Adrenoceptor Antagonist Research Articles

Adenosine 3',5'-cyclic monophosphate involvement in hepatic triacylglyceride lipase release from prazosin-stimulated primary cultured rat hepatocytes.

We recently found that hepatic triglyceride lipase (HTGL) was released from primary cultured rat hepatocytes after treatment with prazosin, an antagonist of alpha-1 adrenoceptors. However, the details of prazosin-induced HTGL release remain uncertain. Here we investigated whether changes in cAMP levels in hepatocytes were related to HTGL release from prazosin-stimulated hepatocytes. When hepatocytes were treated with prazosin, cAMP levels during stimulated release of HTGL increased in a time- and dose-dependent manner. Stimulated release of HTGL was suppressed by the adenylate cyclase inhibitors MDL-12,330A and 2',5'-dideoxyadenosine. Further, cAMP-dependent protein kinase A (PKA) activity in prazosin-stimulated hepatocytes also increased in a time- and dose-dependent manner. Moreover, prazosin-stimulated HTGL release was suppressed by the PKA inhibitors H-89 and KT5720. These results suggest that prazosin-stimulated HTGL release from hepatocytes was due to cAMP production and partly due to subsequent PKA activation in hepatocytes.

Urine Flow Dynamics Through Prostatic Urethra With Tubular Organ Modeling Using Endoscopic Imagery.

Voiding dysfunction is common in the aged male population. However, the obstruction mechanism in the lower urinary tract and critical points for obstruction remains uncertain. The aim of this paper was to develop a system to investigate the relationship between voiding dysfunction and alteration of the shape of the prostatic urethra by processing endoscopic video images of the urethra and analyzing the fluid dynamics of the urine stream. A panoramic image of the prostatic urethra was generated from cystourethroscopic video images. A virtual 3-D model of the urethra was constructed using the luminance values in the image. Fluid dynamics using the constructed model was then calculated assuming a static urethra and maximum urine flow rate. Cystourethroscopic videos from 11 patients with benign prostatic hyperplasia were recorded around administration of an alpha-1 adrenoceptor antagonist. The calculated pressure loss through the prostatic urethra in each model corresponded to the prostatic volume, and the improvements of the pressure loss after treatment correlated to the conventional clinical indices. As shown by the proposed method, the shape of the prostatic urethra affects the transporting urine fluid energy, and this paper implies a possible method for detecting critical lesions responsible for voiding dysfunction. The proposed method provides critical information about deformation of the prostatic urethra on voiding function. Detailed differences in the various types of relaxants for the lower urinary tract could be estimated.

PGE<sub>2</sub> Generation in Myocardium from Isolated Rat Atrium under Hypoxia and Reoxygenation Conditions. Effect of Anti-<i>β</i><sub>1</sub> IgG from Patients with Chronic Severe Periodontitis

Background: Hypoxia is one of the most frequently encountered stresses in health and disease. Methods: We compared the effects of an anti-β1 periodontal IgG (pIgG) and an authentic β1 adrenergic agonist, xamoterol, on isolated myocardium from rat atria contractility. We used an ELISA assay to measure the generation of PGE2 in vitro after the addition of either the antibody or the adrenergic agonist. We analyzed the myocardium histopathologically in the presence of both the antibody and/or the adrenergic agonist drug during normoxia, hypoxia and reperfusion conditions. Results: PGE2 generation increased during the hypoxia and was unchanged during reoxygenation period compared with the production of this prostanoid in atria during normoxia condition. A β1 specific adrenoceptor antagonist atenolol and the β1 synthetic peptide abrogated the increment of the prostanoid in the presence of pIgG but only atenolol due to it in the presence of xamoterol. The increment of PGE2 was dependent on the activation of cox-1 and cox-2 isoforms. Moreover, cox-2 was more active and produced more increments in the production of PGE2 in the presence of the pIgG than cox-1 activation. Histopathologically, studies of myocardium specimens during these different periods of the experimental protocol: basal (B), hypoxia (H) and reoxygenation (R), were also performed and showed tissue necrosis and edematization at the myocardium level. Conclusion: The phenomenon studied here supports the notion that PGE2 may be responsible for tissue edematization. PGE2 maybe acts as a beneficial modulator in the myocardium and prevents a major injury of it. The inflammation damage to the heart organ and cardiomyocytes caused by the actions of the antibodies in the course of heart lesions provoked by cardiovascular autoimmune disease, explains some of these results obtained in the present experiments. Further studies will be needed to establish the real role of PGE2 during hypoxia injury of the heart in the course of autoimmune diseases.

