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1.
Front Immunol ; 12: 628065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220796

RESUMO

Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/ß2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the ß2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Artrite Experimental/prevenção & controle , Articulações/efeitos dos fármacos , Fentolamina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Terbutalina/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Combinação de Medicamentos , Adjuvante de Freund , Articulações/diagnóstico por imagem , Articulações/metabolismo , Articulações/patologia , Masculino , Ratos Endogâmicos Lew , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais
2.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071269

RESUMO

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30-180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.


Assuntos
Analgésicos Opioides/química , Destreza Motora/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Vortioxetina/farmacologia , Analgesia/métodos , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Fenclonina/química , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Naloxona/química , Dor/tratamento farmacológico , Fentolamina/química , Piperazinas/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , alfa-Metiltirosina/química
3.
BMJ Case Rep ; 14(4)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910787

RESUMO

Increased numbers of adrenaline auto-injectors (AAIs) are in circulation in the UK. The rate of accidental auto-injection injuries has increased during this time. Various treatment strategies are described in the literature. We present the case of a 32-year-old, right-hand-dominant man who sustained an unintentional AAI injury to the volar aspect of his right thumb. On presentation to the emergency department, the thumb was ischaemic. There was no improvement with simple conservative measures (warm soaks). The patient was referred to our tertiary hand surgery service and a digital block using 2% lidocaine promoted reversal of ischaemia within 2 hours with no long-term sequelae. Phentolamine rescue, on standby, was not necessary in this case. In this case report, we highlight the therapeutic challenges associated with managing AAI injury and propose an evidence-based treatment algorithm to prevent risk of severe adverse outcomes such as digital necrosis.


Assuntos
Epinefrina , Lidocaína , Adulto , Algoritmos , Humanos , Isquemia/induzido quimicamente , Isquemia/tratamento farmacológico , Masculino , Fentolamina
4.
Am J Health Syst Pharm ; 78(13): 1195-1199, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-33772262

RESUMO

PURPOSE: A case of uncontrolled hypertension nonresponsive to traditional pharmacologic management in a pediatric patient with a ventricular assist device awaiting a heart transplant is reported. SUMMARY: A 4-month-old male in heart failure was experiencing uncontrolled hypertension. Because of a lack of hemodynamic stability, he was unable to be listed as a heart transplant candidate. He received multiple antihypertensive agents (calcium channel blockers, ß-blockers, and direct-acting vasodilators) as both intermittent and continuous infusions over the course of several days without achieving normotension. The decision was then made to administer intravenous phentolamine as a continuous infusion to pursue a different mechanism than with traditional antihypertensive agents to achieve hemodynamic stability. Within 8 hours of initiation of the continuous phentolamine infusion, the patient became normotensive and was listed for a heart transplant. The continuous phentolamine infusion was administered over the next 4 days to maintain normotension, and on day 4 the patient underwent successful orthotopic heart transplantation. CONCLUSION: A 4-month-old male in heart failure with a ventricular assist device, experiencing uncontrolled hypertension nonresponsive to traditional pharmacologic management, was successfully treated with a continuous intravenous infusion of phentolamine.


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Hipertensão , Criança , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Lactente , Masculino , Fentolamina , Resultado do Tratamento
5.
Optom Vis Sci ; 98(3): 234-242, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33633016

RESUMO

SIGNIFICANCE: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations. PURPOSE: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication. METHODS: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points. RESULTS: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours. CONCLUSIONS: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Midriáticos/administração & dosagem , Fentolamina/farmacologia , Pupila/efeitos dos fármacos , Acomodação Ocular/fisiologia , Administração Oftálmica , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Soluções Oftálmicas , Fenilefrina/administração & dosagem , Distúrbios Pupilares , Tropicamida/administração & dosagem , Adulto Jovem
6.
Am J Physiol Heart Circ Physiol ; 320(2): H563-H574, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164582

