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Translational Research : the Journal of... Sep 2021Iodinated contrast is used for imaging and invasive procedures and it can cause contrast induced acute kidney injury (CI-AKI), which is the third leading...
Iodinated contrast is used for imaging and invasive procedures and it can cause contrast induced acute kidney injury (CI-AKI), which is the third leading hospital-acquired health problem. The purpose of the present study was to determine the effect of α-adrenergic receptor-1b (Adra1b) inhibition by using terazosin on change in kidney function, gene, and protein expression in C57BL/6J male mice, 6-8 weeks with chronic kidney disease (CKD). CKD was induced by surgical nephrectomy. Twenty eight days later, 100-µL of iodinated contrast (CI group) or saline (S group) was given via the carotid artery. Whole-transcriptome RNA-sequencing (RNA-Seq) analysis of the kidneys was performed at day 2. Mice received either 50-µL of saline ip or terazosin (2 mg/kg) in 50-µL of saline ip 1 hour before contrast administration which was continued every 12 hours until the animals were euthanized 2 and 7 days later. The kidneys were removed for gene expression, immunohistochemical analysis, and blood serum analyzed for kidney function. Differential gene expression analysis identified 21 upregulated and 436 downregulated genes (fold change >2; P < 0.05) that were common to all sample (n = 3 for both contrast and saline). We identified Adra1b using bioinformatic analysis. Mice treated with terazosin had a significant decrease in serum creatinine, urinary Kim-1 levels, HIF-1α, apoptosis, and downstream Adrab1 genes including Ece1, Edn1, pMAPK14 with increased cell proliferation. Contrast exposure upregulated Adra1b gene expression in HK-2 cells. Inhibition of Adra1b with terazosin abrogated Ece1, Edn1, and contrast-induced Fsp-1, Mmp-2, Mmp-9 expression, and caspase-3/7 activity in HK-2 cells.
Topics: Acute Kidney Injury; Adrenergic alpha-1 Receptor Antagonists; Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Contrast Media; Endothelin-Converting Enzymes; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 14; Prazosin; Receptors, Adrenergic, alpha-1
PubMed: 33711514
DOI: 10.1016/j.trsl.2021.03.005 -
Frontiers in Medicine 2022Selective α1-blockers are commonly administered to patients with lower urinary tract syndrome and benign prostatic hyperplasia, but may increase the risk of...
Selective α1-blockers are commonly administered to patients with lower urinary tract syndrome and benign prostatic hyperplasia, but may increase the risk of intraoperative floppy iris syndrome (IFIS). The purpose of this study aimed to clarify the risk of IFIS among various selective α1-blockers. Four databases were searched for prospective studies comparing alpha-1-antagonists. Data were pooled using the consistency model, and used risk ratio (RR) and mean difference (MD) for IFIS and pupil diameter, respectively. This study finally included 25 prospective comparative studies. Based on 51 direct comparisons with 6488 cases, risks of IFIS in patients who received tamsulosin [RR, 13.85; 95% confidence interval (CI): 7.34 to 26.11], terazosin (RR, 8.94; 95% CI 2.88 to 27.74), alfuzosin (RR, 7.73; 95% CI: 3.05 to 19.62), and doxazosin (RR, 3.88; 95% CI: 1.13 to 13.28) were significantly higher than those did not receive α1-antagonists. Based on 11 direct comparisons with 564 cases, as compared to no α1-antagonists, patients who received tamsulosin (MD, -0.36; 95% CI: -0.71 to -0.01) and alfuzosin (MD, -0.34; 95% CI: -0.62 to -0.07) showed smaller pupil diameter under mesopic light levels, while those received silodosin did not show significantly smaller mesopic pupil diameter than people without α1-antagonists. IFIS seems to be inevitable with the usage of α1-antagonists, and tamsulosin needs to be cautious due to the significantly higher risk of severe IFIS. With regard to silodosin, there is no strong evidence to support the uses of italthough it does not significantly decrease mesopic pupil diameter.
PubMed: 36111121
DOI: 10.3389/fmed.2022.941130 -
The Cochrane Database of Systematic... Nov 2020Shock wave lithotripsy (SWL) is a widely used method to treat renal and ureteral stone. It fragments stones into smaller pieces that are then able to pass spontaneously... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Shock wave lithotripsy (SWL) is a widely used method to treat renal and ureteral stone. It fragments stones into smaller pieces that are then able to pass spontaneously down the ureter and into the bladder. Alpha-blockers may assist in promoting the passage of stone fragments, but their effectiveness remains uncertain. OBJECTIVES: To assess the effects of alpha-blockers as adjuvant medical expulsive therapy plus usual care compared to placebo and usual care or usual care alone in adults undergoing shock wave lithotripsy for renal or ureteral stones.
