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1.
Biol Pharm Bull ; 46(2): 309-319, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36724959

RESUMO

We examined whether the α1L-adrenoceptor (AR), which shows low affinity (pA2 < 9) for prazosin (an α1-AR antagonist) and high affinity (pA2 ≈ 10) for tamsulosin/silodosin (α1A-AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA). Intracellular signaling induced by α1L-AR activation was also examined by focusing on Ca2+ influx pathways. Tension changes of endothelium-denuded TAs were isometrically recorded and mRNA encoding α-ARs/Ca2+ channels and their related molecules were measured using RT-quantitative PCR. Phenylephrine-induced contractions were competitively inhibited by prazosin/tamsulosin, and their pA2 value were calculated to be 8.53/9.74, respectively. These contractions were also inhibited by silodosin concentration-dependently. However, the inhibition was not competitive fashion with the apparent pA2 value being 9.48. In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α1B-AR antagonist), BMY 7378 (an α1D-AR antagonist), yohimbine, and idazoxan (α2-AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca2+, and partially inhibited by verapamil (a voltage-dependent Ca2+ channel (VDCC) inhibitor). The residual contractions in the presence of verapamil were slightly inhibited by LOE 908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) and strongly inhibited by SKF-96365 (a store-operated Ca2+ channel (SOCC) and ROCC inhibitor). Among the mRNA encoding α-ARs/SOCC-related molecules, α1A-AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α1L-AR, followed by activation of SOCCs and VDCCs.


Assuntos
Antagonistas Adrenérgicos alfa , Aorta Torácica , Cobaias , Animais , Fenilefrina/farmacologia , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Tansulosina/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Prazosina/farmacologia , Verapamil/farmacologia , Verapamil/metabolismo , RNA Mensageiro/metabolismo , Contração Muscular
2.
Molecules ; 27(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36234675

RESUMO

Cardiovascular diseases are one of the major causes of mortalities worldwide. In the present research, new synthetic derivatives of thiazole were studied using isolated hearts and blood vessels of rats. The heart and thoracic aorta were tested with six new synthesized thiazole acetic acid derivatives (SMVA-10, SMVA-35, SMVA-40, SMVA-41, SMVA-42 and SMVA-60), and the data obtained were statistically analyzed and compared. Isolated rat hearts were used to record the changes in developed tension and heart rate, while thoracic aortas were used to measure the contractile response, before and after treatments. Analysis of the results indicated a significant (p < 0.01) increase in developed tension with the addition of SMVA-35, SMVA-40, SMVA-41 and SMVA-42, which was augmented in the presence of adrenaline without affecting the heart rate. On the other hand, acetylcholine significantly decreased the developed tension, which was significantly reversed (p < 0.01) in the presence of compounds (SMVA-35 and SMVA-60). However, in the presence of SMVA-35 and SMVA-40, acetylcholine-induced bradycardia was significantly (p < 0.01) reduced. Furthermore, only SMVA-42 induced a dose-dependent contractile response in the isolated blood vessel, which was abolished in the presence of prazosin. Therefore, it can be concluded that some of the new synthesized thiazole derivatives exhibited promising results by raising the developed tension without changing the heart rate or blood vessel function, which could be helpful in failing heart conditions. However, more research is required to fully comprehend the function, mechanism and effectiveness of the compounds.


Assuntos
Ácido Acético , Tiazóis , Acetilcolina , Animais , Epinefrina , Prazosina , Ratos , Tiazóis/farmacologia
3.
Exp Physiol ; 107(12): 1440-1453, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36114662

RESUMO

NEW FINDINGS: What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α1-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. ABSTRACT: We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α1-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α1-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α1-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α1-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.