RESUMO

Heart failure (HF) is associated with neurohumoral activation, which in turn leads to an increased peripheral resistance. In mesenteric vasculature, perivascular innervation plays relevant role maintaining vascular tonus and resistance. Therefore, we aimed to determine the possible alterations in superior mesenteric artery (SMA) perivascular innervation function in HF rats. HF was induced by coronary artery occlusion in male Wistar rats, and sham-operated (SO) rats were used as controls. After 12 wk, a greater vasoconstrictor response to electrical field stimulation (EFS) was observed in endothelium-intact and endothelium-denuded SMA of HF rats. Alpha-adrenoceptor antagonist phentolamine diminished this response in a higher magnitude in HF than in SO animals. However, the noradrenaline (NA) reuptake inhibitor desipramine increased EFS-induced vasoconstriction more in segments from HF rats. Besides, EFS-induced NA release was greater in HF animals, due to a higher tyrosine hydroxylase expression and activity. P2 purinoceptor antagonist suramin reduced EFS-induced vasoconstriction only in segments from SO rats, and adenosine 5'-triphosphate (ATP) release was lower in HF than in SO. Moreover, nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) enhanced EFS-induced vasoconstriction in a similar extent in both groups. HF was not associated with changes in EFS-induced NO release or the vasodilator response to NO donor sodium nitroprusside. In conclusion, HF postmyocardial infarction enhanced noradrenergic function and diminished purinergic cotransmission in SMA and did not change nitrergic innervation. The net effect was an increased sympathetic participation on the EFS-induced vasoconstriction that could help to understand the neurotransduction involved on the control of vascular tonus in HF.NEW & NOTEWORTHY This study reinforces the pivotal role of noradrenergic innervation in the regulation of mesenteric vascular tone in a rat model of heart failure. Moreover, our results highlight the counteracting role of ATP and NA reuptake, and help to understand the signaling pathways involved on the control of vascular tonus and resistance in heart failure postmyocardial infarction.


Assuntos
Trifosfato de Adenosina/metabolismo , Insuficiência Cardíaca/metabolismo , Norepinefrina/metabolismo , Transmissão Sináptica , Inibidores da Captação Adrenérgica/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Desipramina/farmacologia , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , NG-Nitroarginina Metil Éster/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Fentolamina/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Ratos , Ratos Wistar , Suramina/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição
7.
Int J Mol Sci ; 21(24)2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33302363

RESUMO

The catecholamines norepinephrine and epinephrine are important regulators of vertebrate physiology. Insects such as honeybees do not synthesize these neuroactive substances. Instead, they use the phenolamines tyramine and octopamine for similar physiological functions. These biogenic amines activate specific members of the large protein family of G protein-coupled receptors (GPCRs). Based on molecular and pharmacological data, insect octopamine receptors were classified as either α- or ß-adrenergic-like octopamine receptors. Currently, one α- and four ß-receptors have been molecularly and pharmacologically characterized in the honeybee. Recently, an α2-adrenergic-like octopamine receptor was identified in Drosophila melanogaster (DmOctα2R). This receptor is activated by octopamine and other biogenic amines and causes a decrease in intracellular cAMP ([cAMP]i). Here, we show that the orthologous receptor of the honeybee (AmOctα2R), phylogenetically groups in a clade closely related to human α2-adrenergic receptors. When heterologously expressed in an eukaryotic cell line, AmOctα2R causes a decrease in [cAMP]i. The receptor displays a pronounced preference for octopamine over tyramine. In contrast to DmOctα2R, the honeybee receptor is not activated by serotonin. Its activity can be blocked efficiently by 5-carboxamidotryptamine and phentolamine. The functional characterization of AmOctα2R now adds a sixth member to this subfamily of monoaminergic receptors in the honeybee and is an important step towards understanding the actions of octopamine in honeybee behavior and physiology.


Assuntos
Abelhas/metabolismo , Proteínas de Insetos/metabolismo , Receptores de Amina Biogênica/metabolismo , Adenilil Ciclases/metabolismo , Animais , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Octopamina/metabolismo , Fentolamina/farmacologia , Ligação Proteica , Receptores de Amina Biogênica/antagonistas & inibidores , Receptores de Amina Biogênica/genética , Homologia de Sequência , Serotonina/análogos & derivados , Serotonina/metabolismo , Serotonina/farmacologia , Especificidade por Substrato
8.
BMJ Case Rep ; 13(12)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334743

