Α-adrenergic Blocker Research Articles

Evaluation of the Effect of an α-Adrenergic Blocker, a PPAR-γ Receptor Agonist, and a Glycemic Regulator on Chronic Kidney Disease in Diabetic Rats.

Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN.

Comparison of the Role of Anticholinergics and α-1 Adrenergic Blockers in Bladder Management in Posterior Urethral Valves: A Pilot Randomized Control Trial

Introduction: Posterior urethral valve (PUV) is a major cause of congenital bladder dysfunction, often persisting despite treatment. Emerging therapies, including anticholinergics and α-1 blockers, offer potential but lack clear guidelines. This study evaluates their effectiveness in improving bladder function after valve fulguration. Methods: Twenty PUV patients, aged ≥3 years, were randomized into anticholinergic (group A, n = 11) and α-1 adrenergic blocker (group B, n = 9) groups post-fulguration. Follow-up included clinical, radiological, and urodynamic assessments 6 months posttreatment initiation. Results: In group A, the mean maximum detrusor pressure (Pdet) decreased from 30.17 to 23.45 cm H2O (p = 0.033). Two patients normalized from high detrusor pressure (>40 cm H2O). In group B, 1 patient retained high detrusor pressure posttreatment. Group B improved in average urinary flow (Q avg) and maximum flow rate (Q max), with all patients having initially low Q avg (<10 mL/s). Two group B patients showed improved average flow rates posttreatment (p = 0.016); three in group A showed improvement but were not statistically significant (p = 0.197). Q max/flow time ratio was abnormal in all group B patients pretreatment. Two of the nine improved posttreatment, while only one in group A did. Conclusions: Anticholinergic medications positively impact cystometric parameters and are effective for detrusor instability and low compliance bladder. α-Adrenergic blockers influence uroflow parameters and can help treat bladder outflow obstruction. Consideration for a larger study with extended follow-up is warranted.

The Effects of Vibegron Add-on Therapy on Alpha 1-Blocker Therapy for Sexual Function and Overactive Bladder Symptoms in Benign Prostatic Hyperplasia: A Prospective, Open-Label Study.

Background: The effect of combining an α1-adrenergic receptor blocker (α1-blocker) and the β3-adrenoceptor agonist vibegron for treating persistent overactive bladder (OAB) symptoms associated with benign prostatic hyperplasia (BPH) on sexual function remains uncertain. Therefore, we aimed to evaluate the effects of vibegron as an add-on to α1-blocker therapy on both OAB and sexual function. Methods: Forty-three patients with BPH in whom OAB symptoms were inadequately controlled by α1-blocker treatment were included in this prospective open-label study. The OAB Symptom Score (OABSS), International Prostate Symptom Score (IPSS), 15-item International Index of Erectile Function (IIEF-15), and Erection Hardness Score (EHS), as well as the residual urine volume and serum-free testosterone (FT) and C-reactive protein (CRP) levels, were evaluated before and 8 weeks after the daily administration of 50 mg vibegron/α1-blocker combination therapy. Results: Vibegron/α1-blocker combination therapy significantly improved the OABSS (from 6.9 ± 2.6 to 5.1 ± 2.9, p < 0.0001) and IIEF intercourse satisfaction domain (from 1.1 ± 2.3 to 1.9 ± 2.6, p = 0.02). No significant differences were observed for the IPSS, EHS, total IIEF-15 score, residual urine volume, and serum FT and CRP levels. Conclusions: The study findings suggest that vibegron/α1-blocker combination therapy improves OAB and sexual satisfaction.

Levamisole Impairs Vascular Function by Blocking α-Adrenergic Receptors and Reducing NO Bioavailability in Rabbit Renal Artery

Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.Graphical EFS electric field stimulation, NA noradrenaline, AR adrenergic receptor, IP3 inositol 1, 4, 5-trisphosphate, cAMP cyclic adenosine monophosphate, mAChR muscarinic acetylcholine receptor, eNOS endothelial nitric oxide synthase, sGC soluble guanylyl cyclase, SOD superoxide dismutase, NOX4 NAPH oxidase 4

Comparison of the efficacy and complications of tolterodine and α-adrenergic receptor blockers in improving ureteral stent-related symptoms: A systematic review and meta-analysis.

