHg vs. 4 ±2 mmHg, n=6, p&lt;0.01), supporting the hypothesis that B1R activation can induce hypertensive response. To further understand the neuron specific B1R mediated signaling, we isolated mouse neonatal primary hypothalamic neuronal cultures from WT and B1RKO mice and investigated the interaction between Ang II and B1R activation. Stimulation of primary neurons with LDABK (300 nM, 24 h), significantly increased the expression of AT1R mRNA (3‐fold vs. vehicle; n=6; p&lt;0.05) and resulted in neuroinflammation as indicated by upregulated expression of inflammatory markers interleukin (IL)‐1β, IL‐6, tumor necrosis factor, and monocyte chemoattractant protein 1. These changes were attenuated in B1RKO neurons or pretreatment of WT neurons with R715 (a B1R specific peptide antagonist). Together, these data provide novel evidence that kinin B1R plays an important role in mediating hypertension possibly via modulating angiotensin signaling in the brain.

Bradykinin stimulates prostaglandin E2 release in human skeletal muscular fibroblasts

Local mediator prostaglandins and bradykinin are involved in inflammation and pain. We explored bradykinin effects on prostaglandin E2 (PGE2) release from fibroblasts derived from human skeletal muscular biopsies. Bradykinin induced PGE2 release through bradykinin B2 receptors, since PGE2 release was blocked by the bradykinin B2 receptor selective antagonist FR173657 and B2 receptor agonist (Hyp3)-bradykinin showed effects comparable to bradykinin. Consistently, bradykinin induced both mRNA cyclooxygenase 2 (COX-2) and protein. Bradykinin also induced ERK1/2 and p38 phosphorylation and provoked the translocation from the cytosol to the nucleus of p65/NF-kB. The release of PGE2 by bradykinin could be blocked inhibiting COX-2 and p65/NF-kB, ERK1/2 or p38 activation. Both ERK1/2 and p38 were upstream to NF-kB inasmuch siRNAs significantly blocked the p65/NF-kB activation induced by bradykinin. Thus, bradykinin, acting via B2 receptors, induced PGE2 release through ERK1/2 and p38-dependent pathways and consequent p65/NF-kB translocation to nucleus. p65/NF-kB induced COX-2 transcription. The release of PGE2 provide a possible explanation for the role of bradykinin in inflammatory diseases.

β3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release.

The mechanism by which β3 receptor agonists (e.g. mirabegron) control bladder overactivity may involve adenosine release from human and rat detrusor smooth muscle. Retrograde activation of adenosine A1 receptors reduces ACh release from cholinergic bladder nerves. β3 -Adrenoceptors usually couple to adenylyl cyclase. Here we investigated, which of the cAMP targets, protein kinase A or the exchange protein directly activated by cAMP (EPAC) could be involved in this cholinergic inhibition of the bladder. [3 H]ACh and adenosine release from urothelium-denuded detrusor strips of cadaveric human organ donors and rats were measured by liquid scintillation spectrometry and HPLC, respectively. In vivo cystometry was also performed in urethane-anaesthetized rats. The exchange protein directly activated by cAMP (EPAC) inhibitor, ESI-09, prevented mirabegron- and isoprenaline-induced adenosine release from human and rat detrusor strips respectively. ESI-09, but not the PKA inhibitor, H-89, attenuated inhibition of [3 H]ACh release from stimulated (10 Hz) detrusor strips caused by activating β3 -adrenoceptors, AC (forskolin) and EPAC1 (8-CTP-2Me-cAMP). Isoprenaline-induced inhibition of [3 H]ACh release was also prevented by inhibitors of PKC (chelerythrine and Go6976) and of the equilibrative nucleoside transporter 1 (ENT1; dipyridamole and NBTI), but not by PLC inhibition with U73122. Pretreatment with ESI-09, but not with H-89, prevented the reduction of the voiding frequency caused by isoprenaline and forskolin in vivo. Data suggest that β3 -adrenoceptor-induced inhibition of cholinergic neurotransmission in human and rat urinary bladders involves activation of an EPAC1/PKC pathway downstream cAMP production resulting in adenosine outflow via ENT1.