RESUMO

Pheochromocytomas are uncommon tumours that originate in chromaffin cells. They are a representation of 0.1%-1% of all cases of secondary hypertension. Most pheochromocytomas are unilateral and benign, featuring catecholamine production, as well as the production of other neuropeptides. Pheochromocytomas are mostly located in the adrenal gland; the frequency of occurrence is highest between 30 and 50 years of age; however, up to 25% of cases may be linked to multiple endocrine neoplasia type 2, Von-Hippel-Landau disease and type 1 neurofibromatosis in the young.We present a case of ruptured left adrenal pheochromocytoma with an atypical presentation. A 30-year-old male patient presented with severe left flank pain and hypertension. The CT scan of the abdomen showed bleeding from the left adrenal mass, where resuscitation and angioembolisation were done. Embolisation of the inferior and superior arteries was done, but the middle failed. The patient experienced a significant drop in haemoglobin and a haemorrhagic shock post angioembolisation, which called for emergency laparotomy. The patient is currently doing well with an uneventful postoperative course.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Hipertensão/etiologia , Feocromocitoma/diagnóstico , Cólica Renal/etiologia , Ruptura Espontânea/diagnóstico , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/cirurgia , Adulto , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Embolização Terapêutica , Humanos , Hipertensão/tratamento farmacológico , Masculino , Fentolamina/administração & dosagem , Feocromocitoma/complicações , Feocromocitoma/cirurgia , Prazosina/administração & dosagem , Ruptura Espontânea/etiologia , Ruptura Espontânea/terapia , Resultado do Tratamento
10.
Am J Case Rep ; 21: e923877, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32921785

RESUMO

BACKGROUND Accidental finger-stick injuries have been reported with epinephrine autoinjectors, such as EpiPen and EpiPen Jr, and can result in necrosis and digital ischemia. However, long-term adverse effects are very rare. The treatment for accidental finger-stick injuries is controversial and includes intra-arterial injections of vasodilating agents, topical vasodilators, and supportive management as needed. CASE REPORT Here, we report a case of a 26-year-old pharmacist who injected herself accidentally with an EpiPen on the tip of her index finger. Warm water and nitroglycerine gel did not alleviate her symptoms. After three hours, phentolamine was injected around the necrotic area, and the skin normalized. CONCLUSIONS All health professionals should be trained in how to handle epinephrine autoinjectors safely. Phentolamine may be efficacious in treating accidental finger-stick injuries from epinephrine autoinjectors.


Assuntos
Epinefrina , Dedos , Adulto , Epinefrina/uso terapêutico , Feminino , Humanos , Injeções , Isquemia/induzido quimicamente , Isquemia/tratamento farmacológico , Fentolamina/uso terapêutico
11.
Am J Physiol Heart Circ Physiol ; 319(1): H192-H202, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502375

RESUMO

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and ß-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min-1·100 mmHg-1; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Exercício Físico , Músculo Esquelético/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Pressão Sanguínea , Humanos , Masculino , Contração Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Fentolamina/farmacologia , Propranolol/farmacologia , Fluxo Sanguíneo Regional , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstrição , Vasodilatação
13.
Zhonghua Yi Xue Za Zhi ; 100(17): 1320-1325, 2020 May 05.
Artigo em Chinês | MEDLINE | ID: mdl-32375440

RESUMO

Objective: To explore the effect of phenolamine on the outcome and prognosis of patients with myocardial injury due to sepsis. Methods: From January 2015 to December 2017, 62 septic patients with myocardial injury were randomly divided into study group (n=32) and control group (n=30). Two groups were given conventional treatment, while the study group was treated with phentolamine. The NT-pro brain natriuretic pepitide (NT-proBNP), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB) and tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1ß, IL-6 were detected at 0,12, 24, 48, 72 h and 7 d after hospitalization. And left ventricular ejection fraction (LVEF), e', E and A in each time period were observed. The 28 d survival rate and length of ICU stay were observed in both groups. The data were compared with single sample t test between the two groups. Results: After 12, 24, 48, 72 h and 7 d, NT-proBNP, cTnI, LDH, CK-MB, TNF-α, hs-CRP, IL-1ß, IL-6 in the study group were all significantly lower than those in the control group (all P<0.05). The cardiac function indexes of LVEF, E/A and E/e' in the study group were all significantly improved when compared with those in the control group (all P<0.05). The length of ICU stay and 28-day mortality in the study group were significantly lower than those in the control group ((9.8±3.6) d vs (13.0±4.1) d, t=3.152, P=0.004; 21.9% vs 36.7%, χ(2)=5.078, P=0.021). Conclusion: Combined application of phentolamine can significantly improve the outcome of sepsis patients with myocardial injury and improve the survival rate.


Assuntos
Fentolamina/uso terapêutico , Sepse , Humanos , Peptídeo Natriurético Encefálico , Prognóstico , Sepse/tratamento farmacológico , Volume Sistólico , Função Ventricular Esquerda
14.
Circ Res ; 127(2): e1-e13, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32268833

RESUMO

RATIONALE: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. OBJECTIVE: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. METHODS AND RESULTS: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+ß adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. CONCLUSIONS: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.


