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British Journal of Pharmacology Mar 19971. Hypothalamic peptidergic neurones possess an uptake process for amines (transport-P), for which prazosin is a substrate. It is characterized by a paradoxical increase...
1. Hypothalamic peptidergic neurones possess an uptake process for amines (transport-P), for which prazosin is a substrate. It is characterized by a paradoxical increase in the accumulation of [3H]-prazosin when the concentration of unlabelled prazosin is increased above 10(-7) M. This increase is due to activation of a proton-dependent, vacuolar-type ATPase-linked pump that is blocked by tricyclic antidepressants. This study utilized a fluorescence method to detect amine uptake in individual cells. 2. Prazosin is fluorescent but most of its emission spectrum is in the ultraviolet range. We therefore used an analogue of prazosin in which the furan ring had been substituted with a fluorescent group, BODIPY FL. This compound's emission maximum is in the green part of the visible spectrum. 3. BODIPY FL prazosin accumulated in immortalised peptidergic neurones and the characteristic emission spectrum of the compound was evident in these cells. Accumulation of BODIPY FL prazosin was saturable and was inhibited by the tricyclic antidepressant desipramine and by unlabelled prazosin. As previously described for prazosin, uptake of BODIPY FL prazosin was blocked by cold temperature and by the organic base chloroquine. Thus, prazosin and BODIPY FL prazosin were accumulated by the same uptake process. 4. BODIPY FL prazosin accumulated in a granular distribution, which is compatible with storage in intracellular vesicles. 5. Hypothalamic cells from foetal rats in primary culture also accumulated BODIPY FL prazosin by a desipramine-sensitive process. Uptake was predominantly in neurones and glial cells did not accumulate the amine. 6. Fluorescent detection provides visual evidence for amine uptake in peptidergic neurones and should enable detailed study of the distribution of this process in the brain.
Topics: Adrenergic alpha-Antagonists; Amines; Animals; Biological Transport; Boron Compounds; Cell Line, Transformed; Desipramine; Fluorescent Dyes; Hypothalamus; Microscopy, Fluorescence; Neurons; Peptides; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Spectrometry, Fluorescence
PubMed: 9138694
DOI: 10.1038/sj.bjp.0700970 -
British Heart Journal Mar 1986A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the... (Clinical Trial)
Clinical Trial
A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.
Topics: Aged; Captopril; Clinical Trials as Topic; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Prazosin; Renin-Angiotensin System; Rest; Vasodilation; Vasopressins
PubMed: 3513808
DOI: 10.1136/hrt.55.3.265 -
Journal of Clinical Sleep Medicine :... Apr 2016Prazosin is increasingly being used off-label to treat nightmares in patients with posttraumatic stress disorder. The literature about the psychiatric adverse effects of...
Prazosin is increasingly being used off-label to treat nightmares in patients with posttraumatic stress disorder. The literature about the psychiatric adverse effects of prazosin is very limited. We present a case in which low-dose prazosin was associated with nightmares and sleep disturbances in an elderly patient without previously diagnosed mental illness or coexisting environmental risk factors for nightmares. Insomnia and hallucinations are listed as some of the rare side effects of prazosin by the manufacturer. Prazosin could be associated with rare psychiatric adverse effects and sleep disturbances. Particular attention is required in identifying these adverse effects, which can be difficult to distinguish from other drug-related side effects in the elderly particularly because they are often using multiple medications.
Topics: Adrenergic alpha-1 Receptor Antagonists; Aged; Dreams; Humans; Male; Prazosin; Risk Factors; Sleep Wake Disorders
PubMed: 26715405
DOI: 10.5664/jcsm.5708 -
The Journal of Clinical Psychiatry Mar 2021The choice from among approved treatments for relapse prevention in alcohol use disorder (AUD) is not symptom-driven. It is reasonable to speculate that the discomfort...
The choice from among approved treatments for relapse prevention in alcohol use disorder (AUD) is not symptom-driven. It is reasonable to speculate that the discomfort and distress associated with the experience of alcohol withdrawal symptoms (AWS) discourage abstinence and prompt continuation of or relapse into drinking. Adrenergic mechanisms may underlie many of the commonly experienced AWS. This allows the further speculation that drugs with antiadrenergic properties may attenuate AWS and thereby improve treatment outcomes in patients with AUD who attempt to quit drinking. In this context, the α1 adrenoceptor antagonist prazosin is a possible symptom-driven choice for patients with AUD who experience high AWS. Randomized controlled trial (RCT) results with prazosin and doxazosin have however been mixed, perhaps because the role of AWS was not considered in these. In this context, a recent large (n = 100) RCT found that prazosin, uptitrated to 16 mg/d, reduced drinking days, heavy drinking days, and average drinks per day; the benefits were observed only in patients with high AWS at baseline, operationalized as a Clinical Institute Withdrawal Assessment for Alcohol-Revised score of 3 or higher. Concerns about the internal and external validity of this study are discussed. How and when high AWS is determined is also a point of debate. If high AWS is a valid target for the symptom-driven choice of pharmacologic intervention for AUD, then a wide range of drugs merits study; in the long run, some of these drugs may be better tolerated than prazosin.