SEARCH METHODS
We performed a comprehensive literature search of the Cochrane Library, the Cochrane Database of Systematic Reviews, MEDLINE, Embase, several clinical trial registries and grey literature for published and unpublished studies irrespective of language. The date of the most recent search was 27 February 2020.
SELECTION CRITERIA
We included randomized controlled trials of adults undergoing SWL. Participants in the intervention group had to have received an alpha-blocker as adjuvant medical expulsive therapy plus usual care. For the comparator group, we considered studies in which participants received placebo.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies for inclusion/exclusion, and performed data abstraction and risk of bias assessment. We conducted meta-analysis for the identified dichotomous and continuous outcomes using RevManWeb according to Cochrane methods using a random-effects model. We judged the certainty of evidence on a per outcome basis using GRADE.
MAIN RESULTS
We included 40 studies with 4793 participants randomized to usual care and an alpha-blocker versus usual care alone. Only four studies were placebo controlled. The mean age of participants was 28.6 to 56.8 years and the mean stone size prior to SWL was 7.1 mm to 13.2 mm. The most widely used alpha-blocker was tamsulosin; others were silodosin, doxazosin, terazosin and alfuzosin. Alpha-blockers may improve clearance of stone fragments after SWL (risk ratio (RR) 1.16, 95% confidence interval (CI) 1.09 to 1.23; I² = 78%; studies = 36; participants = 4084; low certainty evidence). Based on the stone clearance rate of 69.3% observed in the control arm, an alpha-blocker may increase stone clearance to 80.4%. This corresponds to 111 more (62 more to 159 more) participants per 1000 clearing their stone fragments. Alpha-blockers may reduce the need for auxiliary treatments after SWL (RR 0.67, 95% CI 0.45 to 1.00; I² = 16%; studies = 12; participants = 1251; low certainty evidence), but also includes the possibility of no effect. Based on a rate of auxiliary treatments in the usual care arm of 9.7%, alpha-blockers may reduce the rate to 6.5%. This corresponds 32 fewer (53 fewer to 0 fewer) participants per 1000 undergoing auxiliary treatments. Alpha-blockers may reduce major adverse events (RR 0.60, 95% CI 0.46 to 0.80; I² = 0%; studies = 7; participants = 747; low certainty evidence). Major adverse events occurred in 25.8% of participants in the usual care group; alpha-blockers would reduce this to 15.5%. This corresponds to 103 fewer (139 fewer to 52 fewer) major adverse events per 1000 with alpha-blocker treatment. None of the reported major adverse events appeared drug-related; most were emergency room visits or rehospitalizations. Alpha-blockers may reduce stone clearance time in days (mean difference (MD) -3.74, 95% CI -5.25 to -2.23; I² = 86%; studies = 14; participants = 1790; low certainty evidence). We found no evidence for the outcome of quality of life. For those outcomes for which we were able to perform subgroup analyses, we found no evidence of interaction with stone location, stone size or type of alpha-blocker. We were unable to conduct an analysis by lithotripter type. The results were also largely unchanged when the analyses were limited to placebo controlled studies and those in which participants explicitly only received a single SWL session.
AUTHORS' CONCLUSIONS
Based on low certainty evidence, adjuvant alpha-blocker therapy following SWL in addition to usual care may result in improved stone clearance, less need for auxiliary treatments, fewer major adverse events and a reduced stone clearance time compared to usual care alone. We did not find evidence for quality of life. The low certainty of evidence means that our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxazosin; Humans; Indoles; Kidney Calculi; Lithotripsy; Middle Aged; Prazosin; Quinazolines; Randomized Controlled Trials as Topic; Tamsulosin; Ureteral Calculi
PubMed: 33179245
DOI: 10.1002/14651858.CD013393.pub2 -
Hypertension (Dallas, Tex. : 1979) Nov 2020Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which...
Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α- and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α-adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt-sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α-adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt-sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α-adrenoceptor antagonism initiated before high-salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α-adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Animals; Blood Pressure; Gene Expression Regulation; Hypertension; Male; Phosphorylation; Prazosin; Propranolol; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride Symporters; Sympathetic Nervous System
PubMed: 32981364
DOI: 10.1161/HYPERTENSIONAHA.120.15928 -
MedRxiv : the Preprint Server For... Feb 2021Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (α-AR antagonists)...
Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (α-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of α-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.73; 95% CI 0.63 to 0.85; p ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65 to 0.84; p ≤ 0.001). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% (odds ratio 0.23; 95% CI 0.03 to 0.94; p = 0.028) compared to matched controls not on any α-AR antagonist at the time of admission. These findings suggest that use of α-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.
PubMed: 33398294
DOI: 10.1101/2020.12.18.20248346 -
Beilstein Journal of Organic Chemistry 20242-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the...
2-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the intrinsic azide-tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core, which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α-adrenoceptor blockers terazosin and prazosin by further C2-selective SAr reaction and azide reduction.
PubMed: 38590535
DOI: 10.3762/bjoc.20.61 -
Journal of Neurochemistry May 2022The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the...
The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. 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 (α1-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 an equal volume of saline for 6 months. SH-SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total Aβ plaques, than control mice. α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reducing Aβ production. This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Female; Glycogen Synthase Kinase 3 beta; Mice; Mice, Transgenic; Receptors, Adrenergic; Signal Transduction
PubMed: 35244207
DOI: 10.1111/jnc.15603 -
Frontiers in Medicine 2021Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (α-AR...
Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (α-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of α-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.73; 95% CI 0.63-0.85; ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65-0.84; ≤ 0.001). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% (odds ratio 0.23; 95% CI 0.03-0.94; = 0.028) compared to matched controls not on any α-AR antagonist at the time of admission. These findings suggest that use of α-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.
PubMed: 33869251
DOI: 10.3389/fmed.2021.637647 -
The Journal of Clinical Investigation Jun 2021BACKGROUNDRecently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease... (Comparative Study)
Comparative Study Observational Study
BACKGROUNDRecently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiological study of terazosin users showed a lower incidence of Parkinson disease when compared with users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group.METHODSTo address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the United States with 5 or more years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and Charlson comorbidity index score (n = 45,380).RESULTSIncidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%, P < 0.0001) and matched controls (1.01%, P < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (P = 0.29).CONCLUSIONThese results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression.FUNDINGThis work was supported by Cerevel Therapeutics.
Topics: Adolescent; Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Parkinson Disease; Prostatic Hyperplasia
PubMed: 33822767
DOI: 10.1172/JCI145112 -
Medical Science Monitor : International... Sep 2023BACKGROUND This study aimed to compare the impact of a-1 adrenergic blockers - nonselective (alfuzosin, doxazosin, and terazosin) and selective (silodosin and... (Observational Study)
Observational Study
BACKGROUND This study aimed to compare the impact of a-1 adrenergic blockers - nonselective (alfuzosin, doxazosin, and terazosin) and selective (silodosin and tamsulosin) - on the sedative effects of the alpha-2 adrenergic agonist dexmedetomidine (DMT) in patients undergoing urologic surgery. The primary outcome was the sedative effect of DMT as determined by the bispectral index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scores. MATERIAL AND METHODS One hundred eighteen patients undergoing elective urologic surgery with spinal anesthesia were recruited. Patients were assigned based on their medication status to group N (no medication; n=33), group NS (nonselective alpha-1 blocker; n=27), or group S (selective alpha-1 blocker; n=58). Mean blood pressure (MBP), heart rate (HR), oxygen saturation (SpO₂), BIS, and MOAA/S scale scores were recorded at 5-minute (min) intervals after DMT administration. RESULTS Group NS had significantly higher BIS scores than groups N and S at 25 min (P=0.045) and 30 min (P=0.030) after DMT administration, indicating lower sedation levels. MBP significantly differed between the 3 groups at all time points, with group N experiencing a lower MBP than groups NS and S. No significant differences were found between the groups in MOAA/S scale scores, SpO₂, or HR. CONCLUSIONS Nonselective alpha-1 adrenergic blockers can reduce the sedative effects of DMT. Consequently, there may be a need for individualized anesthesia management considering the specific subtype of alpha-1 adrenergic blocker medication.
Topics: Humans; Dexmedetomidine; Prospective Studies; Adrenergic alpha-1 Receptor Antagonists; Anesthesia, Spinal; Hypnotics and Sedatives
PubMed: 37747845
DOI: 10.12659/MSM.941614