Assuntos
Artéria Braquial , Hipercapnia , Adulto Jovem , Humanos , Feminino , Masculino , Artéria Braquial/fisiologia , Adrenérgicos , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Prazosina , Velocidade do Fluxo Sanguíneo/fisiologia
4.
Psychiatry Res ; 317: 114840, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36162349

RESUMO

Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from January 2011 to November 2021 were identified via PubMed and analyzed for evidence supporting changes. Following consideration of variations required by special patient populations, treatment of sleep impairments remains as the first recommended step. Nightmares and non-nightmare disturbed awakenings are best addressed with the anti-adrenergic agent prazosin, with doxazosin and clonidine as alternatives. First choices for difficulty initiating sleep include hydroxyzine and trazodone. If significant non-sleep PTSD symptoms remain, an SSRI should be tried, followed by a second SSRI or venlafaxine as a third step. Second generation antipsychotics can be considered, particularly for SSRI augmentation when PTSD-associated psychotic symptoms are present, with the caveat that positive evidence is limited and side effects are considerable. Anti-adrenergic agents can also be considered for general PTSD symptoms if not already tried, though evidence for daytime use lags that available for sleep. Regarding other pharmacological and procedural options, e.g., transcranial magnetic stimulation, cannabinoids, ketamine, psychedelics, and stellate ganglion block, evidence does not yet support firm inclusion in the algorithm. An interactive version of this work can be found at www.psychopharm.mobi.


Assuntos
Psicofarmacologia , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Prazosina/uso terapêutico , Prazosina/farmacologia , Sonhos , Transtornos do Sono-Vigília/terapia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico
5.
Drug Dev Ind Pharm ; 48(9): 470-479, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111737

RESUMO

OBJECTIVE: The study aimed to develop a rapid, simple and sensitive LC/ESI-MS/MS method to measure prazosin concentration in human plasma and apply bedside sampling in bioequivalence study of two prazosin tablets to resolve the adverse effect of orthostatic hypotension. SIGNIFICANCE: The LC/ESI-MS/MS prazosin method was highly sensitive and selective. Bedside sampling reduced the orthostatic hypotension incidence and subject dropout rate. METHODS: After sample preparation, prazosin and terazosin (IS) were detected on mass spectrometer operating in multiple reaction monitoring mode using positive ionization. Mobile phase flow rate was set at 0.40 mL/min with sample run time of 1.75 min. The bioanalytical method was validated as per EMEA and FDA guidelines. Bedside sampling was performed in bioequivalence study for the first 4 h after dosing. The three primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞ and 90% confidence interval were determined. RESULTS: The small injection volume of 1 µL minimized instrumentation contamination and prolonged the analytical column lifespan. Linearity was obtained between 0.5 and 30.0 ng/mL, with coefficient of determination, r2 ≥ 0.99. The mean extraction recovery of prazosin and IS was >92%, with precision value (CV, %) ≤ 10.3%. Only two orthostatic hypotension adverse events were reported. The two prazosin formulations were found to be bioequivalent. CONCLUSION: The LC/ESI-MS/MS method has shown robustness and reliability exemplified by the incurred sample re-analysis result. Bedside sampling should be proposed for bioequivalence or pharmacokinetic studies of drugs demonstrating adverse event of orthostatic hypotension.


Assuntos
Hipotensão Ortostática , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica , Reprodutibilidade dos Testes , Hipotensão Ortostática/induzido quimicamente , Prazosina/efeitos adversos
6.
Toxicon ; 218: 57-65, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36113683

RESUMO

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1-0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 µg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.


Assuntos
Bufanolídeos , Venenos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Animais , Bufanolídeos/toxicidade , Bufo marinus/metabolismo , Canais de Cálcio , Endotélio Vascular , Hemodinâmica , Indometacina/farmacologia , Ketanserina/farmacologia , Masculino , Metanol/farmacologia , NADPH Oxidases , NG-Nitroarginina Metil Éster , Nifedipino/farmacologia , Óxido Nítrico/metabolismo , Prazosina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Wistar , Serotonina/farmacologia , Vasoconstritores
7.
Pflugers Arch ; 474(12): 1311-1321, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36131146

RESUMO

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca2+ current (ICaL) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such ICaL-increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and ß-AR antagonists on NA-stimulated atrial ICaL. ICaL was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial ICaL, maximally by ~ 2.5-fold, with EC75 310 nM. Propranolol (ß1 + ß2-AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated ICaL, in human and rabbit. Phentolamine (α1 + α2-AR antagonist, 1 microM) also decreased NA-stimulated ICaL. CGP20712A (ß1-AR antagonist, 0.3 microM) and prazosin (α1-AR antagonist, 0.5 microM) each decreased NA-stimulated ICaL in both species. ICI118551 (ß2-AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on ICaL in human atrial myocytes, but increased it in rabbit. Yohimbine (α2-AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit ICaL. Stimulation of atrial ICaL by NA is mediated, based on AR sub-type antagonist responses, mainly by activating ß1- and α1-ARs in both human and rabbit, with a ß2-inhibitory contribution evident in rabbit, and negligible α2 involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial ICaL could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF.


