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Neurotransmitters released from the sympathetic nervous system attach to the adrenergic receptors on the surface of tumoral cells in response to stress, and alter the expression of genes programming cellular activity. This study aimed to assess the expression of α1 adrenergic receptors in the serum and saliva of patients with oral squamous cell carcinoma (OSCC) compared with healthy controls. In this case–control study, serum and stimulated and unstimulated saliva samples were collected from 26 OSCC patients and 26 healthy controls. ELISA kits were used for measurement of the serum and salivary levels of α1 adrenergic receptors. The level of α1 adrenergic receptors was significantly higher in the stimulated and unstimulated saliva of OSCC patients than healthy controls (P = 0.000). However, their serum level was not significantly different between the two groups (P = 0.389). The serum level of α1 adrenergic receptors significantly increased by an increase in OSCC grade. No significant correlation was noted between the serum and salivary levels of α1 adrenergic receptors in OSCC patients. The salivary level of α1 adrenergic receptors was significantly higher in patients with tumors located in the gingiva, compared with other sites. Significantly higher salivary level of α1 adrenergic receptors in OSCC patients compared with healthy controls, and no significant difference in their serum level between the two groups may indirectly indicate the over-expression of these receptors in OSCC cells, compared with normal oral mucosa. Further studies and particularly histological analyses are required to confirm this finding.

The role of catecholamine receptors in cardiac energy metabolism is unknown. α1-adrenergic receptors (α1-ARs) have been identified to play a role in whole body metabolism but its role in cardiac en...

Background The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer’s disease (AD) has rarely been investigated. Clarifying pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic target of AD. Methods This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or equal saline for 6 months. SH-SY5Y cell lines bearing human Amyloid precurssor protein were treated with terazosin or saline for investigating possible mechanisms. Results α1-ARs knockdown mice exhibited improved behavioral performances than control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total plaques, than control mice. The α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including Tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction, and rescued behavioral deficits of APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reduced Aβ production. Conclusions This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

Posttraumatic stress disorder (PTSD) is an independent risk factor for the development of hypertension and cardiovascular disease. Patients with PTSD have heightened blood pressure and sympathetic nervous system reactivity; however, it is unclear if patients with PTSD have exaggerated vasoconstriction in response to sympathetic nerve activation that could also contribute to increased blood pressure reactivity. Therefore, we hypothesized that patients with PTSD have increased sensitivity of vascular α1-adrenergic receptors (α1ARs), the major mediators of vasoconstriction in response to release of norepinephrine at sympathetic nerve terminals. To assess vascular α1AR sensitivity, we measured the degree of venoconstriction in a dorsal hand vein in response to exponentially increasing doses of the selective α1AR agonist, phenylephrine (PE), in 9 patients with PTSD (age = 59 ± 2 yr) and 10 age-matched controls (age = 60 ± 1 yr). Individual dose-response curves were generated to determine the dose of PE that induces 50% of maximal venoconstriction (i.e., PE ED50) reflective of vascular α1AR sensitivity. In support of our hypothesis, PE ED50values were lower in PTSD compared with controls (245 ± 54 ng/min vs. 1,995 ± 459 ng/min, P = 0.012), indicating increased vascular α1AR sensitivity in PTSD. The PTSD group also had an increase in slope of rise in venoconstriction, indicative of an altered venoconstrictive reactivity to PE compared with controls (19.8% ± 1.2% vs. 15.1% ± 1.2%, P = 0.009). Heightened vascular α1AR sensitivity in PTSD may contribute to augmented vasoconstriction and blood pressure reactivity to sympathoexcitation and to increased cardiovascular disease risk in this patient population.

Diabetic nephropathy is a major complication of diabetes mellitus (DM). Recent studies suggest that immunological mechanisms have a key role in the pathogenesis of DM, therefore these mechanisms may be important targets for diabetes therapy. The present study evaluated the effects of anti-α1-adrenergic receptor antibody (α1-R Ab) mediation and doxazosin treatment in a rat model of DM. It was observed that levels of 24-h urinary protein, serum creatinine and transforming growth factor-β1 in DM were significantly increased after α1-R Ab mediation (all P