Metoprolol reduces proinflammatory cytokines and atherosclerosis in ApoE-/- mice.

A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE−/− mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE−/− mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE−/− mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.

The Mechanism for Analgesic Effects of Electroacupuncture on Surgical Ankle Sprain Model Classified as Grade 3 in Rats

Objectives : Electroacupuncture(EA) has been used effectively in producing analgesia on ankle sprain pain of humans and animals. Currently to examine the underlying mechanisms of the EA-induced analgesia, the effects of EA on weight-bearing forces(WBR) were examined at ankle sprain classified as grade 3 in rats. Methods : The severe ankle sprain classified as grade 3 was induced surgically by ankle ligament injury in the Sprague-Dawley rats. WBR of the affected foot were examined to evaluate effects and mechanism of EA(2 Hz, 1 ms pulse width, 2 mA intensity, for 15 min) which was applied to either SI6, GB34, or GB39 acupoints. The rats were pretreated with naltrexone(10 mg/kg, i.p.) as an opioid receptor antagonist or phentolamine(5 mg/kg, i.p) as an -adrenoceptor antagonist at 30 min before EA. Results : The daily repeat EA at either SI6, GB34, or GB39 showed significant analgesic effects on the severe ankle sprain. Particularly, daily EA at GB34 showed more potent analgesic effect than the others. In addition, the naltrexone pretreatment completely blocked the analgesic effect of EA at GB34, indicating the involvement of the endogenous opioid system in mediating the effect of EA at GB34. However, the phentolamine pretreament blocked analgesic effects of EA at either SI6 or GB39, indicating the involvement of -adrenoceptors in mediating the effect of EA at either SI6 or GB39. Conclusions : These data suggest that EA-induced analgesia on ankle sprain pain is mediated through either endogenous opioids or -adrenoceptors dependant on acupoint specific pattern.

β1-Selective Adrenoceptor Antagonists Increase Plasma Levels of Anti-p2β Antibodies and Decrease Cardiac Involvement in Chronic Progressive Chagas Heart Disease

BackgroundStudies indicate that antibodies cross-reacting with cardiac β1 adrenergic receptors are likely to play a role in the development of chronic Chagas heart disease (CCHD). In parallel, clinical trials have shown that β1 antagonist drugs exert beneficial effects in the prognosis of patients with CCHD. In a group of patients with CCHD undergoing therapy with β1-blockers, we have now evaluated the levels of anti-p2β antibodies and the severity of CCHD. MethodsWe performed a cross-sectional study in Trypanosoma cruzi seropositive patients categorized according to a standard CCHD classification. All individuals were subjected to a complete clinical examination. ResultsThere was no association between CCHD stages, electrocardiographic conduction disturbances, and echocardiogram pathological signs with the levels of autoantibodies. However, when patients were analyzed according to selective cardio-β1-blocker therapy, those receiving treatment had higher levels of anti-p2β. Patients from CCHD stage III treated with combined therapy of cardio-β1-selective blockers, enalapril, and statins, presented decreased cardiac involvement and lower score of risk of mortality than individuals from the same group who were not treated. ConclusionsOur results suggest that selective cardio-β1-blockers might modify the autoantibody anti-p2β levels, and that combined therapy in patients with stage III CCHD might be associated with lower cardiac involvement and risk score of mortality in patients with heart failure. Longitudinal studies will help to ascertain the proper role of β1-blockers in the immunopathological processes underlying chronic Chagas disease.

