Objective: To explore the protective effects of dexmedetomidine (Dex) against high glucose-induced epithelial-mesenchymal transition in HK-2 cells and relevant mechanisms. Methods: HK-2 cells were exposed to either glucose or glucose+Dex for 6 h. The production of ROS, morphology of HK-2 cells, and cell cycle were detected. Moreover, the expression of AKT, p-AKT, ERK, p-ERK, PI3K, E-Cadherin, Claudin-1, and α-SMA were determined and compared between HK-2 cells exposed to glucose and those exposed to both glucose and Dex with or without PI3K/AKT pathway inhibitor LY294002 and ERK pathway inhibitor U0126. Results: Compared with HK-2 cells exposed to high level of glucose, the HK-2 cells exposed to both high level of glucose and Dex showed: (1) lower level of ROS production; (2) cell morphology was complete; (3) more cells in G1 phase; (4) lower expression of p-AKT, p-ERK and α-SMA, higher expression of E-Cadherin and Claudin-1. PI3K/AKT inhibitor LY294002 and ERK inhibitor U0126 decreased the expression of p-AKT, p-ERK and α-SMA, and increased the expression of E-Cadherin and Claudin-1. Conclusion Dex can attenuate high glucose-induced HK-2 epithelial-mesenchymal transition by inhibiting AKT and ERK.
Adrenergic alpha-2 Receptor Agonists ; pharmacology ; Cell Line ; Dexmedetomidine ; pharmacology ; Epithelial-Mesenchymal Transition ; drug effects ; Glucose ; metabolism ; Humans ; MAP Kinase Signaling System ; drug effects ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; Signal Transduction ; drug effects

PURPOSE: The aim of this study was to characterize the responsiveness of miniature excitatory postsynaptic currents (mEPSCs) to α1-adrenoceptor blockers in substantia gelatinosa (SG) neurons from the spinal cord to develop an explanation for the efficacy of α1-adrenoceptor blockers in micturition dysfunction. METHODS: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed using SG neurons in spinal cord slices. Naftopidil (100μM), tamsulosin (100μM), or silodosin (30μM), α1-adrenoceptor blockers, was perfused. The frequency of mEPSCs was recorded in an SG neuron to which the 3 blockers were applied sequentially with wash-out periods. Individual frequencies in a pair before naftopidil and tamsulosin perfusion were plotted as baseline, and the correlation between them was confirmed by Spearman correlation coefficient; linear regression was then performed. The same procedure was performed before naftopidil and silodosin perfusion. Frequencies of pairs after naftopidil and tamsulosin perfusion and after naftopidil and silodosin perfusion were similarly analyzed. The ratios of the frequencies after treatment to before were then calculated. RESULTS: After the treatments, Spearman ρ and the slope were decreased to 0.682 from 0.899 at baseline and 0.469 from 1.004 at baseline, respectively, in the tamsulosin group relative to the naftopidil group. In the silodosin group, Spearman ρ and the slope were also decreased to 0.659 from 0.889 at baseline and 0.305 from 0.989 at baseline, respectively, relative to the naftopidil group. Naftopidil significantly increased the ratio of the frequency of mEPSCs compared to tamsulosin and silodosin (P=0.015 and P=0.004, respectively). CONCLUSIONS: There was a difference in responsiveness in the frequency of mEPSCs to α1-adrenoceptor blockers, with the response to naftopidil being the greatest among the α1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of α1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.
Adrenergic alpha-1 Receptor Antagonists ; Adult ; Animals ; Excitatory Postsynaptic Potentials ; Humans ; Linear Models ; Lower Urinary Tract Symptoms ; Male ; Neurons ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; Substantia Gelatinosa ; Urination