The α1-AR (α1 adrenergic receptor) blockers currently on the market cannot meet clinical needs because of low-selectivity for subtypes of α1-ARs, short half-life, and uncertain role in cardiovascular end point events. The study sought to find a vaccine specifically against α1D-AR (α1D-adrenergic receptor) for treating hypertension. A short peptide ADR-004 (cgiteeagy) belonging to α1D-AR was screened, and the ADRQβ-004 vaccine was produced and injected into spontaneously hypertensive rats model (including a short-term study, 10 weeks, and a long-term observation study, 39 weeks) and NG-nitro- l -arginine methyl ester + spontaneously hypertensive rats model (15 weeks). The antihypertensive effect and target organ protection of the ADRQβ-004 vaccine were carefully evaluated. The possible immune-mediated damage was detected in normal vaccinated Sprague Dawley rats. The ADR-004 peptide has perfect immunogenicity, and the ADRQβ-004 vaccine could induce strong antibody production. In the short-term study, the ADRQβ-004 vaccine averagely decreased the systolic blood pressure of spontaneously hypertensive rats up to 15 mm Hg and that of NG-nitro- l -arginine methyl ester+spontaneously hypertensive rats up to 29 mm Hg. In the long-term observation model, the antihypertensive effect of the ADRQβ-004 vaccine was quite stable, and the average decline of systolic blood pressure was 22 mm Hg. The ADRQβ-004 vaccine effectively prevented vascular structural remodeling, cardiac hypertrophy and fibrosis, and renal injury of hypertensive animals, superior to prazosin at renal level. Moreover, the ADRQβ-004 vaccine obviously downregulated the expression of α1D-AR, but not α1A-AR. Additionally, no significant immune-mediated damage was detected in immunized animals. The present results demonstrate that the ADRQβ-004 vaccine may provide a novel and promising method for the treatment of hypertension.

Heart disease is characterized by the remodelling of cardiac tissue following prolonged stress on the heart, such as myocardial infarction and chronic hypertension. The heart initially undergoes hypertrophy of the individual contractile unit, the cardiomyocyte, in order to preserve cardiac function. However, prolonged stress can lead to fibrosis, cardiomyocyte death, and subsequent heart failure. Cardiac remodelling is mediated predominantly through neurohormonal activation of G protein-coupled receptors (GPCRs) expressed by cardiomyocytes and other cell types in the heart. Current therapeutic approaches target implicated GPCRs to slow disease progression by inhibiting signalling pathways leading to remodelling. While this approach benefits a portion of patients, other therapeutic approaches are required to improve disease prognosis (1). A potential target downstream of GPCR activation is the transcription regulator positive transcription elongation factor b (P-TEFb). Hormonal activation of multiple GPCRs, such as the α1-adrenergic receptor (α1AR) by epinephrine or the endothelin receptor (ETR) by endothelin-1, leads to P-TEFb-dependent cardiomyocyte hypertrophy, a hallmark of cardiac remodelling (2). Active P-TEFb is recruited to chromatin to regulate gene expression as a constituent of two complexes, either through interactions with the Super Elongation Complex (SEC) or the bromodomain and extra-terminal protein Brd4. Small molecule inhibition of Brd4 prevents hypertrophy and activation of inflammatory and profibrotic genes in cardiomyocytes (3). On the other hand, the role of the SEC in regulating cardiomyocyte gene expression has not been examined. Furthermore, the signalling mechanisms leading to activation of either complex and subsequent gene expression changes are not known. We hypothesized that activation and interplay between distinct P-TEFb complexes differs following activation of different GPCRs implicated in heart failure. We assessed the role of Brd4 and the SEC downstream of the endogenous ETR and α1AR stimulated with endothelin-1 or phenylephrine, respectively, in primary neonatal rat cardiomyocytes. Although P-TEFb activity is required downstream of both receptors to drive gene expression changes and cardiomyocyte hypertrophy, we find evidence for receptor-specific differences in the functions of the SEC and the Brd4 complex. We are currently investigating signalling mechanisms regulating each complex downstream of the ETR and α1AR. Understanding how mechanisms downstream of various hormones differentially regulate transcription has clinical implications as therapies targeting transcriptional machinery are being explored for heart failure. (1) Wang et al., Circ Res. 2018; 123:716-35 (2) Sano et al., Nat Med. 2002; 8:1310-7 (3) Duan et al., Sci Transl Med; 9(390)

High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for α1-adrenergic receptors (α1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system. Meanwhile, an “ELISA-like” strategy was designed for FP-based HTS assay in which proteins were adhered into a solid phase to improve the measurement window and S/N ratio. With fluorescent antagonist QGGFL and the ELISA strategy, we succeeded in establishing the first competitive binding FP assay for α1-AR antagonists as...

