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1.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299304

RESUMO

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin's efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Simpatolíticos/farmacologia , Glândulas Suprarrenais/fisiologia , Animais , Compostos Benzidrílicos/química , Fármacos Cardiovasculares/farmacologia , Catecolaminas/biossíntese , Glucosídeos/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Corpos Cetônicos/metabolismo , Modelos Biológicos , Receptores Acoplados a Proteínas G/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Volume Sistólico/efeitos dos fármacos , Relação Estrutura-Atividade
2.
Psychopharmacology (Berl) ; 238(4): 1157-1169, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33483802

RESUMO

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Sistema Límbico/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Clonidina/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/psicologia , Feminino , Giro do Cíngulo/efeitos dos fármacos , Alucinógenos/efeitos adversos , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Ketamina/antagonistas & inibidores , Sistema Límbico/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Simpatolíticos/uso terapêutico , Resultado do Tratamento , Adulto Jovem
3.
J Neurochem ; 157(3): 710-726, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33354763

RESUMO

Apoptotic endoplasmic reticulum (ER) stress is a major mechanism for dopaminergic (DA) loss in Parkinson's disease (PD). We assessed if low doses of the partial α4ß2 nicotinic acetylcholine receptor agonist, cytisine attenuates apoptotic ER stress and exerts neuroprotection in substantia nigra pars compacta (SNc) DA neurons. Alternate day intraperitoneal injections of 0.2 mg/kg cytisine were administered to female and male mice with 6-hydroxydopamine (6-OHDA) lesions in the dorsolateral striatum, which caused unilateral degeneration of SNc DA neurons. Cytisine attenuated 6-OHDA-induced PD-related behaviors in female, but not in male mice. We also found significant reductions in tyrosine hydroxylase (TH) loss within the lesioned SNc of female, but not male mice. In contrast to female mice, DA neurons within the lesioned SNc of male mice showed a cytisine-induced pathological increase in the nuclear translocation of the pro-apoptotic ER stress protein, C/EBP homologous protein (CHOP). To assess the role of estrogen in cytisine neuroprotection in female mice, we exposed primary mouse DA cultures to either 10 nM 17-ß-estradiol and 200 nM cytisine or 10 nM 17-ß-estradiol alone. 17-ß-estradiol reduced expression of CHOP, whereas cytisine exposure reduced 6-OHDA-mediated nuclear translocation of two other ER stress proteins, activating transcription factor 6 and x-box-binding protein 1, but not CHOP. Taken together, these data show that cytisine and 17-ß-estradiol work in combination to inhibit all three arms (activating transcription factor 6, x-box-binding protein 1, and CHOP) of apoptotic ER stress signaling in DA neurons, which can explain the neuroprotective effect of low-dose cytisine in female mice.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estradiol/farmacologia , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Fator 6 Ativador da Transcrição/efeitos dos fármacos , Animais , Azocinas/farmacologia , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/psicologia , Cultura Primária de Células , Quinolizinas/farmacologia , Caracteres Sexuais , Substância Negra/efeitos dos fármacos , Simpatolíticos , Fator de Transcrição CHOP/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
4.
Curr Alzheimer Res ; 17(11): 1043-1051, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33342412

RESUMO

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by motor symptoms related to the deficiency in dopamine levels, and cognitive symptoms that are similar in nature to those manifested during Alzheimer's disease. Levosimendan, on the other hand, is a calcium sensitizer and phosphodiesterase inhibitor that was shown to possess neuroprotective, memoryenhancing, and anti-apoptotic properties. OBJECTIVE: In the current study, the possible protective effect of levosimendan was investigated in two animal models of Parkinson's disease. METHODS: Both intracerebral injection 6-hydroxydopamine (6-OHDA) and the direct injection of lipopolysaccharide (LPS) into the substantia nigra were used as models to induce Parkinson's-like behavior. Levosimendan (12 µg/kg intraperitoneally once weekly) was started 7 days before or 2 days after lesioning of the animals. At day 14 post-lesioning, animals were subjected to apomorphine challenge, which was correlated with dopamine levels in the striatum and tyrosine hydroxylase (TH)-positive nigral cells. RESULTS: Results showed that levosimendan restored the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells when administered 7 days before, but not two days after 6-OHDA lesioning. In the LPS model of PD, the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells were restored when levosimendan was administered 7 days before as well as two days after lesioning. CONCLUSION: Levosimendan seems to provide a promising agent with potential clinical value for PD.