PURPOSE: To investigate the efficacy and safety of 0.4 mg of tamsulosin in patients with nocturia not responding to 0.2 mg.METHODS: Patients with intractable nocturia after treatment with 0.2 mg of tamsulosin for>1 month were included in a multicenter, prospective, observational, single-arm study. Patients were prescribed 0.4 mg of tamsulosin and followed up for 2 months to assess nocturnal voiding and nocturia-related bother. Changes in the mean number of nocturnal voids, the proportion of 50% responders, 3-day frequency-volume chart parameters, and questionnaire scores were assessed.RESULTS: Sixty-two patients were prescribed 0.2 mg of tamsulosin, of whom 56 were prescribed 0.4 mg of tamsulosin. Ten patients dropped out. A single case of orthostatic hypotension was reported. The mean age was 68 years. After 1 and 2 months of taking 0.4 mg of tamsulosin, 23.9% and 22.7% of patients demonstrated a>50% reduction of nocturia, and 16.1% and 19.4% of patients rated the treatment as “very effective,” respectively. Dose escalation to 0.4 mg of tamsulosin, compared to 0.2 mg, did not show an additional effect on reducing nocturnal urine volume. Multivariate logistic regression analysis showed that lower serum sodium levels (odds ratio [OR], 0.41, P=0.037) and the presence of urge incontinence (OR, 7.08, P=0.036) were predictors of a significant improvement of nocturia in response to 0.4 mg of tamsulosin.CONCLUSIONS: Dose escalation may yield a significant improvement of nocturia in>20% of patients, and may be especially helpful in patients with lower sodium levels and urge incontinence.
Adrenergic alpha-Antagonists ; Humans ; Hypotension, Orthostatic ; Logistic Models ; Male ; Nocturia ; Prospective Studies ; Sodium ; Urinary Incontinence, Urge

ObjectiveTo investigate the therapeutic effects of commonly used selective α-adrenergic receptor antagonists (α-ARA) on benign prostatic hyperplasia (BPH).

METHODSPubMed, Embase and CNKI databases were searched for the literature about selective α-ARAs for the treatment of BPH and the information was extracted on the common adverse reactions in the course of treatment. Multivariate meta-analysis was conducted to investigate the therapeutic effects of different α-ARAs.

RESULTSThe total rates of adverse effects of silodosin and tamsulosin were the highest, 51.9% and 34.0% respectively, with the highest incidences of headache (38.3%), weakness (23.6%) and dizziness (17.5%). Besides, tamsulosin ranked the first in inducing sexual dysfunction of the male patients with BPH (70.4%).

CONCLUSIONSDoxazosin is preferable as the first-choice treatment of BPH for its therapeutic effect and improvement of the patient's quality of life. Silodosin and tamsulosin, however, can be selectively used according to the patient's specific tolerance to different adverse effects.

Adrenergic alpha-Antagonists ; adverse effects ; therapeutic use ; Doxazosin ; adverse effects ; therapeutic use ; Humans ; Indoles ; adverse effects ; therapeutic use ; Male ; Network Meta-Analysis ; Prostatic Hyperplasia ; drug therapy ; Quality of Life ; Sexual Dysfunction, Physiological ; chemically induced ; Tamsulosin ; adverse effects ; therapeutic use

PURPOSE: To evaluate the efficacy of an alpha-1 adrenergic receptor (α1-AR) blocker for the treatment of female voiding dysfunction (FVD) through a pressure-flow study. METHODS: This was a randomized, double-blind, placebo-controlled trial. Women aged ≥18 years with voiding symptoms, as defined by an American Urological Association symptom score (AUA-SS) ≥15 and a maximum flow rate (Qmax) < 15 mL/sec with a voided volume of >100 mL and/or a postvoid residual (PVR) volume >150 mL, were randomly allocated to either the alfuzosin or placebo group. After 8 weeks of treatment, changes in the AUA-SS, Bristol female lower urinary tract symptoms (BFLUTS) questionnaire, Qmax/PVR, and voiding diary were compared between groups. Patients’ satisfaction with the treatment was compared. Patients were categorized into 3 groups according to the Blaivas-Groutz bladder outlet obstruction (BOO) nomogram: none, mild, and moderate to severe. Subgroup comparisons were also made. RESULTS: Of a total of 187 women, 154 (79 alfuzosin, 75 placebo) were included in the analysis. After 8 weeks of treatment, the AUA-SS decreased by 7.0 in the alfuzosin group and by 8.0 in the placebo group. Changes in AUA-SS subscores, BFLUTS (except the I-sum), the voiding diary, and Qmax/PVR were not significantly different between groups. Approximately 54% of the alfuzosin group and 62% of the placebo group were satisfied with the treatment. No significant difference was observed between groups according to the presence or grade of BOO. CONCLUSIONS: Alfuzosin might not be more effective than placebo for treating FVD. The presence or the grade of BOO did not affect the results. A further study with sufficient power is needed to determine the efficacy of α1-AR blockers for the treatment of FVD.
Adrenergic alpha-Antagonists ; Female ; Humans ; Lower Urinary Tract Symptoms ; Nomograms ; Receptors, Adrenergic, alpha-1 ; Urinary Bladder Neck Obstruction ; Urodynamics