Topics: Alcoholism; Clinical Decision-Making; Humans; Prazosin; Secondary Prevention; Treatment Outcome
PubMed: 34033270
DOI: 10.4088/JCP.21f13980 -
Physiological Reports Sep 2018Preeclampsia (PE), a disorder of new-onset maternal hypertension and vascular dysfunction during pregnancy, is thought to be linked to placental ischemia-induced release...
Preeclampsia (PE), a disorder of new-onset maternal hypertension and vascular dysfunction during pregnancy, is thought to be linked to placental ischemia-induced release of prohypertensive factors and reductions of vasoprotective factors in the maternal circulation. Although markers of sympathetic nervous activity are elevated in experimental models of placental ischemia-induced hypertension and women with PE compared with their normal pregnant counterparts, the importance of adrenergic receptor signaling in the development of hypertension in PE is unknown. Therefore, we tested the hypothesis that adrenergic receptor blockade attenuates the development of placental ischemia-induced hypertension in rats. Wistar Hannover rats underwent reduced uterine perfusion pressure (RUPP) or Sham surgeries on gestational day 14. By day 19, mean arterial blood pressure (MAP) was increased in RUPP over Sham rats. Groups of RUPP and Sham pregnant rats received terazosin and propranolol (3 mg/kg per day of each via subcutaneous osmotic minipump) to block α- and β-adrenergic receptors, respectively, beginning on gestational day 14. Adrenergic blockade significantly attenuated the development of hypertension in the RUPP rats with a slight blood pressure-lowering response in the Sham, normal pregnant rats by day 19. In conclusion, these data implicate that placental ischemia-induced hypertension involves adrenergic receptor signaling to promote increases in blood pressure during PE.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Animals; Blood Pressure; Female; Ischemia; Placenta; Prazosin; Pre-Eclampsia; Pregnancy; Propranolol; Rats; Rats, Wistar
PubMed: 30229567
DOI: 10.14814/phy2.13814 -
The Journal of Physiology Jul 19951. We studied the effects of systemic administration of the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine and the selective alpha 1-adrenoreceptor...
1. We studied the effects of systemic administration of the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine and the selective alpha 1-adrenoreceptor antagonist prazosin on fetal breathing movements (FBM) and electrocortical activity (ECoG) in fetal sheep. In one group of fetuses (group I; n = 7) the effects of phentolamine were measured during normoxia and hypoxia. In the second group of fetuses (group II; n = 8) the effects of either phentolamine, or combined phentolamine and prazosin, or prazosin alone, were measured during normoxia. 2. In group I fetuses, the incidence of FBM increased after phentolamine treatment. An increase in the incidence and mean episode duration of low-voltage ECoG (LV-ECoG) was also measured after phentolamine treatment. These effects of phentolamine persisted during hypoxia. 3. In group II fetuses a pronounced decrease in the incidence of FBM occurred after administration of prazosin following either phentolamine or saline pretreatment. These effects of prazosin on FBM were independent of an effect on ECoG activity. 4. We conclude that catecholamines have a stimulatory role on FBM mediated via an alpha 1-adrenoreceptor mechanism. Phentolamine leads to an increase in FBM by preferentially antagonizing presynaptic alpha 2-adrenoreceptors over postsynaptic alpha 1-adrenoreceptors. This influence of phentolamine on FBM may be secondary to its effect on ECoG. Promotion of LV-ECoG by catecholamines is mediated via an alpha 1-independent mechanism.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Blood Gas Analysis; Diaphragm; Electroencephalography; Electromyography; Female; Fetal Movement; Phentolamine; Prazosin; Pregnancy; Respiratory Mechanics; Sheep
PubMed: 7562640
DOI: 10.1113/jphysiol.1995.sp020807 -
The Journal of Clinical Psychiatry Sep 2021
Topics: Adrenergic alpha-1 Receptor Antagonists; Alcohol Drinking; Alcoholism; Humans; Prazosin
PubMed: 34551219
DOI: 10.4088/JCP.21lr14076 -
Biochemical Pharmacology Feb 2018The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell...
