mirabegron and Disease-Models--Animal

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and β3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.

Topics: Acetanilides; Adipose Tissue, Brown; Animals; Cold Temperature; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Male; Proteomics; Rats; Subcutaneous Fat; Thermogenesis; Thiazoles; Uncoupling Protein 1; Weight Gain

There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model.. Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, β-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization.. Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Topics: Acetanilides; Animals; Central Nervous System Sensitization; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thiazoles; Urinary Bladder, Overactive

It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates β3 adrenergic receptor (β3 AR). However, the effect of selective β3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown.. We generated a CIH-induced atherosclerosis model through exposing ApoE. The expression of β3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE. This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via β3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.

Topics: Acetanilides; Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Humans; Hypoxia; Mice; Oxygen; Reactive Oxygen Species; Receptors, Adrenergic; Sleep Apnea, Obstructive; Thiazoles

Transient receptor potential melastatin 8 (TRPM8) channels may contribute to the pathophysiological bladder afferent hyperactivity, thus a TRPM8 antagonist would be a promising therapeutic target for the bladder hypersensitive disorders including urinary urgency in overactive bladder (OAB). We aimed to investigate a pharmacological effect of KPR-5714, a novel selective TRPM8 antagonist, on TRPM8 channels, M

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Calcium Signaling; Cyclic AMP; Disease Models, Animal; Drug Therapy, Combination; Female; HEK293 Cells; Humans; Muscarinic Antagonists; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; Thiazoles; Tolterodine Tartrate; TRPM Cation Channels; Urinary Bladder; Urinary Bladder, Overactive; Urodynamics

To investigate the protective effect of mirabegron on bladder dysfunction in an acute urinary retention rat model.. Thirty-six 16-week Sprague-Dawley rats were assigned to the mirabegron and normal saline (N/S) groups. Each group of eighteen was divided into sub-groups of 6 for 30 min, 2 h, and 24 h. They were administered mirabegron (10 mg/kg) and N/S daily for 4 weeks, respectively. Mirabegron and N/S groups were divided into sub-groups of 6 rats for 30 min, 2 h, and 24 h. The changes in bladder blood flow were measured using laser Doppler (moorVMS-LDF2). Histopathological examination of the bladder and nitric oxide (NO) measurement were performed.. During the urinary retention phase in the mirabegron group, it showed higher and rapider recovery of blood flow; the lowest at 19.5% ± 3.68% at 3 min, a significant recovery from the lowest value as 23.7 ± 3.4% at 10 min, than that in the N/S group; 15.1 ± 1.84% at 5 min, 23.7 ± 3.4% at 20 min, respectively (P < 0.05). At 30 min, 120 min, and 24 h after reperfusion, the recovery of blood flow in the mirabegron group was significantly higher than that in the N/S group (mirabegron: 41.1 ± 1.7%, 59.9 ± 7.2%, and 89.7 ± 4.4%, N/S: 31.3 ± 2.1%, 47.3 ± 4.5%, 83.9 ± 3.6%, respectively (P < 0.05)). NO levels tended to be higher in the mirabegron group; however, the difference was not statistically significant. Histological examination revealed that the mirabegron group showed recovery close to normal tissue after 24 h.. In an acute urinary retention rat model, mirabegron maintained and restored higher bladder blood flow, resulting in protective and recovery effect after acute urinary retention.

Topics: Acetanilides; Acute Disease; Adrenergic beta-3 Receptor Agonists; Animals; Disease Models, Animal; Rats; Rats, Sprague-Dawley; Thiazoles; Urinary Retention

To evaluate the effects of mirabegron on bladder blood flow in a rat model of bladder outlet obstruction (BOO).. Adult female Sprague-Dawley rats were divided into three groups based on whether they underwent a sham operation (sham group) or an operation to establish partial BOO (BOO and BOO + mirabegron groups). The BOO + mirabegron group was treated with mirabegron (0.3 mg/kg/h, subcutaneously) for 14 days. Subsequently, we performed continuous cystometry, bladder blood flow measurements with a 2D laser blood flow imager, hematoxylin-eosin staining of the bladder tissue, and malondialdehyde (MDA) measurements in the bladder tissue.. Cystometry revealed significantly higher peak pressure, more residual urine volume, and lower voiding efficiency in the BOO and BOO + mirabegron groups than in the sham group. The BOO + mirabegron group had significantly fewer non-voiding contractions (NVCs) than the BOO group, while the latter had more frequent NVCs than the sham group. The BOO and BOO + mirabegron groups had significantly decreased bladder blood flow than the sham group, whereas the BOO + mirabegron group showed significantly increased bladder blood flow than the BOO group. The bladder tissue in the BOO group contained more hypertrophic detrusor muscle compared to the sham group, while mirabegron treatment suppressed detrusor hypertrophy. The MDA levels were significantly higher in the BOO group than in the BOO + mirabegron and sham groups.. Mirabegron treatment significantly improved BOO-induced bladder dysfunction through the amelioration of bladder blood flow.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Disease Models, Animal; Female; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Thiazoles; Urinary Bladder; Urinary Bladder Neck Obstruction