We conducted a systematic evaluation of the therapeutic efficacy and complications of tolterodine and α-adrenergic receptor blockers in alleviating ureteral stent-related symptoms. Until August 2023, we conducted a comprehensive literature search on PubMed, Embase, Web of Science, and Cochrane Library to identify randomized controlled trials evaluating the efficacy and complications of tolterodine and α-adrenergic receptor blockers in treating ureteral stent-related symptoms. Two reviewers independently screened studies and extracted data. The scores from various domains of the Ureteral Stent Symptom Questionnaire (USSQ) were summarized and compared, and statistical analysis was performed using RevMan 5.4.0 software. A total of 8 studies met the inclusion criteria for our analysis. These studies were conducted at different centers. All studies were randomized controlled trials, involving a total of 487 patients, with 244 patients receiving α-adrenergic receptor blockers and 243 patients receiving tolterodine. The results showed that tolterodine demonstrated significantly better improvement in body pain (MD, 1.56; 95% CI [0.46, 2.66]; p = 0.005) (MD, 0.46; 95% CI [0.12, 0.80]; p = 0.008) (MD, 3.21; 95% CI [1.89, 4.52]; p = 0.00001) among patients after ureteral stent placement compared to α-adrenergic receptor blockers at different time points. Additionally, at 4 weeks, tolterodine showed superior improvement in general health (MD, 0.15; 95% CI [0.03, 0.27]; p = 0.01) and urinary symptoms (MD, 1.62; 95% CI [0.59, 2.66]; p = 0.002) compared to α-adrenergic receptor blockers, while at 6 weeks, tolterodine showed better improvement in work performance (MD, -1.60; 95% CI [-2.73, -0.48]; p = 0.005) compared to α-adrenergic receptor blockers. Additionally, the incidence of dry mouth (RR, 4.21; 95% CI [1.38, 12.87]; p = 0.01) is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, there were no significant statistical differences between the two drugs in other outcomes. This meta-analysis suggests that tolterodine is superior to α-adrenergic receptor blockers in improving physical pain symptoms after ureteral stent placement, while α-adrenergic receptor blockers are more effective than tolterodine in enhancing work performance. Additionally, the incidence of dry mouth is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, higher-quality randomized controlled trials are needed to further investigate this issue.

Efficacy of Phlogenzyme® in men following transurethral laser enucleation of prostate hyperplasia: results of a randomized trial

Introduction. The most advanced and effective method of surgical treatment for benign prostatic hyperplasia (BPH) is transurethral laser enucleation of the prostate (tLEP). Recently, there has been a growing interest in exploring new approaches to reduce the risk of complications following tLEP.Objective. To evaluate the efficacy of using Phlogenzym® as part of a comprehensive treatment plan for patients following tLEP to reduce dysuria (urinary discomfort), leukocyturia (white blood cells in urine), and prevent infectious and fibrosis-related complications.Materials &amp; methods. An open-label, randomized trial enrolled 105 patients undergoing tLEP. The patients were randomly assigned to two groups: the study group (n=50) received standard postoperative care in combination with Phlogenzym® for 30 days, while the control group (n=55) received standard care (α1-adrenergic blocker for 28 days) only. uring the follow-up period, which lasted for 1, 3, and 6 months postoperatively, complaints were evaluated using the IPSS-QoL, and IIEF-5 questionnaires, as well as indicators of urinalysis and urine culture, prostate volume measurements, residual urine volume, and uroflowmetry data.Results. Among all patients, the median preoperative values for prostate volume, IPSS, QoL score, and median peak urine flow rate were 90 cc, 18 points, 5 points, and 7.9 mL/s, respectively, with no significant differences between the groups. One month after surgery, in the study group, there was a more significant decrease in prostate volume (57% vs. 41%), although this difference was not statistically significant (p &gt; 0.05). At the 6-month follow-up, bacteriuria was less common in the study group (42% vs. 67%), and there was a consistent trend toward a reduction in the incidence of fibrous complications, although these differences were not statistically significant either (p &gt; 0.05). No adverse events occurred during the follow-up period.Conclusion. Our experience suggests that the use of Phlogenzym® is safe during the postoperative period following tLEP surgery. The use of this drug leads to a reduction in prostate volume postoperatively and significantly reduces the bacteriuria by the six-month follow-up. Additionally, there is a persistent positive trend towards reducing the overall incidence of fibrotic complications in the surgical site. The results achieved and the absence of significant side effects characterize Phlogenzym® as having a favorable clinical profile.