The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α-AR signalling in CHO-K1 cells co-expressing the human α-AR and GLUT4 (CHOαGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the α-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another α-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHOαGLUT4myc cells, siRNA directed against rictor but not raptor suppressed α-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by α-AR agonists. Our findings identify a novel link between the α-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of α-AR selective agonists as tools in the treatment of cardiac dysfunction.
Topics: Animals; CHO Cells; Calcimycin; Calcium; Cricetinae; Cricetulus; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Myocytes, Cardiac; Norepinephrine; Phosphorylation; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 29175420
DOI: 10.1016/j.bcp.2017.11.016 -
Journal of Medical Case Reports Dec 2021Disruption of the Neurobeachin gene is a rare genetic mutation that has been implicated in the development of autism and enhanced long-term potentiation of the...
BACKGROUND
Disruption of the Neurobeachin gene is a rare genetic mutation that has been implicated in the development of autism and enhanced long-term potentiation of the hippocampal CA1 region, causing a heightened conditioned fear response and impaired fear extinction. Prazosin, an alpha-1 receptor antagonist, has been used in patients with posttraumatic stress disorder to mitigate the increased alpha-1 activity involved in fear and startle responses. Here we report a case of a patient with a rare Neurobeachin gene deletion, who demonstrated marked and sustained improvement in paranoid behavior within days of prazosin initiation.
CASE PRESENTATION
The patient is a 27-year-old White male with autism spectrum disorder, obsessive-compulsive disorder, and schizophrenia, with a chromosome 13q12 deletion including deletion of the Neurobeachin gene, who presented to the emergency department due to worsening functional status and profound weight loss as a result of only eating prepackaged foods. He had not showered or changed clothes in several months prior to presentation. He was hospitalized in the inpatient psychiatric unit for 2 months before prazosin was initiated. During that time, he demonstrated paranoia as evidenced by heightened sensitivity to doors opening, guarded interactions, and limited communication with providers and other patients. He also exhibited poor grooming habits, with aversion to showering, shaving, and changing clothes. Since initiating prazosin, he has demonstrated a brighter affect, initiates and maintains conversations, showers and changes clothes on a regular basis, and eats a variety of foods. At the time of this report, the patient was discharged to live in an apartment with a caregiver after a 7-month inpatient hospitalization.
CONCLUSIONS
Low-dose prazosin shows rapid and sustained improvement in paranoid behavior in a patient with a rare Neurobeachin gene deletion. Prazosin has a relatively favorable side effect profile with once-daily dosing and low cost. Prazosin may provide clinical improvement in patients with Neurobeachin gene deletions due to its theoretical attenuation in fear response through alpha-1 antagonism.
Topics: Adult; Animals; Autism Spectrum Disorder; Extinction, Psychological; Fear; Gene Deletion; Humans; Male; Paranoid Behavior; Prazosin
PubMed: 34949210
DOI: 10.1186/s13256-021-03209-2 -
British Journal of Clinical Pharmacology Jul 19801 The possibility of pharmacodynamic and pharmacokinetic interactions of prazosin with indomethacin and with propranolol have been studied in healthy subjects. 2 In four...
1 The possibility of pharmacodynamic and pharmacokinetic interactions of prazosin with indomethacin and with propranolol have been studied in healthy subjects. 2 In four out of nine individuals indomethacin considerably attenuated prazosin-induced hypotension, but noradrenaline concentrations were unchanged from the day when blood pressure fell greatly. The effect of prazosin in the other five subjects was not influenced by indomethacin. 3 Indomethacin prevented the rise in plasma renin activity seen following administration of prazosin alone. 4 Propranolol did not prevent the syncope associated with the first dose of prazosin. 5 Propranolol affected neither the absorption nor elimination of prazosin. 6 It is concluded that in certain subjects indomethacin can largely prevent the hypotensive effect of parazosin, possible by increasing adrenergic receptor sensitivity. The theoretical possibility that propranolol could influence prazosin disposition or syncope was not substantiated.
Topics: Adult; Blood Pressure; Drug Interactions; Endocrine Glands; Heart Rate; Humans; Indomethacin; Kinetics; Male; Prazosin; Propranolol; Quinazolines; Syncope; Time Factors
PubMed: 7397054
DOI: 10.1111/j.1365-2125.1980.tb00499.x