-
Experimental and Therapeutic Medicine Oct 2018Gestational hypertensive disorder is a complication of pregnancy, which adversely affects mother-child health. Captopril and prazosin are two agents that are frequently...
Gestational hypertensive disorder is a complication of pregnancy, which adversely affects mother-child health. Captopril and prazosin are two agents that are frequently applied for the treatment of patients with gestational hypertension. However, the cooperative efficacy of captopril and prazosin has been not investigated in a previous study. In the present study, the comprehensive treatment of captopril and prazosin for the treatment of patients with gestational hypertension was investigated. A total of 324 patients with gestational hypertension were recruited to analyze the therapeutic effects of captopril and prazosin in patients with gestational hypertension. The duration of the treatment, dose-limiting toxicities and maximum tolerated dose of captopril and prazosin were examined in this cohort. Furthermore, the levels of blood pressure and proteinuria were also examined in patients with gestational hypertension who received treatment with captopril and/or prazosin with placebo as a control. Serum levels of vasodilation-converting enzyme and α-adrenergic receptor were also examined prior to and during the 4-week post-treatment period. It was observed that the most common treatment-emergence adverse events were hypertension and proteinuria following 4-week treatments. The data revealed that captopril or prazosin treatments significantly ameliorated gestational hypertension and symptoms compared with placebo (P<0.01). Notably, the combination of captopril and prazosin treatments significantly ameliorated hypertension and proteinuria and reduced the expression levels of vasodilation-converting enzyme and α-adrenergic receptor (all P<0.01), which contributed to beneficial effects on complications and blood coagulation mechanism compared with either captopril or prazosin treatment. In conclusion, the present clinical study indicated that combination treatment of captopril and prazosin exhibited more efficient outcomes than the single agent by improving gestational hypertension, indicating that a comprehensive therapeutic regimen of captopril and prazosin may be a potential clinical opinion for patients with gestational hypertension.
PubMed: 30233728
DOI: 10.3892/etm.2018.6604 -
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 -
Nature and Science of Sleep 2018Nightmares are considered the hallmark of posttraumatic stress disorder (PTSD). Although the characteristics of these distressing dreams may vary with the type of... (Review)
Review
Nightmares are considered the hallmark of posttraumatic stress disorder (PTSD). Although the characteristics of these distressing dreams may vary with the type of traumatic event, the pathophysiology exposes central dysfunction of brain structures at the level of the hippocampus, amygdala, and locus coeruleus, modulated by neurochemical imbalance in nor-adrenergic, dopaminergic, and serotonin pathways. Underlying comorbid conditions, including other sleep disorders, may contribute to worsening symptoms. Addressing sleep disruption can alleviate the severity of these nocturnal events and augment the effectiveness of other PTSD treatments. The expansion of behavioral treatment modalities for PTSD-related nightmares has been encouraging, but the core of these interventions is heavily structured around memory manipulation and imagery rescripting. A lack of a standardized delivery and a high dropout rate continue to pose significant challenges in achieving successful outcomes. The efficacy of existing pharmacological studies, such as α-adrenergic blocking agents, antidepressants, and atypical antipsychotics, has been undermined by methodological limitations and absence of large randomized controlled trials. This review is aimed at reviewing the available treatment strategies for alleviating nightmares in subjects with PTSD. Given the intricate relationship between PTSD and nightmares, future clinical trials have to adopt a more pragmatic approach focused not only on efficacy of novel interventions but also on adjunctive iteration of existing therapies tailored to individual socio-cultural background.
PubMed: 30538593
DOI: 10.2147/NSS.S166089 -
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 -
The Journal of Physiology Feb 2018While values of arterial pressure during sleep are predictive of cardiovascular risk, the autonomic mechanisms underlying the cardiovascular effects of sleep remain...
KEY POINTS
While values of arterial pressure during sleep are predictive of cardiovascular risk, the autonomic mechanisms underlying the cardiovascular effects of sleep remain poorly understood. Here, we assess the autonomic mechanisms of the cardiovascular effects of sleep in C57Bl/6J mice, taking advantage of a novel technique for continuous intraperitoneal infusion of autonomic blockers. Our results indicate that non-REM sleep decreases arterial pressure by decreasing sympathetic vasoconstriction, decreases heart rate by balancing parasympathetic activation and sympathetic withdrawal, and increases cardiac baroreflex sensitivity mainly by increasing fluctuations in parasympathetic activity. Our results also indicate that REM sleep increases arterial pressure by increasing sympathetic activity to the heart and blood vessels, and increases heart rate, at least in part, by increasing cardiac sympathetic activity. These results provide a framework for generating and testing hypotheses on cardiovascular derangements during sleep in mouse models and human patients.
ABSTRACT
The values of arterial pressure (AP) during sleep predict cardiovascular risk. Sleep exerts similar effects on cardiovascular control in human subjects and mice. We aimed to determine the underlying autonomic mechanisms in 12 C57Bl/6J mice with a novel technique of intraperitoneal infusion of autonomic blockers, while monitoring the electroencephalogram, electromyogram, AP and heart period (HP, i.e. 1/heart rate). In different sessions, we administered atropine methyl nitrate, atenolol and prazosin to block muscarinic cholinergic, β -adrenergic and α -adrenergic receptors, respectively, and compared each drug infusion with a matched vehicle infusion. The decrease in AP from wakefulness to non-rapid-eye-movement sleep (N) was abolished by prazosin but was not significantly affected by atropine and atenolol, which, however, blunted the accompanying increase in HP to a similar extent. On passing from N to rapid-eye-movement sleep (R), the increase in AP was significantly blunted by prazosin and atenolol, whereas the accompanying decrease in HP was blunted by atropine and abolished by atenolol. Cardiac baroreflex sensitivity (cBRS, sequence technique) was dramatically decreased by atropine and slightly increased by prazosin. These data indicate that in C57Bl/6J mice, N decreases mean AP by decreasing sympathetic vasoconstriction, increases HP by balancing parasympathetic activation and sympathetic withdrawal, and increases cBRS mainly by increasing fluctuations in parasympathetic activity. R increases mean AP by increasing sympathetic vasoconstriction and cardiac sympathetic activity, which also explains, at least in part, the concomitant decrease in HP. These data represent the first comprehensive assessment of the autonomic mechanisms of cardiovascular control during sleep in mice.
Topics: Animals; Anti-Arrhythmia Agents; Arterial Pressure; Cardiovascular System; Heart Rate; Humans; Male; Mice; Mice, Inbred C57BL; Sleep; Sympathetic Nervous System; Vasoconstriction; Wakefulness
PubMed: 29266348
DOI: 10.1113/JP275353 -
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 -
Journal of Applied Physiology... Mar 2017Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal...
Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats ( = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats ( = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (HO) treatment groups: nondiabetic-SED-HO, STZ-SED-HO, STZ-EX-HO, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-HO animals (both < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels ( = -0.7015, < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose ( < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone ( < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D. It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an α-adrenergic antagonist) can reduce these complications and improve glycemic control.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Exercise Therapy; Hypoglycemic Agents; Male; Microvascular Rarefaction; Prazosin; Rats; Rats, Sprague-Dawley; Streptozocin; Treatment Outcome; Volition
PubMed: 27932675
DOI: 10.1152/japplphysiol.00762.2016