Effect of (R)-salbutamol on the switch of phenotype and metabolic pattern in LPS-induced macrophage cells.

Evidence demonstrates that M1 macrophage polarization promotes inflammatory disease. Here, we discovered that (R)‐salbutamol, a β2 receptor agonist, inhibits and reprograms the cellular metabolism of RAW264.7 macrophages. (R)‐salbutamol significantly inhibited LPS‐induced M1 macrophage polarization and downregulated expressions of typical M1 macrophage cytokines, including monocyte chemotactic protein‐1 (MCP‐1), interleukin‐1β (IL‐1β) and tumour necrosis factor α (TNF‐α). Also, (R)‐salbutamol significantly decreased the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and reactive oxygen species (ROS), while increasing the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio. In contrast, (S)‐salbutamol increased the production of NO and ROS. Bioenergetic profiles showed that (R)‐salbutamol significantly reduced aerobic glycolysis and enhanced mitochondrial respiration. Untargeted metabolomics analysis demonstrated that (R)‐salbutamol modulated metabolic pathways, of which three metabolic pathways, namely, (a) phenylalanine metabolism, (b) the pentose phosphate pathway and (c) glycerophospholipid metabolism were the most noticeably impacted pathways. The effects of (R)‐salbutamol on M1 polarization were inhibited by a specific β2 receptor antagonist, ICI‐118551. These findings demonstrated that (R)‐salbutamol inhibits the M1 phenotype by downregulating aerobic glycolysis and glycerophospholipid metabolism, which may propose (R)‐salbutamol as the major pharmacologically active component of racemic salbutamol for the treatment of inflammatory diseases and highlight the medicinal value of (R)‐salbutamol.

Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response

Metastatic melanoma is an aggressive type of skin cancer leading half of the patients to death within 8–10 months after diagnosis. Kinins are peptides that interact with B1 and B2 receptors playing diverse biological roles. We investigated whether treatment with B1 receptor agonist, des-Arg9-bradykinin (DABK), has effects in lung metastasis establishment after melanoma induction in mice. We found a lower number of metastatic colonies in lungs of DABK-treated mice, reduced expression of vascular cell adhesion molecule 1 (VCAM-1), and increased CD8+T-cell recruitment to the metastatic area compared to animals that did not receive treatment. To understand whether the effects of DABK observed were due to the activation of the B1 receptor in the tumor cells or in the host, we treated wild-type (WT) and kinin B1 receptor knockout (B1−/−) mice with DABK. No significant differences in the number of melanoma colonies established in lungs were seen between WT and B1−/−mice; however, B1−/−mice presented higher VCAM-1 expression and lower CD8+T-cell infiltration. In conclusion, we believe that activation of kinin B1 receptor by its agonist in the host stimulates the immune response more efficiently, promoting CD8+T-cell recruitment to the metastatic lungs and interfering in VCAM-1 expression. Moreover, treatment with DABK reduced establishment of metastatic colonies by mainly acting on tumor cells; hence, this study brings insights to explore novel approaches to treat metastatic melanoma targeting the B1 receptor.

An assessment of the sublingual immunotherapy with Dermatophagoides farinae on asthma control level and pulmonary function of allergic asthma and rhinitis in adult patient