Anxiogenic Effects of Acute Injection of Sesame oil May be Mediated by β-1 Adrenoceptors in the Basolateral Amygdala.

A few studies have indicates that the sesame oil influences anxiety, but many reports show that β-1 adrenoceptors (ARs) of the basolateral amygdala (BLA) plays a pivotal role in this regard. Therefore, in this study the effect of acute injection of sesame oil on anxiety-like behavior in the presence and absence of the BLA β-1 ARs in the male Wistar rats were investigated. Guide cannulas, for seven groups of rats, were implanted bilaterally into the BLA. Two weeks after the stereotaxic surgery, anxiety-like behaviors (the OAT%, OAE % and locomotor activity) were evaluated by Elevated Plus-Maze (EPM) for all groups. 3 groups received different volumes of sesame oil (i.p.) and they were compared with control group (received saline via i.p.), and the anxiogenic volume of sesame oil (1.5ml/kg) was determined. Then, 3 other groups received constant effective volume of sesame oil (1.5ml/kg) along with 3 different doses of betaxolol, selective β-1 ARs antagonist, intra BLA microinjection in order to be compared with sesame oil group (1.5 ml/kg). The acute injection of sesame oil with the volume dependent manner showed an anxiogenic effect with reduction of the OAT% and OAE% which the maximum effect of sesame oil was observed in the dose of 1.5mg/kg. Also, betaxolol with dose dependent manner attenuated the anxiogenic effects of sesame oil (1.5mg/kg), but this reduction could not remove the anxiety effects completely. It seems that the sesame oil acute (i.p.) injection induces anxiety, and this effect is attenuated by inhibition of β-1ARs in the BLA.

Inflammation in dorsal root ganglia after peripheral nerve injury: Effects of the sympathetic innervation

Following a peripheral nerve injury, a sterile inflammation develops in sympathetic and dorsal root ganglia (DRGs) with axons that project in the damaged nerve trunk. Macrophages and T-lymphocytes invade these ganglia where they are believed to release cytokines that lead to hyperexcitability and ectopic discharge, possibly contributing to neuropathic pain. Here, we examined the role of the sympathetic innervation in the inflammation of L5 DRGs of Wistar rats following transection of the sciatic nerve, comparing the effects of specific surgical interventions 10-14 days prior to the nerve lesion with those of chronic administration of adrenoceptor antagonists. Immunohistochemistry was used to define the invading immune cell populations 7 days after sciatic transection. Removal of sympathetic activity in the hind limb by transecting the preganglionic input to the relevant lumbar sympathetic ganglia (ipsi- or bilateral decentralization) or by ipsilateral removal of these ganglia with degeneration of postganglionic axons (denervation), caused less DRG inflammation than occurred after a sham sympathectomy. By contrast, denervation of the lymph node draining the lesion site potentiated T-cell influx. Systemic treatment with antagonists of α1-adrenoceptors (prazosin) or β-adrenoceptors (propranolol) led to opposite but unexpected effects on infiltration of DRGs after sciatic transection. Prazosin potentiated the influx of macrophages and CD4(+) T-lymphocytes whereas propranolol tended to reduce immune cell invasion. These data are hard to reconcile with many in vitro studies in which catecholamines acting mainly via β2-adrenoceptors have inhibited the activation and proliferation of immune cells following an inflammatory challenge.