Incidental Zinner Syndrome in Nigeria: A Case Report

Zinner syndrome (ZS) is a rare urogenital condition characterised by the triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst, and ipsilateral ejaculatory duct obstruction, resulting from malformation during early embryogenesis of the mesonephric (Wolffian) duct. The authors present a 35-year-old male who was being evaluated for chronic hepatitis B virus infection. He was referred to the urology outpatient clinic on account of incidental ultrasound finding of solitary right kidney. General physical examination revealed a healthy-looking young male with a flat abdomen and no palpable enlarged organs. Digital rectal examination revealed normal sized prostate with no palpable pararectal masses. MRI of the pelvis revealed a triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst, and ipsilateral ejaculatory duct obstruction. The clinical diagnosis was asymptomatic ZS. He is on yearly follow-up at the urology outpatient clinic for lower urinary tract symptoms, pelvic pain, painful ejaculation, features of infertility, and pelvic ultrasound. If any of these symptoms occur, he will be treated with an α-adrenergic receptor blocker, drainage of the seminal vesicle cyst, and appropriate treatment for infertility. He is also on active surveillance for viral hepatitis by the gastroenterology team. In conclusion, prompt referral and comprehensive radiological imaging investigations of patients with unilateral agenesis of the kidney will lead to increased identification and report of patients with ZS. There is paucity of literature reports on ZS in the authors’ environment, and this case report, to the best of the authors’ knowledge, is the first from Nigeria.

The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Phentolamine Protects against Apoptosis and Inflammation in a Neonatal Pneumonia Cell Model Induced by LPS by Regulating the TrkA/Akt Signaling Pathways.

Phentolamine is an α-adrenergic receptor blocker that can be used to treat neonatal pneumonia, but its underlying mechanism is unclear. The purpose of this study is to probe the function of phentolamine on lipopolysaccharide (LPS)-induced inflammation and cell death in an in vitro model of neonatal pneumonia. Human MRC-5 cells were incubated with varying doses of phentolamine in vitro to evaluate cell viability. Subsequently, LPS was introduced to further investigate the combined effects of phentolamine and LPS on cell viability and apoptosis in MRC-5 cells. The effect of phentolamine/LPS treatment on the Neurotrophic Tyrosine Kinase Receptor A (TrkA)/Protein Kinase B (Akt) signaling pathway and the phosphorylation of pathway proteins in MRC-5 cells was further analyzed via western blot. Additionally, knockout of TrkA and Akt genes in MRC-5 cells was performed to explore the effects of phentolamine/LPS treatment on cell viability, apoptosis levels, and inflammatory factor levels in MRC-5 cells. Preincubation of MRC-5 cells with a low concentration of phentolamine (≤6 μg/mL) protected against LPS-induced cell inflammatory injury. Phentolamine promoted both TrkA and Akt phosphorylation and Akt activation induced by LPS in MRC-5 cells. The protective effect of phentolamine against LPS-induced apoptosis and inflammation was significantly reduced in response to TrkA or Akt gene knockdown in MRC-5 cells. Phentolamine may protect LPS-induced apoptosis and inflammation by activating the TrkA and Akt signaling pathways.

Advanced Progress of the Relationship Between Antihypertensive Drugs and Bone Metabolism.

Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective β-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective β-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.

Changes of resistance indices after medication in benign prostatic hyperplasia: a prospective study.

This study aimed to determine the relationship between resistive indices (RIs) and changes in prostate size after medical treatment in patients with benign prostatic hyperplasia (BPH). A total of 86 patients with BPH were included in the study, excluding 42 patients with a total prostate volume (TPV) of <30cc or taking α1-adrenergic blockers and 5α-reductase inhibitors (5ARI) before study participation. Therefore, the data for 44 patients were analyzed. All patients were treated with α1-adrenergic blockers and 5ARIs. The variables examined were prostate-specific antigen, International Prostate Symptom Score, quality of lifescore, maximal urinary flow rate, residual urine volume, TPV, transition zone volume, and RIs of the urethral artery and left and right capsular arteries. These variables were assessed at baseline and after 3and 6months of treatment. The mean TPV was 43.5±10.9 and decreased to 35.2±11.5 and 33.9±9.8 after 3and 6months of treatment, respectively (p<0.001). The mean RI of the urethral artery, right capsular artery, and left capsular artery at pretreatment did not decrease significantly. However, comparing the baseline with 3-month data, TPV at 3months/TPV at baseline was significantly correlated with RI changes in the left capsular artery (r=758; P<0.001). In patients with BPH, α1-adrenergic blocker and 5ARI medications for 3and 6months did not result in a significant reduction in the RI of the urethral artery and both capsular arteries. Larger scale, prospective studies are needed to evaluate the relationship between TPV and RI reductions.