Assuntos
Apomorfina , Cardiotônicos , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Simendana , Simpatolíticos , Animais , Apomorfina/administração & dosagem , Apomorfina/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Dopamina/administração & dosagem , Dopamina/farmacologia , Dopaminérgicos/administração & dosagem , Dopaminérgicos/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Oxidopamina/administração & dosagem , Oxidopamina/farmacologia , Ratos , Simendana/administração & dosagem , Simendana/farmacologia , Substância Negra/metabolismo , Simpatolíticos/administração & dosagem , Simpatolíticos/farmacologia
5.
Neuropharmacology ; 181: 108338, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33002500

RESUMO

Upon retrieval, an aversive memory can undergo destabilization and reconsolidation. A traumatic-like memory, however, may be resistant to this process. The present study sought to contribute with a strategy to overcome this potential issue by investigating whether generalized fear retrieval is susceptible to destabilization-reconsolidation that can be pharmacologically modified. We hypothesized that exposure to a context that elicits moderate generalization levels would allow a malleable memory state. We developed a fear conditioning protocol in context A (cxt-A) paired with yohimbine administration to promote significant fear to a non-conditioned context B (cxt-B) in rats, mimicking the enhanced noradrenergic activity reported after traumatic events in humans. Next, we attempted to impair the reconsolidation phase by administering clonidine (CLO) immediately after exposure to cxt-A, cxt-B, or a third context C (cxt-C) neither conditioned nor generalized. CLO administered post-cxt-B exposure for two consecutive days subsequently resulted in decreased freezing levels in cxt-A. CLO after cxt-B only once, after cxt-A or cxt-C in two consecutive days, or independently of cxt-B exposures did not affect fear in a later test. A 6-h-delay in CLO treatment post-cxt-B exposures produced no effects, and nimodipine administered pre-cxt-B exposures precluded the CLO action. We then quantified the Egr1/Zif268 protein expression following cxt-B exposures and CLO treatments. We found that these factors interact to modulate this memory destabilization-reconsolidation mechanism in the basolateral amygdala but not the dorsal CA1 hippocampus. Altogether, memory destabilization can accompany generalized fear expression; thus, we may exploit it to potentiate reconsolidation blockers' action.


Assuntos
Medo/psicologia , Generalização Psicológica , Consolidação da Memória/fisiologia , Memória/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Clonidina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Extinção Psicológica , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Rememoração Mental , Ratos , Ratos Wistar , Simpatolíticos , Ioimbina
6.
Medicine (Baltimore) ; 99(39): e22326, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991443

RESUMO

RATIONALE: The most common cardiac involvement of Fabry disease (FD) is left ventricular hypertrophy (LVH), which usually occurs in male patients over the age of 30. In rare cases, it can progress to ventricular dilation in the late stage of the disease. PATIENT CONCERNS: A 16-year-old boy presenting with recurrent extremity pain and chest distress was admitted to our hospital. Imaging examinations revealed ventricular dilation. DIAGNOSIS: α-Galactosidase A enzyme assay and GLA gene sequencing confirmed the diagnosis of FD and revealed a novel mutation c.76_77insT. INTERVENTIONS: The patient was treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd). He refused enzyme replacement therapy for financial reasons. OUTCOMES: The echocardiography, electrocardiography, renal function, and routine blood and urine tests performed 20 months after the patients discharge from hospital showed no significant changes. The patient reported a slow and gradual decrease in the frequency and degree of pain and chest distress, starting approximately 24 months after discharge. LESSONS: Cardiac involvement of FD can progress rapidly in some cases. Screening for FD should be considered in patients with unexplained ventricular dilation, especially in those with a history of typical FD manifestations.


