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Pharmacology Research & Perspectives Aug 2020Electrical field stimulation (EFS) induces contractions of both snake aorta and human umbilical cord vessels (HUCV) which were dependent on the presence of the...
Electrical field stimulation (EFS) induces contractions of both snake aorta and human umbilical cord vessels (HUCV) which were dependent on the presence of the endothelium. This study aimed to establish the nature of the mediator(s) responsible for EFS-induced contractions in HUCV. Rings with or without endothelium from human umbilical artery (HUA) or vein (HUV) were mounted in organ bath chambers containing oxygenated, heated Krebs-Henseleit's solution. Basal release of dopamine (DA), noradrenaline, and adrenaline was measured by LC-MS-MS. Cumulative concentration-response curves were performed with dopamine in the absence and in the presence of L-NAME or of dopamine antagonists. EFS studies were performed in the presence and absence of L-NAME, the α-adrenergic blockers prazosin and idazoxan, and the dopamine antagonists SCH-23390 and haloperidol. Tyrosine hydroxylase (TH) and dopa-decarboxylase (DDC) were studied by immunohistochemistry and fluorescence in situ hybridizations. Basal release of dopamine requires an intact endothelium in both HUA and HUV. TH and DDC are present only in the endothelium of both HUA and HUV as determined by immunohistochemistry. Dopamine induced contractions in HUA only in the presence of L-NAME. Dopamine-induced contractions in HUV were strongly potentiated by L-NAME. The EFS-induced contractions in both HUA and HUV were potentiated by L-NAME and inhibited by the D2-like receptor antagonist haloperidol. The α-adrenergic antagonists prazosin and idazoxan and the D1-like receptor antagonist SCH-23390 had no effect on the EFS-induced contractions of HUA and HUV. Endothelium-derived dopamine is a major modulator of HUCV reactivity in vitro.
Topics: Adolescent; Adrenergic alpha-Antagonists; Adult; Chromatography, Liquid; Dopamine; Dopamine Antagonists; Electric Stimulation; Endothelium, Vascular; Epinephrine; Female; Humans; Middle Aged; Norepinephrine; Tandem Mass Spectrometry; Umbilical Arteries; Umbilical Veins; Young Adult
PubMed: 32567793
DOI: 10.1002/prp2.612 -
Endocrinology, Diabetes & Metabolism... Feb 2022Obstructive sleep apnea (OSA) is a condition of intermittent nocturnal upper airway obstruction. OSA increases sympathetic drive which may result in clinical and...
SUMMARY
Obstructive sleep apnea (OSA) is a condition of intermittent nocturnal upper airway obstruction. OSA increases sympathetic drive which may result in clinical and biochemical features suggestive of pheochromocytoma. We present the case of a 65-year-old male with a 2.9-cm left adrenal incidentaloma on CT, hypertension, symptoms of headache, anxiety and diaphoresis, and persistently elevated 24-h urine norepinephrine (initially 818 nmol/day (89-470)) and normetanephrine (initially 11.2 µmol/day (0.6-2.7)). He was started on prazosin and underwent left adrenalectomy. Pathology revealed an adrenal corticoadenoma with no evidence of pheochromocytoma. Over the next 2 years, urine norepinephrine and normetanephrine remained significantly elevated with no MIBG avid disease. Years later, he was diagnosed with severe OSA and treated with continuous positive airway pressure. Urine testing done once OSA was well controlled revealed complete normalization of urine norepinephrine and normetanephrine with substantial symptom improvement. It was concluded that the patient never had a pheochromocytoma but rather an adrenal adenoma with biochemistry and symptoms suggestive of pheochromocytoma due to untreated severe OSA. Pseudo-pheochromocytoma is a rare presentation of OSA and should be considered on the differential of elevated urine catecholamines and metanephrines in the right clinical setting.
LEARNING POINTS
Obstructive sleep apnea (OSA) is a common condition among adults. OSA may rarely present as pseudo-pheochromocytoma with symptoms of pallor, palpitations, perspiration, headache, or anxiety. OSA should be considered on the differential of elevated urine catecholamines and metanephrines, especially in patients with negative metaiodobenzylguanidine (MIBG) scan results.