Assuntos
Adaptação Fisiológica , Doença da Altitude/metabolismo , Policitemia/metabolismo , Receptores Adrenérgicos/metabolismo , Vasodilatação , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Adrenérgicos/farmacologia , Adulto , Altitude , Doença da Altitude/sangue , Doença da Altitude/fisiopatologia , Pressão Sanguínea , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Frequência Cardíaca , Humanos , Masculino , Nitroprussiato/farmacologia , Fentolamina/farmacologia , Policitemia/etiologia , Policitemia/fisiopatologia , Propranolol/farmacologia , Transdução de Sinais , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Vasodilatadores/farmacologia
15.
Pflugers Arch ; 472(4): 481-494, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32211976

RESUMO

Nutrient arteries provide the endosteal blood supply to maintain bone remodelling and energy metabolism. Here, we investigated the distribution and function of perivascular nerves in regulating the contractility of the tibial nutrient artery. Changes in artery diameter were measured using a video tracking system, while the perivascular innervation was investigated using fluorescence immunohistochemistry. Nerve-evoked phasic constrictions of nutrient arteries were suppressed by phentolamine (1 µM), an α-adrenoceptor antagonist, guanethidine (10 µM), a blocker of sympathetic transmission, or fluoxetine (10 µM), a serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor. In arteries pretreated with guanethidine, residual nerve-evoked constrictions were abolished by a high concentration of propranolol (10 µM) that is known to inhibit 5-HT receptors, or ketanserin (100 nM), a 5-HT2 receptor antagonist, but not SB207216 (1 µM), an antagonist of 5-HT3 and 5-HT4 receptors. Bath-applied 5-HT (100 nM) induced arterial constriction that was suppressed by propranolol (10 µM) or ketanserin (100 nM). Nerve-evoked arterial constrictions were enhanced by spantide (1 µM), a substance P (SP) receptor antagonist, or L-nitro arginine (L-NA; 100 µM), an inhibitor of nitric oxide synthase (NOS). Immunohistochemistry revealed 5-HT-positive nerves running along the arteries that are distinct from perivascular sympathetic or substance P-positive primary afferent nerves. For the first time, functional serotonergic nerves are identified in the tibial nutrient artery of the guinea pig. Thus, it appears that tibial nutrient arterial calibre is regulated by the balance between sympathetic and serotonergic vasoconstrictor nerves and vasodilator afferent nerves that release substance P-stimulating endothelial nitric oxide (NO) release.


Assuntos
Artérias/fisiologia , Arteríolas/fisiologia , Contração Muscular/fisiologia , Tíbia/fisiologia , Animais , Artérias/efeitos dos fármacos , Arteríolas/efeitos dos fármacos , Cobaias , Masculino , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Fentolamina/farmacologia , Tíbia/irrigação sanguínea , Vasodilatação/efeitos dos fármacos
16.
Vet Anaesth Analg ; 47(2): 267-273, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007444

RESUMO

OBJECTIVE: To determine the impact of epidural phentolamine on the duration of anaesthesia following epidural injection of lidocaine-epinephrine. STUDY DESIGN: Blinded randomized experimental study. ANIMALS: A group of 12 adult ewes weighing 25.7 ± 2.3 kg and aged 8-9 months. METHODS: All sheep were administered epidural lidocaine (approximately 4 mg kg-1) and epinephrine (5 µg mL-1). Of these, six sheep were randomized into three epidural treatments, separated by 1 week, administered 30 minutes after lidocaine-epinephrine: SAL: normal saline, PHE1: phentolamine (1 mg) and PHE2: phentolamine (2 mg). The other six sheep were administered only epidural lidocaine-epinephrine: treatment LIDEP. Each injection was corrected to 5 mL using 0.9% saline. Noxious stimuli were pinpricks with a hypodermic needle and skin pinch with haemostatic forceps to determine the onset and duration of sensory and motor block. Heart rate, noninvasive mean arterial pressure (MAP), respiratory rate and rectal temperature were recorded. RESULTS: The onset times were not different among treatments. Duration of sensory block was significantly shorter in SAL (57.5 ± 6.2 minutes), PHE1 (60.7 ± 9.0 minutes) and PHE2 (62.0 ± 6.7 minutes) than in LIDEP (81.7 ± 13.4 minutes) (p < 0.05). Duration of motor blockade was significantly shorter in PHE1 (59.4 ± 5.4 minutes) and PHE2 (54.3 ± 4.0 minutes) than in SAL (84.8 ± 7.0 minutes) and LIDEP (91.5 ± 18.2 minutes) (p < 0.01). MAP in PHE2 was decreased at 10 minutes after administration of phentolamine (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Epidural administration of 5 mL normal saline after epidural injection of lidocaine-epinephrine reduced the duration of sensory but not motor block in sheep. Epidural administration of phentolamine diluted to the final volume of 5 mL diminished both the duration of sensory and motor block in sheep administered epidural lidocaine-epinephrine.