Objective:To evaluate the efficacy, asthma control level and pulmonary function of sublingual immunotherapy on allergic asthma and rhinitis in adult patient. Method:This retrospective analysis of 182 cases of adult patient from 18-60 years with allergic asthma and rhinitis, according to the patients' wishes they were divided into drug group（66 patients） and SLIT group（116 patients）. Drug group patients were treated with low to moderate doses of inhaled corticosteroids+long-acting β2 receptor agonists and mometasone furoate nasal spray+desloratadine tablets as symptomatic treatment. SLIT group was treated by SLIT with Dermatophagoides farina drops on this basis. Before treatment and 1 year, 2 year and 3 years after treatment, the ACT, PEF%, DASS, NASS, TNSS and TMS were evaluated. Result:The ACT, PEF%, DASS, NASS, TNSS and TMS had continuously improved significantly 1 year, 2 year and 3 years after treatment in both groups comparing with baseline（P<0.05）. Compared with 1 year after treatment, SLIT group had lower ACT, PEF%, DASS, NASS, TNSS and TMS in 2 years after treatment（all P<0.05）, whereas drug group had lower TMS and DASS（all P<0.05）. In 3 years of treatment, only SLIT group resulted in significant continuous improvement in DASS and TMS（all P<0.05）. After 1 year, 2 and 3 years of treatment, SLIT group resulted in significantly better ACT, PEF%, DASS, NASS and TMS than drug group（all P<0.05）. After 2 and 3 years of treatment, TNSS of SLIT group were significantly lower than in drug group（P<0.05）. Conclusion:Sublingual immunotherapy for 3 yearswith Dermatophagoides farinae dropsin adult patient with allergic asthma and rhinitis was more effective than drug therapy alone, and asthma control and lung function improved significantly.

Evaluation of inhaled long-acting anticholinergic drugs and long-acting β2 receptor agonists in the treatment of the patients with chronic obstructive pulmonary disease

Evaluation of inhaled long-acting anticholinergic drugs and long-acting β2 receptor agonists in the treatment of the patients with chronic obstructive pulmonary disease

Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease.

Gene therapy for Pompe disease with adeno-associated virus (AAV) vectors has advanced into early phase clinical trials; however, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up acid α-glucosidase (GAA), has impeded the efficacy of Pompe disease gene therapy. Long-acting selective β2 receptor agonists previously enhanced the CI-MPR expression in muscle. In this study we have evaluated the selective β2 agonist salmeterol in GAA knockout mice in combination with an AAV vector expressing human GAA specifically in the liver. Quadriceps glycogen content was significantly decreased by administration of the AAV vector with salmeterol, in comparison with the AAV vector alone (p < 0.01). Importantly, glycogen content of the quadriceps was reduced to its lowest level by the combination of AAV vector and salmeterol administration. Rotarod testing revealed significant improvement following treatment, in comparison with untreated mice, and salmeterol improved wirehang performance. Salmeterol treatment decreased abnormalities of autophagy in the quadriceps, as shown be lower LC3 and p62. Vector administration reduced the abnormal vacuolization and accumulation of nuclei in skeletal muscle. Thus, salmeterol could be further developed as adjunctive therapy to improve the efficacy of liver depot gene therapy for Pompe disease.

Clinical and inflammatory phenotypic features of asthmatic patients sensitive to cold stimulation

To explore the clinical symptoms, lung function and airway inflammation phenotype characteristics of asthmatic patients who are sensitive to cold stimulation. Eighty patients with newly diagnosed bronchial asthma or with mild to moderate acute exacerbation of previously diagnosed bronchial asthma but without regular treatment were selected. According to whether cold air stimulation could induce respiratory symptoms such as cough and wheeze, the patients were divided into cold-insensitive group (45 cases) and cold-sensitive group (35 cases). All the patients were treated with inhaled corticosteroid (ICS), long-acting β2 receptor agonist (LABA; salmeterol xinafoate and fluticasone propionate powder for inhalation, 50 μg/250 μg, twice daily) and montelukast sodium tablets (10 mg, once daily); short-acting β2 receptor agonist (SABA) and/or systemic glucocorticoid (prednisone acetate tablets, 10 mg, once daily; or injection of methylprednisolone sodium succinate, 40 mg) were given if necessary. Asthma Control Test (ACT) score before treatment and at 3 months of treatment was used to assess the clinical symptoms such as cough and wheeze; spirometry was performed to determine lung function impairment and recovery. Blood and induced sputum cell counts were examined to determine the characteristics of airway inflammation. The two groups were comparable for age, gender, BMI, proportion of smokers and allergic rhinitis before treatment. The cold-sensitive patients experienced significantly more frequent acute exacerbations than the cold-insensitive patient within 1 year before the visit (P &lt; 0.05), but the use of SABA and glucocorticoid for symptom control during the treatment did not differ significantly between the two groups (P &gt; 0.05). The ACT scores of the cold-sensitive group were significantly lower than those of the cold-insensitive group both before and after the treatment (P &lt; 0.01). Compared with the cold-insensitive patients, the cold-sensitive patients had more obvious impairment of FEV1/FVC% and FEV1%pred before treatment (P &lt; 0.01), and also showed poorer recovery after treatment (P &lt; 0.05). The percentages of eosinophils in blood and induced sputum samples did not differ significantly between the two groups either before and after the treatment, but the percentage of neutrophils was significantly higher in the cold-sensitive group (P &lt; 0.01). In the induced sputum samples collected before treatment, the cell populations consisted mainly of eosinophilic subtype (60%) and neutrophilic subtype (20%) in the cold-insensitive group; in the cold-sensitive patients, the sputum neutrophilic subtype cells increased significantly to 42.86% (P=0.03) and the eosinophilic subtype cells were lowered to 31.43% (P=0.01). The cold-sensitive asthmatic patients experience frequent recurrent and/or aggravated symptoms and have obvious lung function impairment. Different from that in patients with classic asthma, the airway inflammatory phenotype in these patients is characterized by the domination by neutrophilic subtype.

Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva

The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B1 and B2 receptor expression in human gingival fibroblasts and in mouse gingiva. Both P. gingivalis LPS and the synthetic TLR2 agonist Pam2CSK4 increased kinin receptor transcripts. Silencing of TLR2, but not of TLR4, inhibited the induction of kinin receptor transcripts by both P. gingivalis LPS and Pam2CSK4. Human gingival fibroblasts (HGF) exposed to Pam2CSK4 increased binding sites for bradykinin (BK, B2 receptor agonist) and des-Arg10-Lys-bradykinin (DALBK, B1 receptor agonist). Pre-treatment of HGF for 24 h with Pam2CSK4 resulted in increased PGE2 release in response to BK and DALBK. The increase of B1 and B2 receptor transcripts by P. gingivalis LPS was not blocked by IL-1β neutralizing antibody; TNF-α blocking antibody did not affect B1 receptor up-regulation, but partially blocked increase of B2 receptor mRNA. Injection of P. gingivalis LPS in mouse gingiva induced an increase of B1 and B2 receptor mRNA. These data show that activation of TLR2 in human gingival fibroblasts as well as in mouse gingival tissue leads to increase of B1 and B2 receptor mRNA and protein.

Dissecting the roles of β-arrestin2 and GSK-3 signaling in 5-HT1BR-mediated perseverative behavior and prepulse inhibition deficits in mice.

Serotonin-1B receptors (5-HT1BRs) modulate perseverative behaviors and prepulse inhibition (PPI) in humans and mice. These inhibitory G-protein-coupled receptors signal through a canonical G-protein-coupled pathway that is modulated by GSK-3β, and a noncanonical pathway mediated by the adaptor protein β-arrestin2 (Arrb2). Given the development of biased ligands that differentially affect canonical versus noncanonical signaling, we examined which signaling pathway mediates 5-HT1BR agonist-induced locomotor perseveration and PPI deficits, behavioral phenotypes observed in both obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD). To assess the role of canonical 5-HT1BR signaling, mice received acute pretreatment with a GSK-3 inhibitor (SB216763 or AR-A014418) and acute treatment with the 5-HT1A/1B receptor agonist RU24969 prior to assessing perseverative locomotor behavior in the open field, and PPI. To determine the role of noncanonical 5-HT1BR signaling, Arrb2 wild-type (WT), heterozygous (HT), and knockout (KO) mice received acute RU24969 treatment prior to behavioral testing. GSK-3 inhibition increased locomotor perseveration overall, and also failed to influence the RU24969-induced perseverative locomotor pattern in the open field. Yet, GSK-3 inhibition modestly reduced RU24969-induced PPI deficits. On the other hand, Arrb2 HT and KO mice showed reduced locomotion and no changes in perseveration overall, in addition to modest reductions in RU24969-induced locomotion and PPI deficits. In conclusion, our data do not support use of either GSK-3 inhibitors or β-arrestin2 inhibition in treatment of perseverative behaviors.