The antiallodynic action of nortriptyline and terbutaline is mediated by β2 adrenoceptors and δ opioid receptors in the ob/ob model of diabetic polyneuropathy

Peripheral polyneuropathy is a frequent complication of diabetes. One of its consequences is neuropathic pain which is often chronic and difficult to treat. This pain management classically involves anticonvulsant drugs or tricyclic antidepressant drugs (TCA). We have previously shown that β2 adrenoceptors and δ opioid receptors are critical for TCA action in a traumatic model of neuropathic pain. In the present work, we used the obese leptin deficient mice (ob/ob) which are a genetic model of type 2 diabetes in order to study the treatment of diabetic polyneuropathy. ob/ob mice with hyperglycemia develop tactile bilateral allodynia. We investigated the action of the TCA nortriptyline and the β2 adrenoceptor agonist terbutaline on this neuropathic allodynia. The consequences of acute and chronic treatments were tested, and mechanical allodynia was assessed by using von Frey hairs. Chronic but not acute treatment with nortriptyline alleviates allodynia caused by the diabetic neuropathy. This effect depends on β2 adrenoceptors but not on α2 adrenoceptors, as shown by the blockade with repeated co-administration of the β2 adrenoceptor antagonist ICI118551 but not with repeated co-administration of the α2 adrenoceptor antagonist yohimbine. Direct stimulation of β2 adrenoceptors appears sufficient to relieve allodynia, as shown with chronic terbutaline treatment. δ but not mu opioid receptors seem important to these action since acute naltrindole, but not acute naloxonazine, reverses the effect of chronic nortriptyline or terbutaline treatment.

IJU this Issue

This issue contains one Review Article, nine Original Articles and three Short Communications. Sung et al. (Seoul, Korea) reviewed robot-assisted surgery in the field of female urology. The authors introduced new techniques using robotic surgery for the management of pelvic organ prolapse and lower urinary tract fistulas. Intra-corporeal suturing and accurate pelvic dissection will be required for the laparoscopic management of these disorders. These techniques can be carried out easily and accurately in robot-assisted surgery. Robot-assisted repairs might be offered for the treatment of pelvic organ prolapse or lower urinary tract fistulas. Lymphocele is one of the common postoperative complications of pelvic lymph node dissection (PLND). Lee et al. (Seoul, Korea) investigated the incidence of lymphocele after extraperitoneal robot-assisted radical prostatectomy (RARP) and PLND. The authors carried out magnetic resonance imaging (MRI) routinely at 3 or 4 months after RARP. A total of 483 patients underwent extraperitoneal RARP, and 200 patients (41.4%) underwent PLND. Lymphocele was detected in 41 (20.5%) patients. Seminal vesicle invasion (SVI, P = 0.015) and tumor volume (P = 0.042) were significantly different between the two groups. In the multivariate analysis, extracapsular extension (ECE; P = 0.017, odds ratio [OR] 4.231), SVI (P = 0.028, OR 2.643) and the number of positive lymph nodes (P = 0.041, OR 3.532) were independent risk factors. They concluded that ECE, SVI and the number of positive lymph nodes are independent risk factors for postoperative lymphocele after extraperitoneal RARP with PLND. From another viewpoint, lymphocele development might be a prognostic factor of prostate cancer patients who undergo RARP and PLND. Many methods of prostate cancer screening have been evaluated to be more effective than basic screening. De Coninck et al. (Brussels, Belgium) evaluated prostate histoscanning (PHS) as a new method for screening. PHS is a computer-aided ultrasonography, and the data obtained from the transrectal ultrasound were processed. A special volumetric tool provided total prostate volume and total tumor lesion volume. The authors devised the algorithm of prostate cancer screening using PHS. A total of 94 cases were examined with PHS, and 41 cases were referred for prostate biopsy under computer-aided ultrasonographic guidance. A tumor volume increase of 1 mL estimated by PHS was associated with the probability of a positive biopsy (OR 2.9, 95% confidence interval 1.2–7.0, P = 0.02). Prostate cancer was found in 17 men (41%), and the cancer detection rate for random biopsy and directed biopsy was 13% and 58%, respectively. PHS might be helpful for the selection of patients in whom prostate biopsies are necessary. Percutaneous nephrolithotomy (PCNL) is a popular treatment for renal calculi greater than 2 cm or staghorn calculi. Sugihara et al. (Tokyo, Japan) investigated the risk factors of severe adverse events (sAE) after PCNL from the data of 1511 cases from the Japanese nationwide database. A total of 126 (8.34%) sAE were identified. In the multivariate analysis, a linear trend between sAE and operation time was observed (OR 4.72 for 120–179 min to OR 17.95 for ≥300 min, compared with ≤119 min, P < 0.05). Female sex (OR 1.92) and emergency admission (OR 2.04) were also identified. The authors concluded that longer operation time was a salient risk factor for sAE after PCNL. It is important to inform patients of these data and also to prevent sAE. To shorten the operating time, well-planned and careful procedures are required. There were some reports that examined prostate cancer reduction by α-1 adrenoceptor antagonist. Yamada et al. (Tokyo, Japan) investigated the effects of naftopidil, an α1-adrenoceptor antagonist, and transforming growth factor-β to reduce prostate cancer incidence. The men who continued naftopidil (n = 766) or tamsulosin (n = 1015) for 3 months or longer were evaluated. Prostate cancer incidence was significantly lower in men who received naftopidil compared with tamsulosin for 3 months or longer (14; 1.8% vs 32; 3.1%, P = 0.035), remains in multivariate analysis (P = 0.013). The authors also evaluated cell viability and apoptosis in prostate cancer cells, and the effect of naftopidil or tamsulosin. Naftopidil inhibited cell growth, induced apoptosis and blocked Smad2 phospholilation activated by transforming growth factor-β. These results suggest the effect of naftopidil as chemoprevention for prostate cancer. None declared.