Assuntos
Anestesia Epidural/veterinária , Epinefrina/farmacologia , Injeções Epidurais/veterinária , Lidocaína/farmacologia , Fentolamina/farmacologia , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Animais , Epinefrina/administração & dosagem , Feminino , Lidocaína/administração & dosagem , Comitê de Farmácia e Terapêutica , Ovinos
17.
Oxid Med Cell Longev ; 2020: 2563764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104529

RESUMO

Norepinephrine (NE) is the naturally occurring adrenergic agonist that is released in response to hypotension, and it is routinely administered in clinical settings to treat moderate to severe hypotension that may occur during general anesthesia and shock states. Although NE has incontestable beneficial effects on blood pressure maintenance during hypotensive conditions, deleterious effects of NE on endothelial cell function may occur. In particular, the role of reactive oxygen species (ROS) and NADPH oxidase (Nox) on the deleterious effects of NE on endothelial cell function have not been fully elucidated. Therefore, we investigated the effects of NE on ROS production in rat lung microvascular endothelial cells (RLMEC) and its contribution to cell death. RLMEC were treated with NE (5 ng/mL) for 24 hours and ROS production was assessed by CellROX and DCFDA fluorescence. Nox activity was assessed by NADPH-stimulated ROS production in isolated membranes and phosphorylation of p47phox; cell death was assessed by flow cytometry and DNA fragmentation. Caspase activation was assessed by fluorescent microscopy. Nox1, Nox2, and Nox4 mRNA expression was assessed by real-time PCR. NE increased ROS production, Nox activity, p47phox phosphorylation, Nox2 and Nox4 mRNA content, caspase-3 activation, and RLMEC death. Phentolamine, an α 1-adrenoreceptor antagonist, inhibited NE-induced ROS production and Nox activity and partly inhibited cell death while ß-blockade had no effect. Apocynin and PEGSOD inhibited NE-induced caspase-3 activation and cell death while direct inhibition of caspase-3 abrogated NE-induced cell death. PEG-CAT inhibited NE-induced cell death but not caspase-3 activation. Collectively, these results indicate that NE induces RLMEC death via activation of Nox by α-adrenergic signaling and caspase-3-dependent pathways. NE has deleterious effects on RLMECs that may be important to its long-term therapeutic use.


Assuntos
Caspase 3/metabolismo , Células Endoteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , NADPH Oxidases/metabolismo , Norepinefrina/toxicidade , Acetofenonas/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Inibidores de Caspase/farmacologia , Morte Celular , Células Endoteliais/metabolismo , Pulmão/metabolismo , NADPH Oxidase 1/genética , NADPH Oxidase 1/metabolismo , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Fentolamina/farmacologia , Polietilenoglicóis/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/farmacologia
18.
Eur J Pharmacol ; 875: 173034, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32097659

RESUMO

Glucoprivation stimulates a rapid sympathetic response to release and/or secrete catecholamines into the bloodstream. However, the central regulatory mechanisms involving adrenoceptors and prostanoids production in the paraventricular hypothalamic nucleus (PVN) that are responsible for the glucoprivation-induced elevation of plasma catecholamines are still unresolved. In this study, we aimed to clarify whether glucoprivation-induced activation of noradrenergic neurons projecting to the PVN can induce α- and/or ß-adrenergic receptor activation and prostanoids production in the PVN to elevate plasma catecholamine levels. We examined the effects of α- and ß-adrenergic receptor antagonists, a cyclooxygenase inhibitor, a thromboxane A synthase inhibitor, and a PGE2 subtype EP3 receptor antagonist on intravenously administered 2-deoxy-D-glucose (2-DG)-induced elevation of noradrenaline in the PVN and plasma levels of catecholamine in freely moving rats. In addition, we examined whether intravenously administered 2-DG can increase prostanoids levels in the PVN microdialysates. Intracerebroventricular (i.c.v.) pretreatment with phentolamine (a non-selective α-adrenergic receptor antagonist) suppressed the 2-DG-induced increase in the plasma level of adrenaline, whereas i.c.v. pretreatment with propranolol (a non-selective ß-adrenergic receptor antagonist) suppressed the 2-DG-induced elevation of the plasma level of noradrenaline. I.c.v. pretreatment with indomethacin (a cyclooxygenase inhibitor) and furegrelate (a thromboxane synthase inhibitor) attenuated the 2-DG-induced elevations of both noradrenaline and adrenaline levels. Furthermore, 2-DG administration elevated the thromboxane B2 level, a metabolite of thromboxane A2 in PVN microdialysates. Our results suggest that glucoprivation-induced activation of α- and ß-adrenergic receptor in the brain including the PVN and then thromboxane A2 production in the PVN, which are essential for the 2-DG-induced elevations of both plasma adrenaline and noradrenaline levels.