Assuntos
Canais de Cálcio Tipo L , Miócitos Cardíacos , Norepinefrina , Receptores Adrenérgicos alfa , Receptores Adrenérgicos beta , Animais , Humanos , Coelhos , Fibrilação Atrial/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Prazosina/farmacologia , Receptores Adrenérgicos alfa 2 , Átrios do Coração/citologia , Receptores Adrenérgicos beta/fisiologia , Receptores Adrenérgicos alfa/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Canais de Cálcio Tipo L/fisiologia
8.
Chin J Physiol ; 65(4): 179-186, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36073566

RESUMO

Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure (HF), pulmonary edema, and death within hours. Alpha-adrenergic blockers attenuate blood pressure and ameliorate HF and pulmonary edema, thereby prolonging survival time. However, the molecular mechanisms of these blockers are not clear. In this study, we investigated these mechanisms in a rat model of 6-hydroxydopamine (6-OHDA)-induced HF. Sprague-Dawley rats were treated with prazosin 10 min after the microinjection of 6-OHDA into the NTS. Immunohistochemistry and dihydroethidium (DHE) staining were used for analysis. In the cardiac tissue of 6-OHDA-induced HF, in situ expression of tumor necrosis factor-alpha (TNF-α), fibroblast growth factor-23 (FGF23), and FGF receptor 1 (FGFR1) increased, but in situ expression of Vitamin D receptor (VDR) decreased. DHE staining revealed several heart cells with high reactive oxygen species production. Prazosin treatment decreased TNF-α, FGF23, and FGFR1 expression in the heart of rats with 6-OHDA-induced HF. It also prevented cardiomyopathy caused by 6-OHDA-induced bilateral NTS lesions by inhibiting the FGF23-FGFR1 pathway and downregulating TNF-α expression. In situ, FGF23, FGFR1, VDR, superoxide, and TNF-α in the heart were found to be involved in acute HF in our rat model of 6-OHDA-induced bilateral NTS lesions. These findings are potentially useful for treating fatal enterovirus 71 infection-induced NTS lesions and HF.


Assuntos
Insuficiência Cardíaca , Edema Pulmonar , Animais , Regulação para Baixo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Insuficiência Cardíaca/tratamento farmacológico , Oxidopamina , Prazosina/farmacologia , Prazosina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa
9.
Andrology ; 10(8): 1540-1547, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35934935

RESUMO

BACKGROUND: Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α1 -adrenergic receptors such as doxazosin, tamsulosin, and prazosin. OBJECTIVES: To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions. METHODS: The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed. RESULTS: 6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS. DISCUSSION AND CONCLUSION: 6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α1 -adrenergic receptor antagonists.


Assuntos
Dopamina , Ducto Deferente , Antagonistas Adrenérgicos/farmacologia , Amitriptilina/farmacologia , Animais , Antidepressivos Tricíclicos/farmacologia , Carbamazepina/farmacologia , Cromatografia Líquida , Desipramina/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Doxazossina/farmacologia , Epinefrina/farmacologia , Humanos , Masculino , Contração Muscular , Músculo Liso , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico , Norepinefrina/farmacologia , Prazosina/farmacologia , Ratos , Receptores Adrenérgicos , Tansulosina/farmacologia , Espectrometria de Massas em Tandem
10.
Neurochem Res ; 47(11): 3272-3284, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35945308

RESUMO

Phenylephrine (PE) is a canonical α1-adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that cannot be easily explained by its actions on α1-adrenoceptors. The probability of the involvement of α2- and ß-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca2+]o-independent manner. To elucidate this issue, we have investigated the effects of PE on [3H]NA release and α1-mediated smooth muscle contractions in the mouse vas deferens (MVD) as ex vivo preparation. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to electrical field stimulation were used to measure PE effect postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM significantly enhanced the resting release of [3H]NA in a [Ca2+]o-independent manner. In addition, prazosin did not affect the release of NA evoked by PE. On the contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α1-adrenoceptor-mediated effect. When the function of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA and the contractions were reduced by approximately 88%. The remaining part proved to be prazosin-sensitive. The present work supports the substantial indirect effect of PE which relays on the cytoplasmic release of NA, which might explain the reported side effects for PE.