PubMed: 35212265
DOI: 10.1530/EDM-21-0100 -
JAMA Neurology Apr 2021Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely... (Observational Study)
Observational Study
IMPORTANCE
Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases.
OBJECTIVE
To determine whether use of terazosin, doxazosin, and alfuzosin is associated with a decreased risk of developing PD.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used active comparator control and propensity score-matched data from Danish nationwide health registries, including the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Civil Registration System, from January 1996 to December 2017 and data from the Truven Health Analytics MarketScan database from January 2001 to December 2017. Men without PD who newly initiated terazosin/doxazosin/alfuzosin therapy or tamsulosin therapy, which is used for a similar indication (benign prostatic hyperplasia or unspecified urinary problems) but does not enhance glycolysis, and had at least 1 year of follow-up after medication start were included. In Denmark, the database included all residents, while the Truven database is a compilation of insurance claims across the US. Data were analyzed from February 2019 to July 2020.
EXPOSURES
Patients who used terazosin/doxazosin/alfuzosin vs tamsulosin. Additional dose-response analyses were carried out.
MAIN OUTCOMES AND MEASURES
Differences in the hazard of developing PD identified by diagnoses or use of PD-specific medications between patients who ever used terazosin/doxazosin/alfuzosin or tamsulosin.
RESULTS
A cohort of 52 365 propensity score-matched pairs of terazosin/doxazosin/alfuzosin and tamsulosin users were identified in the Danish registries, of which all were male and the mean (SD) age was 67.9 (10.4) years, and 94 883 propensity score-matched pairs were identified in the Truven database, of which all were male and the mean (SD) age was 63.8 (11.1) years. Patients in the Danish cohort who used terazosin/doxazosin/alfuzosin had a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), and patients in the Truven cohort had an HR of 0.63 (95% CI, 0.58-0.69). There was a dose-response association with short-duration, medium-duration, and long-duration use of terazosin/doxazosin/alfuzosin users having a decreasing HR in both the Danish cohort (short: HR, 0.95; 95% CI, 0.84-1.07; medium: HR, 0.88; 95% CI, 0.77-1.01; long: HR, 0.79; 95% CI, 0.66-0.95) and Truven cohort (short: HR, 0.70; 95% CI, 0.64-0.76; medium: HR, 0.58; 95% CI, 0.52-0.64; long: HR, 0.46; 95% CI, 0.36-0.57).
CONCLUSIONS AND RELEVANCE
These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Cohort Studies; Databases, Factual; Denmark; Doxazosin; Female; Follow-Up Studies; Glycolysis; Humans; Male; Middle Aged; Parkinson Disease; Prazosin; Quinazolines; Registries; Risk Factors; Tamsulosin; United States
PubMed: 33523098
DOI: 10.1001/jamaneurol.2020.5157 -
Pharmaceuticals (Basel, Switzerland) Dec 2022(Kunth) Britten & Baker f (Malvaceae) is used for the folk treatment of mood disorders. bark was extracted in ethanol, and the extract (CAE) was chemically...
(Kunth) Britten & Baker f (Malvaceae) is used for the folk treatment of mood disorders. bark was extracted in ethanol, and the extract (CAE) was chemically standardized using gas chromatography-mass spectrometry (GC-MS). This study evaluated the effects of CAE (10-100 mg/kg p.o.) on anxiolytic-like activity, sedation, locomotor activity, depression-like activity, and spatial working memory using in vivo rodent models. A possible mechanism for the anxiolytic-like and antidepressant-like actions induced by CAE was assessed using neurotransmission pathway inhibitors. Myristic acid was one of the compounds found in CAE using GC-MS. This study also evaluated the anxiolytic-like activity and the sedative actions of myristic acid and assessed a possible mechanism of action using neurotransmission pathway inhibitors and an in silico analysis. CAE elicited anxiolytic-like activity and antidepressant-like effects (ED = 57 mg/kg). CAE (10-100 mg/kg) did not affect locomotor coordination or induce sedation. The anxiolytic-like and antidepressant-like actions of CAE were reverted by prazosin, suggesting a possible participation of the noradrenergic system. The anxiolytic-like activity of myristic acid was reverted by the co-administration of prazosin and partially reverted by ketanserin. The docking study revealed that myristic acid can form favorable interactions within 5-HT2A and α1A-adrenoreceptor binding pockets.