Assuntos
Dilatação Patológica/diagnóstico por imagem , Doença de Fabry/complicações , Doença de Fabry/genética , Hipertrofia Ventricular Esquerda/etiologia , alfa-Galactosidase/genética , Adolescente , Assistência ao Convalescente , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ecocardiografia/métodos , Eletrocardiografia/métodos , Terapia de Reposição de Enzimas/economia , Doença de Fabry/tratamento farmacológico , Fosinopril/uso terapêutico , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Metoprolol/uso terapêutico , Mutação , Simpatolíticos/uso terapêutico , Resultado do Tratamento
7.
Cardiovasc Diabetol ; 19(1): 134, 2020 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891175

RESUMO

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.


Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Tolerância ao Exercício/fisiologia , Coração/fisiopatologia , Músculo Esquelético/fisiopatologia , Broncodilatadores , Cardiotônicos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/reabilitação , Cardiomiopatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Ecocardiografia sob Estresse , Teste de Esforço , Terapia por Exercício , Humanos , Microcirculação , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Ventilação Pulmonar , Simpatolíticos , Vasodilatadores
8.
Neurobiol Dis ; 144: 105044, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32798726

RESUMO

Acetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia.


Assuntos
Dopaminérgicos/efeitos adversos , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Neostriado/metabolismo , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo , Substância Negra/metabolismo , Regulação Alostérica , Animais , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Microdiálise , Antagonistas Muscarínicos/farmacologia , Neostriado/efeitos dos fármacos , Vias Neurais , Oxidopamina/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/metabolismo , Ratos , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M4/antagonistas & inibidores , Substância Negra/efeitos dos fármacos , Simpatolíticos/toxicidade , Ácido gama-Aminobutírico/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
9.
Eur J Pharmacol ; 883: 173315, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621912

RESUMO

The acetylcholinesterase inhibitor, galantamine, has shown therapeutic effect in rat model of rheumatoid arthritis. Hence, the current study aims at determining the mode of action of galantamine by examining different synovium-derived microRNAs (miRs) and their related pathogenic pathways. The study also focuses on how parasympathetic and sympathetic pathways in the synovial tissue could affect the mode of action and anti-arthritic effect of galantamine. Chemical sympathectomy was initiated in 12 adjuvant arthritic rats by exposure to 6-hydroxydopamine (6-OHDA; 2 × 50 mg/kg) on day 9 after adjuvant injection and again (2 × 100 mg/kg) one week later. Six rats were treated with galantamine (2.5 mg/kg/day) to explore the influence of sympathetic impairment on galantamine effect. Another twelve additional adjuvant arthritic rats were exposed to the selective α7 nicotinic acetylcholine receptor blocker methylcaconitine citrate (MLA; 5.6 mg/kg/day), 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine alone. Treatment proceeded for 5 days, from day 14 till day 18 post-adjuvant injection. Different miRs and their related pathogenic pathways were examined. Tyrosine hydroxylase (TH) expression was also measured in joint tissue. Galantamine affected the expression of the different miRs and their related parameters. Both, 6-OHDA and MLA, interrupted the anti-inflammatory/anti-arthritic effect of galantamine to different extent. Additionally, TH expression in the synovium was affected by galantamine, suggesting a novel pathogenic target in the treatment of rheumatoid arthritis.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Galantamina/farmacologia , MicroRNAs/metabolismo , Sistema Nervoso Parassimpático/efeitos dos fármacos , Simpatectomia Química , Membrana Sinovial/efeitos dos fármacos , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/fisiopatologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Regulação da Expressão Gênica , Masculino , MicroRNAs/genética , Antagonistas Nicotínicos/farmacologia , Oxidopamina/farmacologia , Sistema Nervoso Parassimpático/metabolismo , Sistema Nervoso Parassimpático/fisiopatologia , Ratos Sprague-Dawley , Simpatolíticos/farmacologia , Membrana Sinovial/inervação , Membrana Sinovial/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Neurotox Res ; 38(2): 461-477, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32394056

RESUMO

In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.