Assuntos
Antagonistas Adrenérgicos alfa , Norepinefrina , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Citoplasma , Masculino , Camundongos , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Prazosina/farmacologia , Receptores Adrenérgicos alfa 1
11.
J Clin Sleep Med ; 18(12): 2775-2784, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-35962771

RESUMO

STUDY OBJECTIVES: Trauma associated sleep disorder is a proposed parasomnia that develops after trauma with clinical features of trauma related nightmares, disruptive nocturnal behaviors, and autonomic disturbances. The purpose of this case series is to better characterize the clinical and video-polysomnographic features of patients meeting clinical criteria for this proposed parasomnia. METHODS: Semistructured clinical interview and detailed video-polysomnography review of 40 patients. Movements and vocalizations in rapid eye movement sleep were quantified according to the rapid eye movement sleep behavior disorder severity scale. RESULTS: Patients (n = 40, 32 males) were service members and veterans with a median age of 38.9 years (range 24-57 years) who reported trauma related nightmares and disruptive nocturnal behaviors at home. On video-polysomnography, 28 (71.8%) patients had disruptive nocturnal behaviors in rapid eye movement sleep consisting of limb, head, and axial movements; vocalizations were present in 8 (20%). On the rapid eye movement sleep behavior disorder severity scale, most (n = 28, 71.8%) had a low rating but those with greater severity (n = 11, 28.2%) had a higher prevalence of posttraumatic stress disorder (P = .013) and markedly less N3 sleep (P = .002). The cohort had a high rate of insomnia (n = 35, 87.5%) and obstructive sleep apnea (n = 19, 47.5%). Most patients were treated with prazosin (n = 29, 72.5%) with concomitant behavioral health interventions (n = 25, 64.1%); 15 (51.7%) patients receiving prazosin reported improved symptomatology. CONCLUSIONS: Disruptive nocturnal behaviors can be captured on video-polysomnography during rapid eye movement sleep, although they may be less pronounced than what patients report in their habitual sleeping environment. Clinical and video-polysomnographic correlations are invaluable in assessing patients with trauma associated sleep disorder to document objective abnormalities. This case series provides a further basis for establishing trauma associated sleep disorder as a unique parasomnia. CITATION: Brock MS, Matsangas P, Creamer JL, et al. Clinical and polysomnographic features of trauma associated sleep disorder. J Clin Sleep Med. 2022;18(12):2775-2784.


Assuntos
Parassonias , Transtorno do Comportamento do Sono REM , Transtornos do Sono-Vigília , Masculino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Transtorno do Comportamento do Sono REM/complicações , Sonhos , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/diagnóstico , Parassonias/diagnóstico , Parassonias/complicações , Prazosina
12.
EBioMedicine ; 83: 104202, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35963713

RESUMO

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-43M337V, 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].


Assuntos
Esclerose Amiotrófica Lateral , Fosfoglicerato Quinase/metabolismo , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Humanos , Camundongos , Neurônios Motores/metabolismo , Fenótipo , Fosfoglicerato Quinase/genética , Prazosina/análogos & derivados , Peixe-Zebra/metabolismo
13.
J Physiol Biochem ; 78(4): 793-805, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35802254

RESUMO

The development of interatrial septum (IAS) is a complicated process, which continues during postnatal life. The hypertrophic signals in developing heart are mediated among others by α-adrenergic pathways. These facts suggest the presence of specific electrophysiological features in developing IAS. This study was aimed to investigate the electrical activity in the tissue preparations of IAS from rat heart in normal conditions and under stimulation of adrenoreceptors. Intracellular recording of electrical activity revealed less negative level of resting membrane potential in IAS if compared to myocardium of left atrium. In normal conditions, non-paced IAS preparations were quiescent, but noradrenaline (10-5 M) and phenylephrine (10-5 M) induced spontaneous action potentials, which could be abolished by α1-blocker prazosin (10-5 M), but not ß1-blocker atenolol (10-5 M). Optical mapping showed drastic phenylephrine-induced slowing of conduction in adult rat IAS. The α1-dependent ectopic automaticity of IAS myocardium might be explained by immunohistochemical data indicating the presence of transcription factor GATA4 and abundant α1A-adrenoreceptors in myocytes from adult rat IAS. An elevated sensitivity to adrenergic stimulation due to involvement of α1-adrenergic pathways may underlie increased proarrhythmic potential of adult IAS at least in rats.