The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar–Kyoto rats

Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval≤3 min) vs. single REMS (interval>3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on Days 1, 7, and 14 following FC, with either prazosin (0.01mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0mA, 0.5s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on Days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity.

The modulation of catecholamines on immune response of scallop Chlamys farreri under heat stress

Catecholamines (CAs) play key roles in mediating the physiological responses to various stresses. In the present study, the expression of CA-related genes were examined in the hemocytes of scallop Chlamys farreri under heat stress, and several immune or metabolism-related parameters were investigated after heat stress and adrenoceptor antagonist stimulation. After the scallops were cultured at 28°C, the mRNA expression level of dopa decarboxylase (CfDDC) and α-adrenoceptor (CfαAR) increased significantly (P<0.01), whereas that of monoamine oxidase (CfMAO) was down-regulated in the first 6h (P<0.05), and then up-regulated to the maximum level at 24h (P<0.01). In the hemocytes of scallops injected with adrenoceptor antagonist, the expression levels of peptidoglycan-recognition protein (CfPGRP-S1) and C-type lectin (CfLec-1) began to increase significantly at 2 and 3h post propranolol and high temperature treatment, respectively (P<0.01). While the up-regulation of heat shock protein 70 (CfHSP70) post heat stress was significantly inhibited by prazosin injection (P<0.01), and that of hexokinase (CfHK) was inhibited by both prazosin and propranolol injection (P<0.01). Moreover, the remarkable increase of relative specific activity of SOD in the hemolymph post heat stress (P<0.01) was further up-regulated early after prazosin or propranolol injection (P<0.01), while that of the relative anti-bacterial ability was down-regulated by prazosin or propranolol treatment (P<0.01). These results collectively indicated that the catecholaminergic neuroendocrine system in scallop could be activated by heat stress to release CAs, which subsequently modulated the immune response and energy metabolism via α- and β-adrenoceptors.