PURPOSE: To investigate whether seasonal changes occurred in lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). METHODS: Patients aged 50 years and older with BPH treated with α1-blockers were enrolled. The International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum and average flow rate, voided volume, and postvoid residual volume were measured in summer and winter. RESULTS: A total of 164 patients were enrolled. The total IPSS and QoL index did not show a significant difference between the 2 seasons. When the IPSS was divided into storage symptoms and voiding symptoms, storage symptoms in winter were substantially but nonsignificantly higher than those in summer (P=0.056). Of the 7 individual symptoms in the IPSS, a significant seasonal difference was observed only for nocturia, with a higher score in winter. Moreover, none of the uroflowmetric parameters showed a seasonal change. Voided volume had significant correlations with each symptom (urgency and nocturia) and overall subjective scores (storage, total IPSS, and QoL) exclusively in summer, while this correlation remained only for nocturia in winter. CONCLUSIONS: As it has generally been assumed that LUTS deteriorate in winter, the present study corroborated that the severity of storage symptoms was higher in winter than in summer, even in patients treated with α₁-blockers. In contrast, a seasonal difference was not observed in the uroflowmetric parameters, which may be partly due to the loss of the correlation between subjective and objective measurements of storage symptoms in winter.
Adrenergic alpha-Antagonists ; Asian Continental Ancestry Group* ; Humans ; Lower Urinary Tract Symptoms* ; Male ; Nocturia ; Prostate ; Prostatic Hyperplasia* ; Quality of Life ; Residual Volume ; Seasons* ; Urodynamics

OBJECTIVETo study the clinical effect and mechanism of action of esmolol in the treatment of severe hand, foot, and mouth disease (HFMD).

METHODSA prospective randomized controlled trial was performed. A total of 102 children with severe HFMD were enrolled in the study and were randomly divided into conventional treatment and esmolol treatment groups (n=51 each). The children in the conventional treatment group were given conventional treatment according to the guidelines for the diagnosis and treatment of HFMD. Those in the esmolol treatment group were given esmolol in addition to the conventional treatment. The heart rate (HR), systolic blood pressure (SBP), and respiratory rate (RR) were continuously monitored for all children. Blood samples were collected from all children before treatment and 1, 3, and 5 days after treatment to measure the levels of norepinephrine (NE), tumor necrosis factor-&alpha; (TNF-&alpha;), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB) p65 in mononuclear cells. Serum levels of myocardial enzymes and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured before treatment and after 5 days of treatment.

RESULTSThere were no significant differences in HR, SBP, RR, NE, TNF-&alpha;, IL-6, NF-κB p65, serum myocardial enzymes, and NT-proBNP before treatment between the conventional treatment and esmolol treatment groups. Both groups had significant reductions in these parameters at each time point (P<0.05). Compared with the conventional treatment group, the esmolol treatment group had significant improvements in the above parameters after 1 and 3 days of treatment (P<0.05). After 5 days of treatment, the esmolol treatment group had significant improvements in serum levels of myocardial enzymes and NT-proBNP compared with the conventional treatment group (P<0.05).

CONCLUSIONSEarly application of esmolol can effectively stabilize the vital signs of the children with severe HFMD. Its mechanism of action may be related to reducing serum catecholamine concentration, alleviating myocardial damage, improving cardiac function, and reducing inflammatory response.

Adrenergic beta-1 Receptor Antagonists ; therapeutic use ; Child, Preschool ; Female ; Hand, Foot and Mouth Disease ; blood ; drug therapy ; physiopathology ; Humans ; Infant ; Interleukin-6 ; blood ; Male ; Natriuretic Peptide, Brain ; blood ; Peptide Fragments ; blood ; Propanolamines ; pharmacology ; therapeutic use ; Prospective Studies ; Tumor Necrosis Factor-alpha ; blood