Assuntos
Prazosina , Receptores Adrenérgicos alfa 1 , Ratos , Animais , Receptores Adrenérgicos alfa 1/metabolismo , Prazosina/farmacologia , Fenilefrina/farmacologia , Átrios do Coração/metabolismo , Adrenérgicos , Fator de Transcrição GATA4/genética
14.
Pharmacol Res Perspect ; 10(4): e00991, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35892277

RESUMO

The relationship between cardiovascular diseases and iron disorders has gained increasing attention; however, the effects of hypotensive drugs on iron metabolic alterations in hypertension are not well understood. The purpose of this study was to investigate iron metabolic changes after prazosin treatment of spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Our second objective was to examine the effects of hypertension and anti-hypertensive drugs on bone formation and resorption. SHRs and WKY rats were randomized into either prazosin-treated groups (WKY + PZ and SHR + PZ) or untreated groups (WKY and SHR). After 7 days of intragastric prazosin administration, the rats were sacrificed for analysis; blood samples and organs (the duodenum, liver, kidneys, spleen, and femur) were collected. Both WKY + PZ and SHR groups exhibited iron deficiency in the serum and liver. Prazosin increased the iron levels in the bone tissue of SHRs. Prazosin stimulated the expression of hepcidin mRNA in the liver of SHRs and inhibited the expression of this iron-regulatory hormone in WKY rats. FPN1 expression in the duodenum was increased significantly in SHRs, however markedly decreased after prazosin treatment. The expression of TLR4 and Ctsk was enhanced in the bone tissue of SHRs, whereas CLC-7 expression was inhibited. Both hypotension and hypertension can lead to iron deficiency. Treatment with prazosin restored iron homeostasis in SHRs. The inverse impacts of prazosin on hepatic hepcidin expression in SHRs versus WKY rats indicates differing iron regulatory mechanisms between hypertensive and normal animals. The osteoclast activity was found to be enhanced in SHRs. Further study is needed to address whether the changes in osteoblast and osteoclast activity in SHRs correlates with the effects on iron metabolism.


Assuntos
Hipertensão , Ferro , Prazosina , Animais , Hepcidinas/genética , Hipertensão/tratamento farmacológico , Ferro/metabolismo , Prazosina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
ACS Infect Dis ; 8(8): 1711-1726, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35894227

RESUMO

Human African trypanosomiasis (HAT) remains a health threat to sub-Saharan Africa. The current treatments suffer from drug resistance and life-threatening side effects, making drug discovery for HAT still important. A high-throughput screening of the library of pharmaceutically active compounds identified prazosin, an α-adrenoceptor antagonist, that showed selective activity toward Trypanosoma brucei brucei. Furthermore, a series of prazosin analogues were examined, and overall, the new analogues had improved activity and selectivity. To elucidate the binding partner, a biotin-conjugated probe was synthesized, and a protein pulldown assay combined with a proteomic analysis identified the flagellum attachment zone 1 (FAZ1) filament as an interacting partner. Additionally, prazosin treatment resulted in dysfunction of the flagellum of trypanosome cells, which is indicative of a FAZ1 irregularity. We also examined the drug distribution by utilizing immunofluorescence with a designed fluorescent analogue that showed partial colocalization with FAZ1. With the activity of the prazosin analogues, a structure-activity relationship (SAR) was summarized for future lead optimization. Our findings provide a new group of FAZ1 inhibitors as novel antitrypanosomal agents.


Assuntos
Tripanossomicidas , Tripanossomíase Africana , Animais , Flagelos , Humanos , Prazosina/uso terapêutico , Proteômica , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico
16.
Alcohol Clin Exp Res ; 46(8): 1384-1396, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35791038

RESUMO

BACKGROUND: Individuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropin-releasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD. METHODS: Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10 µM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10 µM) or the α2AR antagonist atipamezole (10 µM). The experiments were performed using whole-cell patch clamp recordings in slices from CIE rats and air-exposed controls. RESULTS: NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex- and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males. CONCLUSIONS: NE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.