Olanzapine-Induced Hyperglycemia: Possible Involvement of Histaminergic, Dopaminergic and Adrenergic Functions in the Central Nervous System

Background/Aims: Atypical antipsychotic drugs such as olanzapine are known to induce metabolic disturbance. We have already shown that olanzapine induces hepatic glucose production through the activation of hypothalamic adenosine 5′-monophosphate-activated protein kinase (AMPK). However, it is unclear how olanzapine activates hypothalamic AMPK. Since olanzapine is known to antagonize several receptors, including histaminergic, muscarinic, serotonergic, dopaminergic and adrenergic receptors, we examined the effect of each receptor antagonist on blood glucose levels in mice. Moreover, we also investigated whether these antagonists activate hypothalamic AMPK. Methods: Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. AMPK expression was measured by Western blotting. Results: Central administration of olanzapine (5-15 nmol i.c.v.) dose-dependently increased blood glucose levels in mice, whereas olanzapine did not change blood insulin levels. Histamine H₁ receptor antagonist chlorpheniramine (1-10 μg i.c.v.), dopamine D₂ receptor antagonist <smlcap>L</smlcap>-sulpiride (1-10 μg i.c.v.) and α₁-adrenoceptor antagonist prazosin (0.3-3 μg i.c.v.) also significantly increased blood glucose levels in mice. In contrast, the blood glucose levels were not affected by muscarinic M₁ receptor antagonist dicyclomine (1-10 μg i.c.v.) or serotonin 5-HT_2A receptor antagonist M100907 (1-10 ng i.c.v.). Olanzapine-induced hyperglycemia was inhibited by the AMPK inhibitor compound C, and AMPK activator AICAR (10 ng to 1 μg i.c.v.) significantly increased blood glucose levels. Olanzapine (15 nmol), chlorpheniramine (10 μg), <smlcap>L</smlcap>-sulpiride (10 μg) and prazosin (3 μg) significantly increased phosphorylated AMPK in the hypothalamus of mice. Conclusion: These results suggest that olanzapine activates hypothalamic AMPK by antagonizing histamine H₁ receptors, dopamine D₂ receptors and α₁-adrenoceptors, which induces hyperglycemia.

Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer's disease: A randomized, double-blind, proof-of-concept study

Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer's disease: A randomized, double-blind, proof-of-concept study

Advantageous safety profile of a dual selective alpha2Cagonist/alpha2Aantagonist antinociceptive agent

A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.

Exploration of supraspinal mechanisms in effects of spinal cord stimulation: Role of the locus coeruleus

The neurobiological mechanisms of spinal cord stimulation (SCS) when applied for neuropathic pain are still incompletely known. Previous research indicates that brainstem circuitry is pivotal for the SCS effect. The present study aims at exploring the possible contribution to the SCS effects of the pain controlling system emanating from the locus coeruleus (LC) in the brain stem. Experiments were performed on the rat-spared nerve injury pain model. After evaluation of the attenuation of mechanical hypersensitivity induced by SCS, the effects of SCS on neuronal activity in the LC and on the noradrenaline (NA) content in the dorsal spinal cord were analyzed. SCS produced a significant increase in the discharge rate of LC neurons only in rats behaviorally responding to SCS as compared to non-responding and control animals. The NA content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was analyzed using enzyme-linked immunosorbent assay in responding, non-responding and intact control rats both immediately following SCS and without SCS. No differences were found between these groups. In awake animals, lidocaine silencing of the ipsilateral LC or blocking of spinal noradrenergic system by intrathecal administration of α1,2 adrenoceptor antagonists failed to influence the antihypersensitivity effect of SCS. The present results indicate that the SCS-induced control of hypersensitivity in an experimental animal model of peripheral neuropathic pain may not be explained by the activation of direct spinal projections of noradrenergic LC neurons, while supraspinal projections of LC neurons still may play a role in the SCS effect.