To examine the effect of combining a nonselective muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (an active metabolite of fesoterodine), with a β3 adrenoceptor agonist, mirabegron, in a rat model of pelvic congestion.. The rat pelvic congestion model used female Sprague-Dawley rats with their bilateral common iliac and uterine veins ligated. Expressions of M2 and M3 receptor subtypes in the urothelium and detrusor were detected by real-time polymerase chain reaction assays. The effects of both drugs were investigated on isolated bladder strips contracted by electrical field stimulation. in vivo single cystometry was used to assess the effects of 5-hydroxymethyl tolterodine and mirabegron independently or in combination on bladder capacity, micturition pressure, and threshold pressure.. Pelvic congestion rats showed decreased bladder capacity compared with controls, but micturition pressure and threshold pressure were unchanged. Pelvic congestion model rats also demonstrated an approximately two-fold increase in expression of both M2 and M3 receptor subtypes in the urothelium. Additive relaxant effects of 5-hydroxymethyl tolterodine and mirabegron were observed in vitro in the electrical field stimulation-induced contractions of bladder strips from pelvic congestion rats. In vivo, bladder capacity was increased significantly by a combination of 5-hydroxymethyl tolterodine and mirabegron, with the combined effect exceeding the sum of the effects of monotherapies. Micturition pressure and threshold pressure did not significantly differ between groups.. The combination of 5-hydroxymethyl tolterodine with mirabegron suggests the potential of synergistic effects in a rat pelvic congestion model.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Benzhydryl Compounds; Cresols; Disease Models, Animal; Drug Monitoring; Drug Therapy, Combination; Female; Muscarinic Antagonists; Rats; Rats, Sprague-Dawley; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive

Though the association between overactive bladder (OAB) and depression was noticed years ago, the pharmaceutical market does not offer one universal drug that would cure both conditions at the same time. The main goal of our present experiments was to determine whether a 14-day administration of solifenacin (0.03 mg/kg/day), mirabegron (1 mg/kg/day), or duloxetine (1 mg/kg/day) would reverse detrusor overactivity and depression-like signs in female Wistar rats subjected to corticosterone treatment. Surgical procedures, cystometric studies, biochemical analyses, and the forced swim test were performed according to published literature. After 14 days of exposure to corticosterone (20 mg/kg/day, subcutaneously), the tested animals presented symptoms of depression, detrusor overactivity, inflammation, and disturbances in neurotrophic factors. The obtained results demonstrated that solifenacin and mirabegron act mainly via peripheral pathways in OAB, whereas the central pathways are responsible for the effects of duloxetine. 72 h after discontinuation of duloxetine treatment, positive changes in the corticosterone-induced depression, detrusor overactivity, and inflammation were observed. Duloxetine seems to have a potential to become a new treatment option for patients with OAB co-existing with depression.

Topics: Acetanilides; Animals; Antidepressive Agents; Behavior, Animal; Corticosterone; Depression; Disease Models, Animal; Duloxetine Hydrochloride; Female; Locomotion; Rats; Rats, Wistar; Signal Transduction; Solifenacin Succinate; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive; Urological Agents

Today, monotherapy is the most common pharmacological treatment option for patients suffering from overactive bladder (OAB). Recent reports have indicated potential benefits of combination therapy, using a muscarinic antagonist and a β

Topics: Acetanilides; Animals; Cyclophosphamide; Cystitis; Disease Models, Animal; Drug Therapy, Combination; Male; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Thiazoles; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive

Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of β

Topics: Acetanilides; Adrenergic beta-1 Receptor Agonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Isoproterenol; Lung; Nebivolol; Propranolol; Pulmonary Circulation; Pulmonary Embolism; Rabbits; Receptors, Adrenergic, beta; Thiazoles; Vascular Resistance

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03-3 mg/kg) or mirabegron (0.03-3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non-voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine.