Differential Effects of Ca2+ Channel Blockers Nifedipine and Cilnidipine on Arterial Elasticity in the Aortic and Femoral Arterial Segments of Anesthetized Rabbits.

Ca2+ channel blockers have potent vasodilatory effects and excellent efficacy in preserving organ blood flow. These hemodynamic actions may be partly controlled by the functional stiffness of conduit arteries. In this study, we assessed the effects of the L-type Ca2+ channel blocker nifedipine on aortic and femoral arterial stiffness (referred to as aortic β and femoral β, respectively) in anesthetized rabbits. To further clarify the involvement of the autonomic nervous system, we compared the effects of nifedipine with those of the L/N-type Ca2+ channel blocker cilnidipine. Further, the effect of the α-adrenergic receptor blocker doxazosin on the effects of nifedipine on arterial elasticity was examined. An antihypertensive dose of nifedipine (300 µg/kg, administered intravenously) was found to increase the aortic β but hardly affected the femoral β. An antihypertensive dose of cilnidipine (30 µg/kg, administered intravenously) increased the aortic β but decreased the femoral β. Interestingly, nifedipine decreased the femoral β in the presence of the α-adrenoceptor blocker doxazosin (1 mg/kg, administered intravenously). These effects suggest that L-type Ca2+ channel blockers essentially increase vascular elasticity via the decrement in arterial stiffness in the femoral artery segment, which is modified by the presence or absence of the inhibitory effect of each drug on reflex sympathetic nerve activity, while decreasing vascular elasticity via the increment in arterial stiffness in the aortic segment independently of sympathetic nerve activity.

Clinical outcomes of withdrawing one medication from long-term combination therapy comprising α-blocker and 5α-reductase inhibitor for benign prostatic hyperplasia.

To assess adherence to combination therapy comprising α-adrenergic blocker (AB) and 5α-reductase inhibitor (5ARI) for benign prostatic hyperplasia (BPH) in a real-world setting and whether lower urinary tract symptoms (LUTS) will relapse after discontinuing one medication from long-term combination therapy. BPH/LUTS patients receiving initial AB +5ARI combination therapy for at least 1 year between January 2012 and January 2017 were retrospectively analyzed. The patients were classified into DC-AB group (n = 65, AB discontinued) and DC-5ARI group (n = 77, 5ARI discontinued) and followed up. Clinical effects were assessed at baseline and annually using the International Prostatic Symptoms Score (IPSS), quality of life (QoL) index, total prostate volume (TPV), maximal flow rate (Qmax), and prostate-specific antigen (PSA) level. Of total 1783 patients, 809 (45.4%) patients were identified with more than 1-year combination therapy. After withdrawal of one medication from combination therapy, the TPV progression (27.6% vs. - 10.8%; P < 0.001) and the requirement for prostate surgery (14.3% vs. 6.1%; P = 0.038) were significantly higher in the DC-5ARI group than in the DC-AB group. The rate of resuming combination therapy was significantly higher in the DC-5ARI group than in the DC-AB group (38.9% vs. 23.0%; P = 0.009). Adherence to combination BPH therapy is relatively low. Although patients adhered to combination therapy for more than 1 year, a higher risk of requiring prostate surgery or resuming combination therapy was observed in patients who discontinued 5ARI.

PSAT014 Pheochromocytoma in a Pregnant Woman with VHL leading to First Trimester Fetal Demise