PURPOSE: To investigate long-term therapeutic effects and patient adherence to a combination therapy of a 5α-reductase inhibitor and an α-blocker and to identify causes of withdrawal from medication in patients with clinical benign prostatic hyperplasia (BPH). METHODS: BPH patients with lower urinary tract symptoms (LUTS) receiving combination therapy with follow-ups for 1–12 years were retrospectively analyzed. Therapeutic effects were assessed at baseline and annually by measuring International Prostatic Symptoms Score, quality of life index, total prostate volume (TPV), maximal flow rate, voided volume, postvoid residual volume and prostate-specific antigen level. Causes of discontinued combination therapy were also investigated. RESULTS: A total of 625 patients, aged 40–97 years (mean, 73 years) were retrospectively analyzed. All measured parameters showed significant improvements after combination therapy. Three hundred sixty-nine patients (59%) discontinued combination therapy with a mean treatment duration of 2.2 years. The most common reasons for discontinued treatment were changing medication to monotherapy with α-blockers or antimuscarinics (124 patients, 19.8%), receiving surgical intervention (39 patients, 6.2%), and LUTS improvement (53 patients, 8.5%). Only 64 patients (10.2%) were loss to follow-up and 6 (1.0%) discontinued combined treatment due to adverse effects. Smaller TPV after short-term combination treatment caused withdrawal from combination therapy. CONCLUSIONS: BPH patients receiving long-term combination therapy showed significant improvement in all measured parameters. Changing medication, improved LUTS and choosing surgery are common reasons for discontinuing combination herapy. A smaller TPV after short-term combination treatment was among the factors that caused withdrawal from combination therapy.
Adrenergic alpha-1 Receptor Antagonists ; Follow-Up Studies ; Humans ; Lower Urinary Tract Symptoms ; Medication Adherence ; Muscarinic Antagonists ; Patient Compliance* ; Prostate ; Prostate-Specific Antigen ; Prostatic Hyperplasia* ; Quality of Life ; Residual Volume ; Retrospective Studies ; Therapeutic Uses

PURPOSE: Tamsulosin 0.2 mg is used widely in Asian people, but the low dose has been studied less than tamsulosin 0.4 mg or other alpha blockers of standard dose. This study investigated the efficacy and safety of tamsulosin 0.2 mg by a meta-analysis and meta-regression. MATERIALS AND METHODS: We conducted a meta-analysis of efficacy of tamsulosin 0.2 mg using International Prostate Symptom Score (IPSS), maximal urinary flow rate (Qmax), post-voided residual volume (PVR), and quality of life (QoL). Safety was analyzed using adverse events. Relevant studies were searched using MEDLINE, EMBASE, and Cochrane library from January 1980 to June 2013. RESULTS: Ten studies were included with a total sample size of 1418 subjects [722 tamsulosin 0.2 mg group and 696 other alpha-blockers (terazosin, doxazosin, naftopidil, silodosin) group]. Study duration ranged from 4 to 24 weeks. The pooled overall standardized mean differences (SMD) in the mean change of IPSS from baseline for the tamsulosin group versus the control group was 0.02 [95% confidence interval (CI); -0.20, 0.25]. The pooled overall SMD in the mean change of QoL from baseline for the tamsulosin group versus the control group was 0.16 (95% CI; -0.16, 0.48). The regression analysis with the continuous variables (number of patients, study duration) revealed no significance in all outcomes as IPSS, QoL, and Qmax. CONCLUSION: This study clarifies that tamsulosin 0.2 mg has similar efficacy and fewer adverse events compared with other alpha-blockers as an initial treatment strategy for men with lower urinary tract symptoms.
Adrenergic alpha-1 Receptor Antagonists/*administration & dosage/therapeutic use ; Adrenergic alpha-Antagonists ; Dose-Response Relationship, Drug ; Humans ; Male ; Middle Aged ; Prostatic Hyperplasia/*complications ; *Quality of Life ; Sulfonamides/*administration & dosage/therapeutic use

OBJECTIVEPostural tachycardia syndrome (POTS) is one of the major causes of orthostatic intolerance in children. We systematically reviewed the pathogenesis and the progress of individualized treatment for POTS in children.

DATA SOURCESThe data analyzed in this review are mainly from articles included in PubMed and EMBASE.

STUDY SELECTIONThe original articles and critical reviews about POTS were selected for this review.

RESULTSStudies have shown that POTS might be related to several factors including hypovolemia, high catecholamine status, abnormal local vascular tension, and decreased skeletal muscle pump activity. In addition to exercise training, the first-line treatments mainly include oral rehydration salts, beta-adrenoreceptor blockers, and alpha-adrenoreceptor agonists. However, reports about the effectiveness of various treatments are diverse. By analyzing the patient's physiological indexes and biomarkers before the treatment, the efficacy of medication could be well predicted.

CONCLUSIONSThe pathogenesis of POTS is multifactorial, including hypovolemia, abnormal catecholamine state, and vascular dysfunction. Biomarker-directed individualized treatment is an important strategy for the management of POTS children.

Adrenergic alpha-Agonists ; therapeutic use ; Adrenergic beta-Antagonists ; therapeutic use ; Catecholamines ; metabolism ; Humans ; Postural Orthostatic Tachycardia Syndrome ; drug therapy ; metabolism ; pathology ; therapy