Topics: Acetanilides; Animals; Disease Models, Animal; Female; Rats; Rats, Sprague-Dawley; Solifenacin Succinate; Spinal Cord Injuries; Thiazoles; Urethra; Urinary Bladder; Urological Agents

The administration of the selective β3 adrenergic receptor (β3AR) agonist BRL-37344 protects from myocardial ischemia/reperfusion injury (IRI), although the lack of clinical approval limits its translatability. We tested the cardioprotective effect of mirabegron, the first-in-class β3AR agonist approved for human use. A dose-response study was conducted in 6 pigs to select the highest intravenous dose of mirabegron without significant detrimental hemodynamic effect. Subsequently, closed chest anterior myocardial infarction (45 min ischemia followed by reperfusion) was performed in 26 pigs which randomly received either mirabegron (10 μg/kg) or placebo 5 min before reperfusion. Day-7 cardiac magnetic resonance (CMR) showed no differences in infarct size (35.0 ± 2.0% of left ventricle (LV) vs. 35.9 ± 2.4% in mirabegron and placebo respectively, p = 0.782) or LV ejection fraction (36.3 ± 1.1 vs. 34.6 ± 1.9%, p = 0.430). Consistent results were obtained on day-45 CMR. In conclusion, the intravenous administration of the clinically available selective β3AR agonist mirabegron does not reduce infarct size in a swine model of IRI.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Disease Models, Animal; Magnetic Resonance Imaging, Cine; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Random Allocation; Swine; Thiazoles; Ventricular Function, Left; Ventricular Remodeling

Androgen deficiency has been implicated in urological complications of postmenopausal women. This study examined the effects of testosterone replacements on the lower urinary tract dysfunction in 4-month old ovariectomized (OVX) rats.. Sprague-Dawley female rats were OVX bilaterally. Three months later, rats received single intramuscular injections of testosterone undecanoate. Cystometric study, and bladder and urethra smooth muscle reactivities were evaluated.. The improvement of micturition dysfunction by testosterone replacement suggests that androgen therapy might be of therapeutic benefit for urological complications associated with post-menopause.

Topics: Acetanilides; Androgens; Angiotensin II; Animals; Carbachol; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Injections, Intramuscular; Letrozole; Muscle, Smooth; Nitriles; Ovariectomy; Postmenopause; Rats; Rats, Sprague-Dawley; Testosterone; Thiazoles; Triazoles; Urethra; Urination Disorders

This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β. Thirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β. Just after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M. This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026-1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Cold Temperature; Disease Models, Animal; Drug Therapy, Combination; Female; Muscarinic Antagonists; Rats; Rats, Inbred SHR; Solifenacin Succinate; Stress, Physiological; Thiazoles; Urinary Bladder; Urinary Bladder, Overactive; Urological Agents

To investigate the effects of combined therapy with an anticholinergic agent and a β3-adrenoceptor agonist on bladder dysfunction and proliferation-related molecule expression in rats with spinal cord injury (SCI).. The spinal cord was transected at the level of T8-9 in female Sprague-Dawley rats, which were divided into four groups; A: Vehicle, B: 10 mg/kg/day of oxybutynin, C: 10 mg/kg/day of mirabegron, and D: combined administration of oxybutynin and mirabegron. Drugs were administered by oral gavage from 2 to 4 weeks after spinal cord transection. We evaluated urodynamic parameters and bladder tissue remodeling factors.. Non-voiding contractions (NVCs) during the storage phase of cystometrograms tended to be decreased in all three treated groups with a significant reduction in group D versus A. Bladder compliance was improved, and intercontraction intervals, voided volume and bladder capacity were increased in group D. In all three treated groups (B-D), the expression of HIF1-α and TGF-β1 was decreased compared to group A. The expression of collagen-III and bFGF was decreased in groups B and D. The total bladder elastin level was increased in group D.. The combination therapy of an anticholinergic agent and a β3-adrenoceptor agonist elevated the bladder elastin level, reduced NVCs, and increased bladder compliance more effectively than the monotherapy in SCI rats. Thus, the combination therapy could be effective for the treatment of neurogenic bladder dysfunction including bladder remodeling. Neurourol. Urodynam. 36:1039-1045, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Disease Models, Animal; Drug Therapy, Combination; Female; Mandelic Acids; Muscarinic Antagonists; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Thiazoles; Urinary Bladder; Urinary Bladder, Neurogenic; Urination; Urodynamics; Urological Agents