PubMed: 36559031
DOI: 10.3390/ph15121580 -
Philosophical Transactions of the Royal... Jun 2023Atrial fibrillation (AF) is the most common chronic arrhythmia presenting a heavy disease burden. We report a new approach for generating cardiomyocytes (CMs)...
Atrial fibrillation (AF) is the most common chronic arrhythmia presenting a heavy disease burden. We report a new approach for generating cardiomyocytes (CMs) resembling atrial cells from human-induced pluripotent stem cells (hiPSCs) using a combination of Gremlin 2 and retinoic acid treatment. More than 40% of myocytes showed rod-shaped morphology, expression of CM proteins (including ryanodine receptor 2, -actinin-2 and F-actin) and striated appearance, all of which were broadly similar to the characteristics of adult atrial myocytes (AMs). Isolated myocytes were electrically quiescent until stimulated to fire action potentials with an AM profile and an amplitude of approximately 100 mV, arising from a resting potential of approximately -70 mV. Single-cell RNA sequence analysis showed a high level of expression of several atrial-specific transcripts including , , , , , and . Amplitudes of calcium transients recorded from spontaneously beating cultures were increased by the stimulation of -adrenoceptors (activated by phenylephrine and blocked by prazosin) or -adrenoceptors (activated by isoproterenol and blocked by CGP20712A). Our new approach provides human AMs with mature characteristics from hiPSCs which will facilitate drug discovery by enabling the study of human atrial cell signalling pathways and AF. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Adult; Humans; Myocytes, Cardiac; Induced Pluripotent Stem Cells; Cell Differentiation; Atrial Fibrillation; Receptors, Adrenergic; G Protein-Coupled Inwardly-Rectifying Potassium Channels
PubMed: 37122218
DOI: 10.1098/rstb.2022.0312 -
American Journal of Physiology.... Aug 2020Understanding mouse thermal physiology informs the usefulness of mice as models of human disease. It is widely assumed that the mouse tail contributes greatly to heat...
Understanding mouse thermal physiology informs the usefulness of mice as models of human disease. It is widely assumed that the mouse tail contributes greatly to heat loss (as it does in rat), but this has not been quantitated. We studied C57BL/6J mice after tail amputation. Tailless mice housed at 22°C did not differ from littermate controls in body weight, lean or fat content, or energy expenditure. With acute changes in ambient temperature from 19 to 39°C, tailless and control mice demonstrated similar body temperatures (Tb), metabolic rates, and heat conductances and no difference in thermoneutral point. Treatment with prazosin, an α1-adrenergic antagonist and vasodilator, increased tail temperature in control mice by up to 4.8 ± 0.8°C. Comparing prazosin treatment in tailless and control mice suggested that the tail's contribution to total heat loss was a nonsignificant 3.4%. Major heat stress produced by treatment at 30°C with CL316243, a β3-adrenergic agonist, increased metabolic rate and Tb and, at a matched increase in metabolic rate, the tailless mice showed a 0.72 ± 0.14°C greater Tb increase and 7.6% lower whole body heat conductance. Thus, the mouse tail is a useful biomarker of vasodilation and thermoregulation, but in our experiments contributes only 5-8% of whole body heat dissipation, less than the 17% reported for rat. Heat dissipation through the tail is important under extreme scenarios such as pharmacological activation of brown adipose tissue; however, non-tail contributions to heat loss may have been underestimated in the mouse.
Topics: Adrenergic alpha-1 Receptor Antagonists; Amputation, Surgical; Animals; Body Composition; Body Surface Area; Body Temperature Regulation; Body Weight; Energy Metabolism; Heat-Shock Response; Mice; Mice, Inbred C57BL; Models, Animal; Prazosin; Rats; Tail; Vasodilation
PubMed: 32691633
DOI: 10.1152/ajpendo.00133.2020 -
Journal of Ayub Medical College,... 2020Autonomic nervous system modulates acetaminophen induced hepatotoxicity. The purpose of the study was to determine the hepatoprotective effect of α1 antagonist...