Background Recently, we provided evidence that α 1 ‐adrenergic receptors ( ARs ) in vascular smooth muscle are regulated by chemokine (C‐X‐C motif) receptor ( CXCR ) 4 and atypical chemokine receptor 3 ( ACKR 3). While we showed that CXCR 4 controls α 1 ‐ ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells ( hVSMCs ), the molecular basis underlying cross‐talk between ACKR 3 and α 1 ‐ ARs is unknown. Methods and Results We show that ACKR 3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine. In proximity ligation assays and co‐immunoprecipitation experiments, we observed that recombinant and endogenous ACKR 3 form heteromeric complexes with α 1A/B/D ‐ AR . While small interfering RNA knockdown of ACKR 3 in hVSMCs reduced α 1B/D ‐ AR : ACKR 3, CXCR 4: ACKR 3, and α 1B/D ‐ AR : CXCR 4 complexes, small interfering RNA knockdown of CXCR 4 reduced α 1B/D ‐ AR : ACKR 3 heteromers. Phenylephrine‐induced inositol trisphosphate production from hVSMCs was abolished after ACKR 3 and CXCR 4 small interfering RNA knockdown. Peptide analogs of transmembrane domains 2/4/7 of ACKR 3 showed differential effects on heteromerization between ACKR 3, α 1A/B/D ‐ AR, and CXCR 4. While the transmembrane domain 2 peptide interfered with α 1B/D ‐ AR : ACKR 3 and CXCR 4: ACKR 3 heteromerization, it increased heteromerization between CXCR 4 and α 1A/B ‐ AR . The transmembrane domain 2 peptide inhibited ACKR 3 but did not affect α 1b ‐ AR in β‐arrestin recruitment assays. Furthermore, the transmembrane domain 2 peptide inhibited phenylephrine‐induced inositol trisphosphate production in hVSMCs and attenuated phenylephrine‐induced constriction of mesenteric arteries. Conclusions α 1 ‐ ARs form hetero‐oligomeric complexes with the ACKR 3: CXCR 4 heteromer, which is required for α 1B/D ‐ AR function, and activation of ACKR 3 negatively regulates α 1 ‐ AR s. G protein–coupled receptor hetero‐oligomerization is a dynamic process, which depends on the relative abundance of available receptor partners. Endogenous α 1 ‐ AR s function within a network of hetero‐oligomeric receptor complexes.

Aims In temporomandibular disorders sufferers, muscle pain is more severe in individuals who have undergone a traumatic stress. Why stress exacerbates masticatory muscle pain in these individuals is not known. One possibility is that under conditions of stress there is an interaction between the sympathetic and sensory nervous systems. This study investigated whether trigeminal ganglion neurons that innervate the masseter muscle express α1 adrenergic receptor subtypes to identify whether a direct interaction between the sympathetic and sensory nervous systems is feasible. Methods Masseter muscle ganglion neurons were identified by injection of the fluorescent dye fast blue into the masseter muscle of 4 Sprague Dawley rats (2 male, 2 female). Trigeminal ganglion sections were stained for α1a, α1b or α1d adrenergic receptors, as well as the transient receptor potential vanilloid 1 (TrpV1) receptor. Sections were examined with a Leica confocal microscope. The percent of masseter ganglion neurons expressing each receptor was calculated. Results Masseter muscle ganglion neurons expressed α1a(29 ± 9%), α1b (34 ± 4%) and α1d (19 ± 13%) adrenergic receptors. Expression of all three α1 receptor subtypes was higher in female rats than in male rats. Expression of α1b receptors was more commonly found on larger diameter masseter ganglion neurons. Overall 11±3% of masseter ganglion neurons expressed the TrpV1 receptor, which suggests they served a nociceptive function. The TrpV1 receptor was co-expressed by about ~10% of α1a and α1b receptor positive masseter ganglion neurons. Conclusions Afferent fibers that innervate the masseter muscle express all three α1 adrenergic receptor subtypes. Agonists at the α1 receptor have been previously shown to depolarize trigeminal ganglion neurons, which suggests that activation of these receptors on masseter muscle afferents would be excitatory. The expression of α1 receptors by putative nociceptors that innervate the masseter may permit a direct interaction between the sensory and sympathetic system that contributes to pain in this muscle.

To investigate the effect of prazosin on patients with diabetic nephropathy (DN), α1-adrenergic receptor (α1-R) autoantibodies and refractory hypertension, a total of 126 patients with DN and hypertension were recruited. The patients were divided into a refractory hypertension group, (n=76) and a non-refractory hypertension group (n=50). The epitope of the second extracellular loop of the α1-R (192–218) was synthesized and an enzyme-linked immunosorbent assay (ELISA) was performed to detect serum autoantibodies. In the group with DN-associated refractory hypertension, the positive rate of autoantibodies against the α1-R was 80.3% (n=61). The 61 patients who were positive for α1-R autoantibodies were randomly divided into a treatment group (n=31) and a control group (n=30). The patients were given drugs at the same dosage and administration, with the exception of prazosin, which was provided only to the patients in the treatment group [1 mg, three times a day (tid)] for a duration of six weeks. Subsequently, prazosin was added (1 mg, tid) to the therapeutic schedule of the patients in the control group and the α1-R autoantibody-negative group for another six weeks. The analysis was carried out on an intention-to-treat basis. The prazosin treatment resulted in significant improvements in hypertension in the treatment group (P