Beta-3 adrenergic receptor (β3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of β3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of β3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of β3AR mRNA and the vasodilator response of β3AR agonists in pulmonary arteries. Single intravenous administration of the β3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different β3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. +1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. +1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in β3AR agonists-treated pigs. β3AR was expressed in human pulmonary arteries and β3AR agonists produced vasodilatation. β3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Blotting, Western; Disease Models, Animal; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Nebivolol; Pulmonary Artery; Random Allocation; Real-Time Polymerase Chain Reaction; Receptors, Adrenergic, beta-3; Swine; Thiazoles; Vascular Resistance; Ventricular Remodeling

Urological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking.. Thus, the aim of this study was to evaluate urinary function, in vivo and ex vivo, in the Berkeley SCD murine model (SS).. Urine output was measured in metabolic cage for both wild type and SS mice (25-30 g). Bladder strips and urethra rings were dissected free and mounted in organ baths. In isolated detrusor smooth muscle (DSM), relaxant response to mirabegron and isoproterenol (1nM-10μM) and contractile response to (carbachol (CCh; 1 nM-100μM), KCl (1 mM-300mM), CaCl2 (1μM-100mM), α,β-methylene ATP (1, 3 and 10 μM) and electrical field stimulation (EFS; 1-32 Hz) were measured. Phenylephrine (Phe; 10nM-100μM) was used to evaluate the contraction mechanism in the urethra rings. Cystometry and histomorphometry were also performed in the urinary bladder.. SS mice present a reduced urine output and incapacity to produce typical bladder contractions and bladder emptying (ex vivo), compared to control animals. In DSM, relaxation in response to a selective β3-adrenergic agonist (mirabegron) and to a non-selective β-adrenergic (isoproterenol) agonist were lower in SS mice. Additionally, carbachol, α, β-methylene ATP, KCl, extracellular Ca2+ and electrical-field stimulation promoted smaller bladder contractions in SS group. Urethra contraction induced by phenylephrine was markedly reduced in SS mice. Histological analyses of SS mice bladder revealed severe structural abnormalities, such as reductions in detrusor thickness and bladder volume, and cell infiltration.. Taken together, our data demonstrate, for the first time, that SS mice display features of urinary bladder dysfunction, leading to impairment in urinary continence, which may have an important role in the pathogenesis of the enuresis and infections observed the SCD patients.

Topics: Acetanilides; Adenosine Triphosphate; Anemia, Sickle Cell; Animals; Atropine; Calcium Chloride; Carbachol; Disease Models, Animal; Diuresis; Electric Stimulation; Hemoglobin, Sickle; Humans; Isoproterenol; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle Contraction; Muscle, Smooth; Phenylephrine; Potassium Chloride; Thiazoles; Urethra; Urinary Bladder

The β3-adrenoceptor (AR) agonist mirabegron has been introduced as a treatment for the overactive bladder. Its effects on the function of the ischemic bladder are not known.. To investigate the effect of mirabegron in a rat model of chronic ischemia-related bladder dysfunction.. Male Sprague-Dawley rats were divided into three groups: control (n=10), arterial endothelial injury (AI; n=16), and AI with mirabegron treatment (AI-mirabegron; n=10). AI and AI-mirabegron groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-mirabegron rats received mirabegron (10mg/kg/d) orally for 8 wk. The control group received a regular diet.. After 8 wk, urodynamic investigation was performed in awake animals. Pharmacologic in vitro studies and histologic examination of the iliac arteries and bladders were performed.. Iliac arteries from both AI and AI-mirabegron rats displayed neointimal formation and luminal occlusion. Micturition interval (MI), bladder capacity (Bcap), and voided volume (VV) in the AI group were significantly less than in the control group (p<0.01). In the AI-mirabegron group, MI, Bcap, and VV were significantly larger than in the AI group (p<0.05) but significantly less than in the control group (p<0.05). Contractile responses of bladder strips to potassium chloride, electrical field stimulation, and carbachol were significantly lower after AI than in controls; responses in preparations from AI-mirabegron-treated animals were similar to those of controls. The AI group showed a significantly higher percentage of collagen (28.6 ± 1.57%) compared with the controls (8.65 ± 0.67%) and AI-mirabegron-treated animals (17.2 ± 2.32%). The mirabegron dose used in this study may potentially limit the translational value of the results.. In the chronically ischemic rat bladder, treatment with mirabegron seems to protect bladder function and morphology, resulting in reduced bladder hyperactivity. If the results are valid for humans, they support β3-AR agonism as a potential treatment of chronic ischemia-related bladder dysfunction.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Cholesterol, Dietary; Chronic Disease; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Iliac Artery; Ischemia; Male; Neointima; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; Thiazoles; Time Factors; Urinary Bladder; Urinary Bladder, Overactive; Urination; Urodynamics; Vascular System Injuries