Sympathetic Nervous System Catecholamines and Neuropeptide Y Neurotransmitters Are Upregulated in Human NAFLD and Modulate the Fibrogenic Function of Hepatic Stellate Cells

Background Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. NAFLD may lead to cirrhosis. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood.Aimsto determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers.MethodsFreshly isolated hHSC were assessed for expression of cathecholamine/neuropeptide Y receptors and for the synthesis of NE/EPI. The effects of NE/EPI/NPY and adrenoceptor antagonists prazosin (PRZ)/propranolol (PRL) on hHSC fibrogenic functions and the involved kinases and interleukin pathways were examined. Human livers with proven NAFLD were then assessed for upregulation of SNS signalling components.ResultsActivated hHSC express functional α/β-adrenoceptors and NPY receptors, which are upregulated in the livers of patients with cirrhotic NAFLD. hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival. Exogenous NE/EPI and NPY dose-dependently induced hHSC proliferation, mediated via p38 MAP, PI3K and MEK signalling. NE and EPI but not NPY increased expression of collagen-1α2 via TGF-β without involvement of the pro-fibrogenic cytokines leptin, IL-4 and IL-13 or the anti-fibrotic cytokine IL-10.ConclusionshHSC synthesize and require cathecholamines for optimal survival and fibrogenic functionality. Activated hHSC express directly fibrogenic α/β-adrenoceptors and NPY receptors, upregulated in human cirrhotic NAFLD. Adrenoceptor and NPY antagonists may be novel anti-fibrotic agents in human NAFLD.

E80 Administration of the selective alpha 1A adrenoceptor antagonist silodosin facilitates expulsion of size 5–10 mm distal ureteral stones, as compared to control

Objective Recently, we reported that alpha 1A-adrenoceptor (AR) is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha 1A AR antagonist, as a medical expulsive therapy (MET) for distal ureteral stones.

Prostatic α1‐adrenoceptors: New concepts of function, regulation, and intracellular signaling

Prostatic α1 -adrenoceptors are known to be involved in the pathophysiology of lower urinary tract symptoms (LUTS) in patients with benign prostate obstruction (BPO). It is widely accepted that enhanced α1 -adrenergic smooth muscle contraction can contribute to bladder outlet obstruction; α1 -adrenoceptor antagonists still represent a gold standard in the treatment of LUTS. Accordingly, expression and function of α1 -adrenoceptors in the prostate have attracted large attention over the last three decades. However, recent preclinical studies have challenged our understanding of prostatic α1 -adrenoceptors. In the current review article, we summarize "modern" concepts of prostatic α1 -adrenoceptors which include novel intracellular mediators of contraction as well as non-contractile signaling and post-translational receptor regulation. Configuration of α1 -adrenoceptors with binding partners may determine its function, leading to a dynamic receptor with high functional plasticity. Cooperative regulation of different intracellular effectors (MAPK, Akt, transcription factors) by α1 -adrenoceptors, hormones or growth factors has been suggested. The prostatic α1 -adrenoceptor is no longer being regarded as an isolated, static receptor exclusively mediating prostatic smooth muscle contraction by G proteins, but a dynamic receptor interacting with other receptors within a complex network of mediators.

Mirabegron for Male Lower Urinary Tract Symptoms

Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with BPH often present with a combination of obstructive and overactive bladder (OAB) symptoms. It is postulated that bladder outlet obstruction (BOO) from BPH results in concomitant OAB symptoms through ischemic induced variations in the response to neurotransmitters of both the detrusor and the urothelium. This altered response leads to the pathologic activation of the micturition reflex, generating sensory dysfunction and involuntary bladder contractions. Alpha-1 adrenoceptor antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5-ARIs) are commonly used to treat the BOO caused by BPH. Anticholinergic agents are frequently used to treat concurrently OAB symptoms caused by the BOO. Unfortunately, anticholinergic medications demonstrate bothersome side effects and a theoretical risk of urinary retention. Basic science and clinical research has led to the development of a new class of pharmaceuticals for the treatment of overactive bladder with diminished risk of urinary retention and lacking many anticholinergic side effects. This novel compound, mirabegron (Mybertriq, Astellas Pharma US, Inc.), is a β₃-adrenoceptor agonist and represents a promising new class of oral agents designed for the treatment of OAB symptoms, with minimal effect on voiding.