Abstract Introduction Pheochromocytomas (PCCs) are rare neuroendocrine tumors that secrete catecholamines. They may be associated with familial syndromes such as Multiple Endocrine Neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL), and Neurofibromatosis type 1 (NF 1). PCCs are a common cause of malignant hypertension in pregnancy and can lead to adverse maternal and fetal outcomes if left undiagnosed or untreated. Case Description A 39-year-old Latin American primigravid woman at 8 weeks 4 days gestation was referred to the endocrinology clinic for labile blood pressure (160/90 mmHg at recent ER visit) and a lab finding of elevated catecholamines (plasma norepinephrine 4720 pg/ml; normal 0-874 pg/ml). She reported chronic headaches and 2-lb unintentional weight loss during pregnancy. Past medical history was significant for right adrenal PCC diagnosed at age 13 (currently status post adrenalectomy), and a cerebrovascular accident at age 29. Family history was relevant for PCC in the patient's sister and mother. The patient's home medications were nifedipine 30 mg daily and prenatal vitamins. On physical exam, her blood pressure was 126/76 mm Hg, heart rate was 67/min and a scar of previous right adrenalectomy was noted. Doxazosin 1 mg daily was added to her regimen and nifedipine was discontinued. The patient was initially planned for an elective cesarean section at term. However, at 10 weeks 5 days of gestation, she had a missed abortion. Further genetic testing of syndromic PCC revealed a heterozygous mutation in the VHL gene. Abdominal MRI showed a left adrenal mass (3.6×2.6×3.6 cm3) and retroperitoneal lymphadenopathy. The patient underwent left adrenalectomy and is currently hemodynamically stable on maintenance hydrocortisone and fludrocortisone. Discussion We report a case of PCC complicating pregnancy in a 39-year-old primigravida who had a family history of PCC. In females of reproductive age with a known PCC diagnosis, we suggest early genetic testing as it can further advise family planning, antepartum monitoring, and management. Medically, these patients can be managed with α-adrenergic blockers and calcium-channel blockers, followed by β-blockers. This can improve maternal and fetal outcomes primarily by minimizing paroxysmal elevations in catecholamines. Definitive treatment of PCC is surgical excision, usually performed during the second trimester or postpartum. Management of patients with VHL requires lifelong clinical, laboratory, and imaging surveillance for other manifestations of the disease. References Bancos, Irina et al. Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature. Lancet Diabetes Endocrinol 2021; 9: 13–21 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Ligamentum arteriosum: Muscular and contractile.

Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from pulmonary circulation into systemic circulation thus by-passing the fluid-filled lungs. Postnatally, it changes name to the ligamentum arteriosum (LA), when a cascade of anatomical and physiological processes leads to its closure. Though the LA has generally been considered as a fibrosed remnant of the ductus arteriosus, anecdotal and contradictory reports still describe the LA as a small muscular artery. We hypothesized the likelihood of contractile muscular elements retainment in this so-called ligament. To investigate this, mediastinum of wild-type mouse, pig, and human LA were subjected to routine and special histological staining, single-immunolabeling, electron microscopy (mouse and pig only), and tension recording of explanted pig LA in organ bath experiments. Contrary to a canonical ligament, the LA was mainly made up of α-smooth muscle actin-positive cells in all three species, confirmed by routine and special histological staining as well as transmission electron microscopy. Myocytes within the LA contracted in response to exogenous noradrenalin (NA). NA-induced precontracted LA relaxed upon administration of the α1-adrenergic blockers (prazosin and tamsulosin). Though the LA does not function in its original capacity as fetal shunt, it is clearly not a passive structure, and may be described as muscular and contractile. The contractile abilities of LA myocytes may act on the two great vessels to which it is attached causing a change in their distensibility.

A Review on Analytical Method Development for the Estimation of a Potent Muscarinic Receptor Antagonist Tolterodine Tartrate

Background: A pharmaceutical will be clinically accepted if it is impurity-free and its dose is accurately maintained. For this, the contribution of analytical techniques for developing and validating a new pharmaceutical dosage form cannot be overlooked. Introduction: Tolterodine tartrate is a potent competitive muscarinic receptor antagonist. It binds to the muscarinic M3 receptors in the bladder selectively and competitively. It is used to treat urinary incontinence and overactive bladder syndrome. The 5-hydroxymethyl derivative is the pharmacologically active metabolite of Tolterodine tartrate, which is as potent as the main drug. It is available with α-adrenergic blocker Tamsulosin in combined pharmaceutical formulations, treating benign prostatic hyperplasia in men. This review article presents several analytical methods, including HPLC, HPTLC, UV-Visible spectrophotometry, spectrofluorimetry, electroanalytical, and various hyphenated techniques like GC-MS, LC-MS, LC-MS-MS, etc., for estimation of Tolterodine tartrate is present as a single material or in combined form in bulk materials, different pharmaceutical formulations, and biological matrices. Conclusion: HPLC and spectrophotometry are the most widely used methods for determining the drug in the bulk and pharmaceutical dosage form among all these methods. LC-MS and LC-MSMS are widely used for the estimation of Tolterodine tartrate from plasma and other biological fluids. All the methods included in this article are accurate, sensitive, and cost-effective.