Mirabegron is a β3-adrenoreceptor agonist developed for treatment of overactive bladder (OAB). α1-Adrenergic receptor blockers are effective for lower urinary tract symptoms (LUTS) in male patients. However, the efficacy of mirabegron additional treatment in elderly male patients with persistent male LUTS, especially in OAB after monotherapy with α1-adrenergic blockers, is not fully understood. This study was conducted in male LUTS patients who were ≥ 65 years of age and had persistent OAB symptoms, regardless of whether they took an α1-adrenergic receptor blocker orally. Before and 12 weeks after mirabegron additional therapy (50 mg once daily), we evaluated the efficacy of this treatment using the Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score (IPSS), and changes in the maximum flow rate (Qmax) and post-void residual urine volume (PVR). We evaluated patients overall and divided into two groups by age: young-old (from 65 to 74 years old) and old-old (from 75 to 84 years old). Fifty men were enrolled in this study. Mirabegron additional therapy improved the total OABSS, total IPSS, and IPSS-quality of life (QOL) score. The voided volume (VV) and Qmax improved after treatment in patients overall. However, there was no significant change in PVR. The total OABSS, total IPSS, and IPSS-QOL score significantly improved in both of the young-old and old-old groups. However, a significant increasing of VV was detected in the young-old group. There were no significant differences in the Qmax or PVR in either group. Mirabegron additional therapy was effective for male patients whose persistent LUTS and particularly OAB was not controlled with α1-adrenergic receptor blocker monotherapy, and mirabegron did not have negative effects on voiding function. Additionally, mirabegron additional therapy was considered effective regardless of patient age. Trial registration number (TRN) trial registration number (TRN) and date of registration: ISRCTN16759097 in July 8, 2016.

α1-Adrenergic receptors (α1-ARs) are important players in peripheral and central nervous system (CNS) regulation and function and in mediating various behavioral responses. The α1-AR family consists of three subtypes, α1A, α1B and α1D, which differ in their subcellular distribution, efficacy in evoking intracellular signals and transcriptional profiles. All three α1-AR subtypes are present at relatively high densities throughout the CNS, but the contributions of the individual subtypes to various central functions are currently unclear. Because of the lack of specific ligands, functionally characterizing the α1-ARs and discriminating between the three subtypes are difficult. To date, studies using genetically engineered mice have provided some information on subtype-related functions of the CNS α1-ARs. In this mini-review, we discuss several CNS processes where the α1-ARs role has been delineated with pharmacological tools and by studies using mutated mice strains that infer specific α1-AR subtype functions through evaluation of behavioral phenotypes.

This study was designed to systematically analyze and evaluate the effects of in vivo blockade of α1-adrenergic receptors (α1-ADRs) on the stress-induced disturbance of steroidogenic machinery in Leydig cells. Parameters followed 1) steroidogenic enzymes/proteins, transcription factors, and cAMP/testosterone production; 2) the main hallmarks of stress (epinephrine, glucocorticoids); and 3) transcription profiles of ADRs and oxidases with high affinity to inactivate glucocorticoids. Results showed that sustained blockade of α1-ADRs prevented stress-induced 1) decrease of the transcripts/proteins for main steroidogenic CYPs (CYP11A1, CYP17A1); 2) decrease of Scarb1 and Hsd3b1 transcripts; 3) decrease of transcript for Nur77, one of the main activator of the steroidogenic expression; and 4) increase of Dax1 and Arr19, the main steroidogenic repressors in Leydig cells. In the same cells, the expression of steroidogenic stimulatory factor Creb1, StAR, and androgen receptor increased. In this signaling scenario, stress-induced stimulation of Adra1a/Adra1b/Adrbk1 and Hsd11b2 (the unidirectional oxidase with high affinity to inactivate glucocorticoids) was not changed. Blockade additionally stimulated stress-increased transcription of the most abundantly expressed ADRs Adra1d/Adrb1/Adrb2 in Leydig cells. In the same cells, stress-decreased testosterone production, the main marker of Leydig cells functionality, was completely prevented, while reduction of cAMP, the main regulator of androgenesis, was partially prevented. Accordingly, the presented data provide a new molecular/transcriptional base for “fight/adaptation” of steroidogenic cells and new molecular insights into the role of α1-ADRs in stress-impaired Leydig cell steroidogenesis. The results are important in term of wide use of α1-ADR selective antagonists, alone/in combination, to treat high blood pressure, nightmares associated with posttraumatic stress disorder, and disrupted sexual health.