Assuntos
Alcoolismo , Sistema Hipotálamo-Hipofisário , Animais , Hormônio Liberador da Corticotropina/metabolismo , Etanol/toxicidade , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Masculino , Plasticidade Neuronal , Norepinefrina/farmacologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa , Caracteres Sexuais
17.
Arch Razi Inst ; 77(1): 141-149, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35891757

RESUMO

The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first experiment, the intracerebroventricular (ICV) injection of solutions was conducted which included 10 nmol of prazosin (an α1-receptor antagonist), 300 nmol of histamine, co-injection of prazosin and histamine. Experiments two to five were conducted similarly the same as the first experiment, in which chickens were ICV injected with 13 nmol of yohimbine (an α2-receptor antagonist), 24 nmol of metoprolol (a ß1 adrenergic receptor antagonist), 5 nmol of ICI 118,551 (a ß2 adrenergic receptor antagonist), and 20 nmol of SR 59230R (a ß3 adrenergic receptor antagonist). The injected solutions in the sixth experiment included 300 nmol of noradrenaline, 250 nmol of α-FMH (an alpha fluoromethyl histidine), noradrenaline, and α-FMH. Seventh to ninth experiments were similar to the sixth experiment, except that the chickens were ICV injected with 300 nmol of chlorpheniramine (a histamine H1 receptors antagonist), 82 nmol of famotidine (a histamine H2 receptors antagonist), and 300 nmol of thioperamide (a histamine H3 receptors antagonist), rather than α-FMH. Afterward, the cumulative food intake was measured 120 min after injection. Based on the obtained results, both histamine ICV injection and noradrenaline injection reduced food intake (P<0.05). Moreover, co-injection of histamine and ICI 118,551 (P<0.05), and co-injection of noradrenaline and Chlorpheniramine reduced food intake (P<0.05). In addition, noradrenaline and Thioperamide co-injection improved hypophagic effect of noradrenaline in neonatal chicken (P<0.05). These findings suggested the effect of interconnection between adrenergic and histaminergic systems, which may be mediated by H1 and H3 histaminergic and ß2 adrenergic receptors, on the regulation of food intake in the neonatal broiler chicken.


Assuntos
Apetite , Galinhas , Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Animais , Animais Recém-Nascidos , Clorfeniramina/farmacologia , Comportamento Alimentar/fisiologia , Histamina/farmacologia , Norepinefrina/farmacologia , Prazosina/farmacologia , Receptores Adrenérgicos , Receptores Histamínicos
18.
Neurosci Biobehav Rev ; 139: 104717, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35661755

RESUMO

This network meta-analysis compares the efficacy and acceptability of all published psychotherapeutic and pharmacological interventions for trauma-related nightmares (TRN) in adults. The analysis included data from 29 randomized clinical trials involving 14 psychotherapeutic and pharmacological interventions and involved 2214 trauma survivors. Prazosin and image rehearsal therapy (IRT) were found to be the two effective interventions for TRN. Other interventions such as risperidone, paroxetine, cognitive behavioral therapy for insomnia (CBT-I), CBT-I+IRT, prolonged exposure (PE), and IRT+PE, did not show significantly greater efficacy compared with control conditions. The rates of all-cause discontinuations were comparable among majority of the interventions and did not show significant differences compared with control conditions. Prazosin and IRT should be considered as the initial choice of pharmacological and psychotherapeutic interventions for TRN. The efficacy of other pharmacological and psychotherapeutic interventions remains to be demonstrated. Future guidelines and daily clinical decision making on the choice of interventions for TRN should consider these findings.