The impact of Mirabegron on sexual function in women with idiopathic overactive bladder

BackgroundOveractive bladder (OAB) can frequently exert a negative effect on female sexual function. Mirabegron, a β3 receptor agonist, improves OAB symptoms, but there are very few information about its role on female sexual dysfunction (FSD). Aim of the study was to assess the impact of Mirabegron on FSD in women affected by OAB.MethodsFifty sexually active women suffering from idiopathic OAB were included in the study. Patients were assessed by means of a urogynecologic physical examination and were asked to complete the 3-day voiding diary, the International Consultation on Incontinence Questionnaire- Short Form (ICIQ-SF), the Female Sexual Function Index (FSFI) questionnaire and VAS, before and 12 weeks after treatment with Mirabegron. In addition, at the same time points, patients underwent uroflowmetry with the measurement of post- void residual volume (PVR).ResultsAt baseline all patients were affected by OAB symptoms, with 49/50 patients (98%) presenting with FSD. At 12- weeks follow- up, OAB symptoms improved significantly in all patients, with 59.5% of subjects achieving a complete urinary continence. FSFI Total Score significantly improved in 42/50 patients (84%) from 18.9 ± 4.3 to 21.8 ± 4.5 (p < 0.0001). Sixteen cases (32%) presented with no FSD. Also mean ± SD scores of ICIQ-SF and VAS significantly improved (from 17.1 ± 5 to 7.9 ± 4.8 and from 3.9 ± 1.2 to 6.9 ± 1.2 respectively, p < 0.000).ConclusionsMirabegron not only is able to control urinary symptoms in women with OAB, but also induces a significant improvement in their sexual life.

Weight Loss and Overactive Bladder

We sought to explore the relationship between obesity and overactive bladder (OAB) and to review the available literature that supports weight loss as a means to alter OAB severity and bother. Over the past 15 years, several population-based human studies and animal models have identified obesity as a risk factor for the development of OAB. The bariatric surgery literature demonstrates that substantial weight loss following some form of gastric bypass can lead to at least subjective improvement in OAB symptoms. Ongoing research seeks to further elucidate the role of anti-inflammatory agents, anti-oxidants, and β3-receptor agonists in obesity-associated OAB. The currently available literature has identified obesity as a risk factor for the development OAB. Data taken from the bariatric surgery literature indicates that surgical weight loss can lead to a significant improvement in OAB severity and bother. Future studies will determine if less dramatic weight changes can lead to significant and sustained changes in OAB parameters. Based on the available literature, clinicians should start to counsel their obese patients with OAB that weight loss can help improve their OAB severity and bother.

Intracellular Ca2+ mobilization pathway via bradykinin B1 receptor activation in rat trigeminal ganglion neurons.

Bradykinin (BK) and its receptors, B1 and B2, in trigeminal ganglion (TG) neurons are involved in the regulation of pain. Recent studies have revealed that B1 receptors are expressed in neonatal rat TG neurons; however, the intracellular signaling pathway following B1 receptor activation remains to be elucidated. To investigate the mechanism by which B1 receptor activation leads to intracellular Ca2+ mobilization, we measured the intracellular free Ca2+ concentration ([Ca2+]i) in primary-cultured TG neurons. The application of Lys-[Des-Arg9]BK (B1 receptor agonist) increased the [Ca2+]i in these TG neurons even in the absence of extracellular Ca2+. Pretreatment with inhibitors of ryanodine receptors or sarco/endoplasmic reticulum Ca2+-ATPase suppressed the increase in Lys-[Des-Arg9]BK-induced [Ca2+]i. The Lys-[Des-Arg9]BK-induced [Ca2+]i increase was unaffected by phospholipase-C inhibitor. B1 receptor activation-induced [Ca2+]i increase was suppressed by phosphodiesterase inhibitor and enhanced by adenylyl cyclase inhibitor. These results suggest that B1 receptor activation suppresses intracellular cAMP production via adenylyl cyclase inhibition and mobilizes intracellular Ca2+ via ryanodine receptors that access intracellular Ca2+ stores.