The stress-induced initiation of proapoptotic signaling in Leydig cells is relatively well defined, but the duration of this signaling and the mechanism(s) involved in opposing the stress responses have not been addressed. In this study, immobilization stress (IMO) was applied for 2 h daily, and animals were euthanized immediately after the first (IMO1), second (IMO2), and 10th (IMO10) sessions. In IMO1 and IMO2 rats, serum corticosterone and adrenaline were elevated, whereas serum androgens and mRNA transcription of insulin-like factor-3 in Leydig cells were inhibited. Reduced oxygen consumption and the mitochondrial membrane potential coupled with a leak of cytochrome c from mitochondria and increased caspase-9 expression, caspase-3 activity, and number of apoptotic Leydig cells was also observed. Corticosterone and adrenaline were also elevated in IMO10 rats but were accompanied with a partial recovery of androgen secretion and normalization of insulin-like factor-3 transcription coupled with increased cytochrome c expression, abolition of proapoptotic signaling, and normalization of the apoptotic events. Blockade of intratesticular glucocorticoid receptors diminished proapoptotic effects without affecting antiapoptotic effects, whereas blockade of intratesticular α1-adrenergic receptors diminished the antiapoptotic effects without affecting proapoptotic effects. These results confirmed a critical role of glucocorticoids in mitochondria-dependent apoptosis and showed for the first time the relevance of stress-induced upregulation of α1-adrenergic receptor expression in cell apoptotic resistance to repetitive IMOs. The opposite role of two hormones in control of the apoptotic rate in Leydig cells also provides a rationale for a partial recovery of androgen production in chronically stressed animals.

Purpose Whereas many studies have focused on the vesical changes of the α1 adrenergic receptor (AR) subtypes in partial outlet obstruction, few studies have addressed the modulation of the α1 AR subtypes after spinal cord injury (SCI). Therefore, we studied the modulation of the α1 ARs in urinary bladder in a rat SCI model. Methods Four weeks after a SCI, the whole vesical bodies from eight female Sprague-Dawley rats and from eight controls were harvested. The total RNA was extracted from the samples and was used to prepare cDNA. We developed standard plasmid constructs of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and three α1 ARs (α1a, α1b, and α1d) to convert the cycle threshold (Ct) values from real-time polymerase chain reaction (RT-PCR) into subtype mRNA concentrations. The detected Ct values of 16 samples from RT-PCR were interpolated into the standard plasmid curves. Results All serially diluted standard samples showed very good linearity. The mRNA expression of GAPDH was higher in the SCI group, whereas the mRNA expression of all α1 ARs was lower in the SCI group than in the control animals. The α1a, α1b, and α1d mRNA expression in the controls was 81.7%, 3.3%, and 15.1%, respectively, whereas the α1a, α1b, and α1d mRNA expression in the SCI group was 33.5%, 5.2%, and 60.9%, respectively. Conclusions SCI moderates the α1 AR mRNA subtypes in the urinary bladder. The relatively increased α1d or decreased α1a AR mRNA expression may be a therapeutic candidate for controlling the symptoms of neurogenic bladder after SCI.

To observe the relaxant effect of Aike Mixture (AKM) on isolated bladder and prostatic urethral smooth muscle of rabbits.The isolated bladder and prostatic urethral smooth muscle from male rabbits were placed in a Magnus bath and smooth muscle contraction was measured using a biological signal acquisition and analysis system. The effects of AKM in combination with methoxyamine, carbachol and CaCl2 on the contractile tension of muscle strips were determined by cumulative dosing.AKM dose-dependently reduced contractile tension of bladder trigone smooth muscle (r=0.831, P0.05), reduced contractile wave amplitude (r=0.837, P0.05) and decreased contractile frequency (r=-0.917, P0.01). AKM significantly inhibited the increases in smooth muscle contraction induced by methoxyamine, carbachol and CaCl2.AKM dose-dependently inhibited the contraction of rabbit isolated bladder and prostatic urethral smooth muscle by antagonizing α1-adrenergic receptors and M-cholinergic receptors.

Since the subtypes of α(1)-adrenergic receptor have been thoroughly determined, to date medicinal chemists raise their deliberation on how to conceive selective α(1)-adrenergic receptor antagonist with the minimal side effects. It needs to be well recognized that natural products can exist as a significant source of drug leads, thus portraying a consequential capacity in drug design and development. The current review article would like to present a comprehensive survey on natural products, mainly including alkaloids and flavonoids, which exhibit α(1)-adrenergic receptor antagonistic activities.