BACKGROUND
Autonomic nervous system modulates acetaminophen induced hepatotoxicity. The purpose of the study was to determine the hepatoprotective effect of α1 antagonist (prazosin) and β2 agonist (salbutamol) on acetaminophen induced hepatotoxicity in mice.
METHODS
This experimental study was conducted at Post Graduate Medical Institute, Lahore in which 50 adult mice were divided in to five groups. With the exception of normal control, hepatotoxicity was induced in all other study groups by giving single intraperitoneal injection of acetaminophen 300 mg/ kg. First and second groups served as normal and toxic control were given distilled water 6 ml/ kg while third, fourth and fifth experimental groups were given N-acetylcysteine (300 mg/ kg), prazosin (0.18 mg/ kg) and salbutamol (0.35 mg/kg) intraperitoneally at 2,4 and 8 hours after acetaminophen injection. Serum liver enzymes were analysed at 0 and 72 hours while histopathological finding were assessed at the end of study by using SPSS-20.
RESULTS
All the groups treated with toxic dose of acetaminophen showed significant increase in serum ALT, i.e., B (Toxic control 3372%), C (NAC treated 282%), D (Prazosin treated 582%), E(Salbutamol treated 3297%) and AST levels, i.e., B (Toxic control 2750% ), C (NAC treated 230% ), D (Prazosin treated 280%), E (Salbutamol treated 828%) with p-value ˂0.001. When this increase was compared between groups, the lowest increase in serum ALT and AST levels was observed in Nacetylcysteine and prazosin group with no significant difference. Similarly, experimental animals receiving prazosin and N-acetylcysteine had the lowest inflammation, degeneration and necrosis scores than the toxic control group in histopathological analysis of the liver with p-value <0.001.
CONCLUSIONS
The hepatoprotective effect of prazosin is comparable to N- acetylcysteine against acetaminophen induced hepatotoxicity in mice.
Topics: Acetaminophen; Acetylcysteine; Adrenergic alpha-1 Receptor Antagonists; Albuterol; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Free Radical Scavengers; Liver; Male; Mice; Necrosis; Prazosin
PubMed: 32468750
DOI: No ID Found -
EBioMedicine Sep 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
METHODS
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
FINDINGS
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
INTERPRETATION
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
FUNDING
This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].
Topics: Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Humans; Mice; Motor Neurons; Phenotype; Phosphoglycerate Kinase; Prazosin; Zebrafish
PubMed: 35963713
DOI: 10.1016/j.ebiom.2022.104202 -
Cell Reports Jul 2020Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens...
Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers.
Topics: Animals; Antigens; Antineoplastic Agents; Biological Transport; Cross-Priming; Cytosol; Dendritic Cells; Endoplasmic Reticulum-Associated Degradation; Endosomes; Immunity; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Permeability; Prazosin; Quinazolines; Small Molecule Libraries; Tamoxifen; beta-Lactamases
PubMed: 32668257
DOI: 10.1016/j.celrep.2020.107905 -
Indian Journal of Medical Ethics 2023I have been practising medicine in an under-served rural setting since 1976, and have published around 109 papers in PubMed-indexed journals - including The Lancet, BMJ,...
I have been practising medicine in an under-served rural setting since 1976, and have published around 109 papers in PubMed-indexed journals - including The Lancet, BMJ, NEJM and several tropical medicine journals - on scorpion and snakebite cases causing acute life-threatening conditions. I have researched in detail, with restricted resources, the acute clinical effects of envenomation and management of scorpion and snakebite cases [1, 2]. In Mahad, the fatality rate due to refractory heart failure arising from autonomic storm evoked by scorpion venom was previously 30% [3]. Since the advent of prazosin and scorpion antivenom, it has dropped to less than 1% [4]. Similarly, fatalities due to snakebite poisoning have been reduced from 18% to 5.
Topics: Animals; Humans; Snake Bites; Scorpion Stings; Prazosin; Antivenins; Scorpion Venoms; Scorpions
PubMed: 36420604
DOI: 10.20529/IJME.2022.068