Assuntos
Medula Suprarrenal/metabolismo , Glicemia/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Tromboxano A2/metabolismo , Animais , Benzofuranos/administração & dosagem , Desoxiglucose/administração & dosagem , Epinefrina/sangue , Epinefrina/metabolismo , Indometacina/administração & dosagem , Injeções Intraventriculares , Masculino , Neurônios/metabolismo , Norepinefrina/sangue , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fentolamina/administração & dosagem , Ratos , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo
19.
J Med Entomol ; 57(2): 627-630, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31637445

RESUMO

Eugenol is a major component of the essential oils in cloves and other aromatic plants. In insects, it produces toxic effects and repellency, and there is evidence that its site of action is the octopamine receptor. The objective of the present study was to explore whether the octopamine receptor is involved in the hyperactivity produced by eugenol in the blood-sucking bug Triatoma infestans (Klug). This insect is the main vector of Chagas disease in Latin America. Four treatments were topically applied on third instar nymphs: 1) octopamine, 2) eugenol, 3) phentolamine hydrochloride (an antagonist of the octopamine receptor) followed by octopamine, and 4) phentolamine hydrochloride followed by eugenol. Both octopamine and eugenol hyperactivated the nymphs. However, pretreatment with phentolamine hydrochloride inhibited the hyperactivating effect of both compounds. These results are in agreement with previous works on Drosophila melanogaster (Meigen) (Diptera: Drosophilidae) and the American cockroach. They suggest that the octopamine receptor is a possible site of action for eugenol.


Assuntos
Antiparasitários/farmacologia , Eugenol/farmacologia , Repelentes de Insetos/farmacologia , Fentolamina/farmacologia , Triatoma/efeitos dos fármacos , Animais , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Ninfa/efeitos dos fármacos , Ninfa/crescimento & desenvolvimento , Ninfa/fisiologia , Octopamina/administração & dosagem , Receptores de Amina Biogênica/antagonistas & inibidores , Receptores de Amina Biogênica/metabolismo , Triatoma/crescimento & desenvolvimento , Triatoma/fisiologia
20.
Neuroscience ; 423: 162-171, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31698023

RESUMO

Despite the long history of investigations of adrenergic compounds and their biological effects, specific mechanisms of their action in distinct compartments of the motor unit remain obscure. Recent results have suggested that not only skeletal muscles but also the neuromuscular junctions represent important targets for the action of catecholamines. In this paper, we describe the effects of adrenaline and noradrenaline on the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal release in the motor nerve endings of the mouse diaphragm. Noradrenaline and adrenaline decreased the frequency of the spontaneous release of acetylcholine quanta. The effect of noradrenaline was prevented by the ß adrenoreceptor blocker propranolol, whereas the action of adrenaline was abolished by the α adrenoreceptor antagonist phentolamine. Noradrenaline did not alter the quantal content of endplate potentials, while adrenaline suppressed the evoked release of acetylcholine. Blocking the α adrenoreceptors prevented the decrease in quantal secretion caused by adrenaline. Quantal release became more asynchronous under noradrenaline, as evidenced by a greater dispersion of real synaptic delays; in contrast, adrenaline synchronized the release process. Our data suggest an involvement of α and ß adrenoreceptors in the diverse modulation of the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal secretion in the mouse neuromuscular junction. Moreover, the adrenoblockers affected both the evoked and spontaneous quantal release of acetylcholine, suggesting the presence of endogenous catecholamines in the vicinity of cholinergic synapses.


Assuntos
Acetilcolina/metabolismo , Epinefrina/fisiologia , Junção Neuromuscular/metabolismo , Norepinefrina/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Diafragma/fisiologia , Epinefrina/antagonistas & inibidores , Epinefrina/farmacologia , Feminino , Cinética , Masculino , Camundongos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacologia , Fentolamina/farmacologia , Propranolol/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia
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