α1-Adrenergic receptor subtypes are widely distributed in the central nervous system and are involved in autonomic functions such as micturition. We investigated the presence and the role of supraspinal and/or spinal α1-adrenergic receptors in modulating the micturition reflex in conscious female Wistar rats. The expression of α1-adrenergic receptor subtypes in rat brain and lumbosacral spinal cord was studied using RT-PCR. Continuous-infusion cystometrograms were obtained in conscious rats, and α1-adrenergic receptor antagonists were administered via intracerebroventricular or intrathecal routes. The mRNA expression of α1A-, α1B-, and α1D-adrenergic receptors was detected in rat brain (midbrain and pons) and lumbosacral spinal cord (dorsal and ventral parts of spinal cord). In addition, intracerebroventricular injection of the α1-adrenergic receptor antagonist tamsulosin (1–10 μg), the selective α1A-adrenergic receptor antagonist silodosin (1–10 μg), and the selective α1D-adrenergic receptor antagonist BMY 7378 (1–10 μg) significantly prolonged the intercontraction interval (ICI) but did not alter maximum voiding pressure (MVP). Although intrathecal injection of BMY 7378 (0.0001–10 μg) did not affect ICI, tamsulosin and silodosin prolonged ICI in a dose-dependent manner. MVP was significantly reduced by intrathecal injection of tamsulosin (10 μg) but not by silodosin or BMY 7378 (0.0001–10 μg). Supraspinal α1A- and α1D-adrenergic receptors are apparently important for the regulation of reflex-bladder activity in conscious rats. Noradrenergic projection from the brain stem to the lumbosacral spinal cord may promote the afferent limb rather than the efferent limb of the micturition reflex pathway via α1A-adrenergic receptors.

Hypotension frequently complicates spinal anesthesia for cesarean delivery, and vasopressors are the mainstay for treatment. The most effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension has not been estimated.Healthy nonlaboring women undergoing a cesarean delivery were recruited. All women received spinal anesthesia using hyperbaric bupivacaine 12 mg with fentanyl and morphine. Each subject received an i.v. crystalloid fluid bolus before and at the time of initiation of spinal anesthesia (preload and coload). An up-down sequential allocation method using the biased-coin design was used to estimate the 90% effective dose (ED(90)) of phenylephrine. The assigned phenylephrine dose was based on the response of the preceding subject. If the systolic blood pressure (SBP) decreased20% of baseline (i.e., SBP 20%) or to an SBP90 mm Hg, the assigned dose of phenylephrine was administered. If the SBP returned to within 20% of baseline oror = 90 mm Hg within 1 min, this was considered a success, otherwise it was a failure. The initial dose of phenylephrine was 100 microg. The ED(90) with 95% confidence intervals (CIs) was calculated using the maximum likelihood estimation and Firth logistic regression.Sixty-nine subjects were screened to participate, of whom 66 subjects consented. Forty-five of the enrolled subjects experienced spinal anesthesia-induced hypotension and received a blinded dose of phenylephrine. Those subjects who developed hypotension received doses of phenylephrine between 80 and 180 microg. No subjects experienced hypertension. Determined with the maximum likelihood estimation method, the ED(90) of phenylephrine was 147 microg (95% CI, 98-222 microg). With Firth regression, the probability of a successful response at 150 microg is 90.5% (95% CI, 66.0%-99.0%).In this study, we estimated that the ED(90) of phenylephrine required to treat spinal anesthesia-induced hypotension in cesarean delivery is approximately 150 microg.

To evaluate the effects of tolterodine extended release (ER) and alfuzosin for the treatment of Double-J stent-related lower urinary tract symptoms.Fifty-two patients (33 men and 19 women; mean age 52.0 years) who underwent insertion of a Double-J stent after urological surgery were prospectively randomized into three groups. Group 1 included 20 patients who received 10 mg of alfuzosin, once daily for 6 weeks; group 2 included 20 patients who received 4 mg of tolterodine ER, once daily for 6 weeks; group 3 included 12 patients who received a placebo for the same protocol. All patients completed a validated Ureteral Stent Symptom Questionnaire at 6 weeks after the stent placement.The mean urinary symptom index was 22.1 in group 1, 22.1 in group 2, and 28.1 in the placebo group (p = 0.032). The mean pain scores were 8.2, 11.7, and 16.2, respectively (p = 0.020). There were no significant differences in urinary symptoms and pain between the alfuzosin and tolterodine ER groups. In addition, there was no significant difference in the general health, work performance, and sexual performance scores among the groups.Tolterodine ER and alfuzosin improve stent-related urinary symptoms and body pain.