Assuntos
Terapia Implosiva , Transtornos de Estresse Pós-Traumáticos , Adulto , Sonhos , Humanos , Metanálise em Rede , Prazosina/farmacologia , Prazosina/uso terapêutico , Psicotrópicos/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia
19.
CNS Drugs ; 36(7): 721-737, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35688992

RESUMO

Posttraumatic stress disorder (PTSD) can be a chronic and disabling condition. Post-traumatic nightmares (PTNs) form a core component of PTSD and are highly prevalent in this patient population. Nightmares in PTSD have been associated with significant distress, functional impairment, poor health outcomes, and decreased quality of life. Nightmares in PTSD are also an independent risk factor for suicide. Nightmare cessation can lead to improved quality of life, fewer hospital admissions, lower healthcare costs, and reduced all-cause mortality. Effective treatment of nightmares is critical and often leads to improvement of other PTSD symptomatology. However, approved pharmacological agents for the treatment of PTSD have modest effects on sleep and nightmares, and may cause adverse effects. No pharmacological agent has been approved specifically for the treatment of PTNs, but multiple agents have been studied. This current narrative review aimed to critically appraise proven as well as novel pharmacological agents used in the treatment of PTNs. Evidence of varying quality exists for the use of prazosin, doxazosin, clonidine, tricyclic antidepressants, trazodone, mirtazapine, atypical antipsychotics (especially risperidone, olanzapine and quetiapine), gabapentin, topiramate, and cyproheptadine. Evidence does not support the use of venlafaxine, ß-blockers, benzodiazepines, or sedative hypnotics. Novel agents such as ramelteon, cannabinoids, ketamine, psychedelic agents, and trihexyphenidyl have shown promising results. Large randomized controlled trials (RCTs) are needed to evaluate the use of these novel agents. Future research directions are identified to optimize the treatment of nightmares in patients with PTSD.


Assuntos
Transtornos do Sono-Vigília , Transtornos de Estresse Pós-Traumáticos , Sonhos , Humanos , Prazosina/farmacologia , Prazosina/uso terapêutico , Sono , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
20.
Peptides ; 153: 170803, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35490830

RESUMO

There are some differences between mammals and birds in terms of central food intake regulation. In avian species, the hypophagic role of nesfatin-1 has not been investigated with other neurotransmitters. Therefore, this study aimed to determine the alteration of feeding behavior following intracerebroventricular (ICV) injection of nesfatin-1 and its possible interaction with central noradrenergic, serotoninergic, and oxytocin systems in newborn broiler chicks. In experiment 1, birds received ICV injection of phosphate-buffered saline (PBS), prazosin (α1 receptors antagonist, 10 nmol), nesfatin-1 (40 ng), and co-administration of prazosin and nesfatin-1. Experiments 2-10 were similar to experiment 1, except that yohimbine (α2 receptors antagonist, 13 nmol), metoprolol (ß1 receptors antagonist, 24 nmol), IC1118,551 (ß2 receptors antagonist for, 5nmol), SR59230R (ß3 receptors antagonist, 20 nmol), fluoxetine (serotonin reuptake inhibitor, 10 µg), PCPA (serotonin synthesis inhibitor, 1.5 µg), 8-OH-DPAT (5-HT1A receptors agonist, 15.25 nmol), SB242084 (5-HT2C receptors antagonist,1.5 µg) and tocinoic acid (oxytocin receptors antagonist, 2 µg) were injected instead of prazosin. Immediately after the injection, food consumption and behavioral traits were recorded. Nesfatin-1 decreased food consumption (P < 0.05). Nesfatin-1 along with ICI118551 decreased food consumption (P < 0.05). The nesfatin-1- induced hypophagia were reduced by the simultaneous injection of PCPA and nesfatin-1 (P < 0.05). Nesfatin-1induced hypophagia were decreased by the simultaneous injection of SB242084 (P < 0.05). The nesfatin-1 -induced hypophagia were abolished by the simultaneous injection of the tocinoic acid and nesfatin-1 (P < 0.05). ICV injection of the nesfatin-1 decreased the number of steps, jumps, exploratory food, and pecks (P < 0.05) with no effect on drink pecks (P > 0.05). Nesfatin-1 significantly decreased standing time and increased both sitting time and rest time (P < 0.05). Nesfatin-1 could play an important role in feeding behavior, and its hypophagic effects were mediated by ß2 adrenergic, 5-HT2C serotoninergic, and oxytocin receptors in neonatal chickens.


Assuntos
Galinhas , Ingestão de Alimentos , Animais , Animais Recém-Nascidos , Galinhas/fisiologia , Comportamento Alimentar , Mamíferos , Ocitocina/farmacologia , Prazosina/farmacologia , Receptores de Ocitocina , Serotonina
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