Meta-Analysis of the Safety and Efficacy of α-Adrenergic Blockers for Pediatric Urolithiasis in the Distal Ureter.

ObjectivePediatric urolithiasis is a common condition, and medical expulsive therapy has grown to be accepted by many parents. We carried out a meta-analysis to identify the efficacy and safety of α-adrenergic blockers for the treatment of pediatric urolithiasis.MethodsWe identified related articles from the PubMed, Embase, and Cochrane Library databases. All published randomized controlled trials (RCTs) describing the use of α-adrenergic blockers and placebo treatment for pediatric distal urolithiasis were involved. The outcomes included stone expulsion rate, stone expulsion time, pain episodes, need for analgesia, adverse events, and related subgroup analyses.ResultsA total of nine RCTs were involved in our study, including 586 patients. We found that α-adrenergic blockers could significantly increase the rate of stone expulsion [odds ratio (OR), 3.49; 95% confidence interval (CI), 2.38–5.12; p < 0.00001], reduce the stone expulsion time [mean difference (MD), −5.15; 95% CI, −8.51 to −1.80; p = 0.003], and decrease pain episodes (MD, −1.02; 95% CI, −1.33 to −0.72; p < 0.00001) and analgesia demand (MD, −0.92; 95% CI, −1.32 to −0.53; p < 0.00001) but had a higher incidence of side effects (MD, 2.83; 95% CI, 1.55 to 5.15; p = 0.0007). During subgroup analyses, different medications (tamsulosin, doxazosin, and silodosin) also exhibited better efficiencies than placebo, except for doxazosin, which showed no difference in expulsion time (MD, −1.23; 95% CI, −2.98 to 0.51; p = 0.17). The three kinds of α-adrenergic blockers also appeared to be better tolerated, except for tamsulosin with its greater number of adverse events (MD, 2.85; 95% CI, 1.34 to 6.03; p = 0.006). Silodosin led to a better expulsion rate than tamsulosin (OR, 0.42; 95% CI, 0.20 to 0.92; p = 0.03). In addition, α-adrenergic blockers increased the stone expulsion rate regardless of stone size and decreased the expulsion time of stones measuring <5 mm (MD, −1.71; 95% CI, −2.91 to −0.52; p = 0.005), which was not the case for stones measuring >5 mm in expulsion time (MD, −3.61; 95% CI, −10.17 to 2.96; p = 0.28).ConclusionOur review suggests that α-adrenergic blockers are well-tolerated and efficient for treating pediatric distal urolithiasis. We also conclude that silodosin is the best choice of drug, offering a better expulsion rate, but it remains to be evaluated further by future studies.

Influence of Receptor Polymorphisms on the Response to α-Adrenergic Receptor Blockers in Pheochromocytoma Patients.

Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations.

Repurposing α-Adrenoreceptor Blockers as Promising Anti-Virulence Agents in Gram-Negative Bacteria.

Antimicrobial resistance is among the world’s most urgent public health problems. Diminishing of the virulence of bacteria is a promising approach to decrease the development of bacterial resistance. Quorum sensing (QS) systems orchestrate the bacterial virulence in inducer–receptors manner. Bacteria can spy on the cells of the host by sensing adrenergic hormones and other neurotransmitters, and in turn, these neurotransmitters can induce bacterial pathogenesis. In this direction, α-adrenergic blockers were proposed as an anti-virulence agents through inhibiting the bacterial espionage. The current study aimed to explore the α-blockers’ anti-QS activities. Within comprehensive in silico investigation, the binding affinities of seven α-adrenoreceptor blockers were evaluated towards structurally different QS receptors. From the best docked α-blockers into QS receptors, terazosin was nominated to be subjected for further in vivo and in vitro anti-QS and anti-virulence activities against Chromobacterium violaceum and Pseudomonas aeruginosa. Terazosin showed a significant ability to diminish the QS-controlled pigment production in C. violaceum. Moreover, Terazosin decreased the P. aeruginosa biofilm formation and down-regulated its QS-encoding genes. Terazosin protected mice from the P. aeruginosa pathogenesis. In conclusion, α-adrenergic blockers are proposed as promising anti-virulence agents as they hinder QS receptors and inhibit bacterial espionage.

Delayed Decline of Cognitive Function by Antihypertensive Agents: A Cohort Study Linked with Genotype Data.

Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results. We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI). The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus β-blockers (βBs), and α1-AB plus βBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug. Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.