This study was performed to characterize the α1-adrenoceptor subtypes in mouse ureters as regards gene expressions and contractile functions.The mRNAs for these subtypes were quantified by the real-time quantitative reverse transcription polymerase chain reaction. In a functional study, α1-adrenoceptor antagonists were evaluated against the noradrenaline-induced contraction in mouse isolated ureteral preparations.In mouse ureter, the relative mRNA expression levels for α1a-, α1b- and α1d-adrenoceptors were 74.5, 14.3 and 11.2%, respectively. Adrenaline and noradrenaline each produced a concentration-dependent phasic contraction (pD 2 values, 5.73±0.05 and 5.69±0.06, respectively). Prazosin (non-selective α1-adrenoceptor antagonist), silodosin (selective α1A-adrenoceptor antagonist), and BMY-7378 (selective α1D-adrenoceptor antagonist) all shifted the concentration–response curve for noradrenaline to the right, the rank order of potencies (apparent pA 2 values) being silodosin (9.32±0.11)prazosin (8.55±0.10)BMY-7378 (6.06±0.15). The α1A-adrenoceptor antagonist silodosin was thus much more effective than the α1D-adrenoceptor antagonist BYM-7378.Our results demonstrate that in mouse ureters: the mRNA for the α1A-adrenoceptor was more prevalent than those for the α1B- and α1D-adrenoceptors, and that among these subtypes, the α1A-adrenoceptor plays the major role in noradrenaline-induced contraction.

Background: Although α1 adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature of many current drugs. To overcome this problem, it was hypothesized that an α1a/1d subtype selective antagonist would be efficacious yet produce less side effects, and hence would bring greater benefit for the therapy of BPH/LUTS. Unfortunately, such highly selective α1a/1d antagonists were not available, making the validation of the new hypothesis impossible. Objective/method: This review disclosed several series of α1a/1d subtype selective antagonists that have been discovered and developed by Johnson & Johnson recently. These compounds show equal and potent affinity for both α1a and α1d subtypes with good selectivity versus the α1b subtype. Some analogues also possess favorable pharmacokinetic properties. Conclusion: Although d...

Hypertension is one of the most serious health problems of the modern world with a continuous rise in the number of patients. Selective alpha(1)-adrenoreceptor antagonists though have many advantages and uses in the management of arterial hypertension, their lack of specificity at the level of alpha(1)-adr subtypes leads to multiple side effects. Existence of multiple alpha(1)-adr subtypes holds great promise for the discovery and development of more specific and selective drug molecules, targeting only one alpha(1)-adr subtype at a time and thus relative freedom from side effects. Herein, the research done on the discovery and evaluation of a variety of chemically diverse structures as selective antagonists of alpha(1)-adr and alpha(1)-adr subtypes in recent years has been reviewed.

Resume Objectif Analyser les differentes strategies preventives et therapeutiques de prise en charge de l'hypotension arterielle au cours de la rachianesthesie pour cesarienne. Acquisition des donnees Revue de la litterature. Recueil de donnees a partir de la base Medline, concernant l'hypotension arterielle au cours de la rachianesthesie pour cesarienne. Les articles publies en anglais ou en francais ont ete analyses. Synthese des donnees L'hypotension arterielle au cours de la rachianesthesie pour cesarienne est tres frequente (55 a 90 %) si elle n'est pas prevenue. Elle peut avoir des consequences nefastes pour la mere et le fœtus. Le preremplissage par cristalloide est inefficace. Le preremplissage par colloide est efficace mais plutot indique en deuxieme intention. L'ephedrine a longtemps represente le vasopresseur de reference. Cependant, sa faible efficacite en prophylaxie et ses effets cardiovasculaires maternels ainsi que sur le pH arteriel ombilical ont remis en question son utilisation, notamment au-dela de 15 a 20 mg. La phenylephrine, agent alpha-agoniste pur, en association ou non avec l'ephedrine selon la frequence cardiaque maternelle, a une efficacite au moins equivalente, voire superieure en prophylaxie et moins d'effets secondaires que l'ephedrine seule. Un co-/post-remplissage par cristalloide au moment de l'injection intrathecale ameliore le controle hemodynamique obtenu avec les vasopresseurs. Conclusion L'hypotension arterielle au cours de la rachianesthesie pour cesarienne doit systematiquement etre recherchee, prevenue et traitee sans delai. L'association de vasopresseur(s) (phenylephrine ± ephedrine) avec un remplissage rapide par cristalloide au moment de l'injection intrathecale represente la strategie la plus interessante actuellement.

To evaluate the efficacy of doxazosin in inducing spontaneous passage of stones in the distal ureter and to compare its efficacy according to the size of the stone.Seventy-three patients with a mean age of 46.38 +/- 10.17 years who presented with a distal-ureteral stone were divided into four groups according to stone size and drug treatment:5 mm without doxazosin (group A; n=15); 5-10 mm (group B; n=16);5 mm with doxazosin 4 mg/day for 4 weeks (group C; n=20); and 5-10 mm with doxazosin 4 mg/day for 4 weeks (group D; n=22). Groups A and B served as controls for groups C and D, respectively.Spontaneous stone passage was documented in 9 patients (60%) in group A v 17 (85%) in group C (P=0.047) and 7 (43.75%) in group B v 16 (72.73%) in group D (P=0.036). The average expulsion time was 8.78 +/- 1.09 days in group A v 7.59 +/- 0.80 days in group C (P=0.004) and 12.14 +/- 1.35 days in group B v 7.06 +/- 1.29 days in group D (P0.0001). The number of pain episodes in group D patients was significantly lower than in group B (P +/- 0.0078).Doxazosin treatment proved to be safe and effective for distal-ureteral stones, as determined by earlier expulsion, decreased colic frequency, and absence of side effects. The efficacy of doxazosin was significantly higher for 5-to 10-mm stones than for smaller ones.

α1-adrenergic receptor signaling has been implicated in cancer progression through the stimulation of cell proliferation, cell migration and cell invasion. Conversely, blocking α1-adrenergic recept...

Objectifs L’objectif principal etait de determiner si la qualite de la mydriase preoperatoire obtenue avec un protocole de dilatation utilisant un insert etait au moins egale a celle obtenue avec un protocole utilisant exclusivement des collyres. Les objectifs secondaires etaient d’evaluer la tolerance locale et la facilite d’utilisation. Patients et methodes Nous avons mene une etude prospective randomisee, controlee, dans le service d’Ophtalmologie de l’Hopital Lariboisiere sur une periode de 3 semaines. Les 51 patients inclus ont ete repartis en deux groupes : 25 dans le groupe insert (atropine 1 %, diclofenac 0,1 % collyres et Mydriasert ® ) et 26 dans le groupe collyres (atropine 1 %, diclofenac 0,1 %, tropicamide 0,5 % et phenylephrine 10 % collyres). L’intensite de la mydriase a ete evaluee par une infirmiere et un chirurgien. La facilite d’utilisation a ete evaluee par le nombre de gestes infirmiers necessaires a l’obtention de la mydriase. La tolerance a ete appreciee par interrogatoire du patient. Resultats Une mydriase superieure a 6 mm a ete obtenue chez 92 % des patients du groupe insert (23/25) et 85 % des patients du groupe collyres (22/26) (difference non significative). Quatre patients ont perdu leur insert en cours de protocole. Respectivement 16 % (4/25) et 23 % (6/26) des patients des groupes insert et collyres ont rapporte des picotements (difference non significative). Le protocole avec insert a necessite cinq gestes infirmiers de moins par patient pour obtenir une mydriase satisfaisante (p Conclusions Le protocole de dilatation utilisant un insert permet d’obtenir une mydriase preoperatoire non inferieure a celle obtenue avec un protocole utilisant exclusivement des collyres, tout en permettant un gain de temps infirmier. Une formation des infirmieres a la pose de l’insert est indispensable afin d’eviter la perte du dispositif.

The present experiments were undertaken to clarify the role of central alpha(1)-adrenoceptors in reward processes. Rats, trained to self-stimulate via electrodes in the medial forebrain bundle of the lateral hypothalamus, were administered alpha(1)-selective drugs near the locus coeruleus (LC), a site of a dense concentration of alpha(1)-receptors. Effects on reward potency were assessed from shifts in rate-frequency curves while effects on motor response capacity were judged from changes in the maximal rates of responding. It was found that local blockade of LC alpha(1)-receptors with terazosin produced a significant dose-dependent and site-dependent rightward shift of 0.08 log units and a significant decrease of 16.3% in the maximum response rate. Both effects were completely reversed by coadministration of the alpha(1)-agonist, phenylephrine and were not attributable to terazosin's weak action at alpha(2)-adrenoceptors. It is concluded that LC alpha(1)-adrenoceptors are involved both in reward/motivational processes and operant response elaboration which are postulated to work together to facilitate goal attainment.

This paper was published as BJU International, 2006, 97 (2), pp. 329-332. It is available from http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1464-410X. Doi: 10.1111/j.1464-410X.2006.05956.x