Assuntos
Inibidores Enzimáticos/farmacologia , Mitocôndrias/efeitos dos fármacos , Monoterpenos/farmacologia , Movimento/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Dinaminas/efeitos dos fármacos , Dinaminas/metabolismo , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Oxidopamina/toxicidade , Transtornos Parkinsonianos/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Simpatolíticos/toxicidade , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
11.
Am J Physiol Regul Integr Comp Physiol ; 318(4): R781-R789, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32130024

RESUMO

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. Both acute and chronic SF elevated mRNA and protein levels of cytokines in peripheral tissues. Changes in inflammatory responses mirrored stress-axes activation, with increased corticosterone and norepinephrine in SF mice. 6-OHDA treatment significantly alleviated SF-induced inflammation, thus providing evidence of SNS regulation of peripheral inflammation from SF. Effects of chronic SF were more severe than acute SF, and 1 wk of recovery from SF sufficiently alleviated peripheral inflammatory responses but not NE responses.


Assuntos
Inflamação/prevenção & controle , Privação do Sono/patologia , Simpatectomia Química , Animais , Cortisona/sangue , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/sangue , Oxidopamina/toxicidade , Estresse Fisiológico , Simpatolíticos/toxicidade
12.
Nat Chem Biol ; 16(5): 507-512, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152538

RESUMO

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to ßAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/química , Dexmedetomidina/química , Receptores Adrenérgicos alfa 2/química , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Sítios de Ligação , Microscopia Crioeletrônica , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacologia , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Insetos/citologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Receptores Adrenérgicos alfa 2/genética , Simpatolíticos/química , Simpatolíticos/farmacologia
13.
Hypertension ; 75(3): 650-659, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008436

RESUMO

Resistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 persons with hypertension and excluded persons with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 persons ages 18 to <90 from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in persons with resistant hypertension was 2.1%. Screened persons were younger (55.9±13.3 versus 65.5±11.6 years; P<0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; P=0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; P<0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; P=0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; P=0.04) than unscreened persons. Screened persons had significantly higher rates of prescription for calcium channel blockers, mixed α/ß-adrenergic receptor antagonists, sympatholytics, and vasodilators, and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (P=0.20). In conclusion, only 2.1% of eligible persons received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.


Assuntos
Aldosterona/sangue , Anti-Hipertensivos/uso terapêutico , Hiperaldosteronismo/complicações , Hipertensão/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/uso terapêutico , Resistência a Medicamentos , Feminino , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiologia , Hipertensão/tratamento farmacológico , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Prevalência , Renina/sangue , Estudos Retrospectivos , Simpatolíticos/uso terapêutico , Vasodilatadores/uso terapêutico , Adulto Jovem
14.
Toxicol Pathol ; 48(1): 228-237, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30987556

RESUMO

The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations. Both morphometric and stereologic evaluations confirmed neuron loss following guanethidine treatment. Morphometric analysis revealed a 50% to 60% lower number of tyrosine hydroxylase (TH)-positive neurons per unit area of SCG at both 3 and 6 months of recovery, compared to ganglia of age-matched controls, with no evidence of restoration of neuron density between 3 and 6 months. Reductions in TH-positive neurons following guanethidine treatment were corroborated by unbiased stereology of total hematoxylin and eosin-stained neuron numbers in SCG. Stereologic analyses revealed that total neuron counts were lower by 37% at 3 months of recovery when compared to age-matched vehicle controls, again with no obvious restoration between 3 and 6 months. Thus, no evidence was found that postganglionic neurons of the sympathetic nervous system in the adult rat have a neurogenic capacity.


Assuntos
Gânglios Simpáticos/fisiologia , Guanetidina/toxicidade , Neurogênese , Simpatolíticos/toxicidade , Animais , Degeneração Neural , Neurônios , Ratos , Sistema Nervoso Simpático , Tirosina 3-Mono-Oxigenase
15.
Acta Physiol (Oxf) ; 228(2): e13404, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31610091

RESUMO

Acute kidney injury (AKI) is frequently accompanied by activation of the sympathetic nervous system (SNS). This may result from pre-exisiting chronic diseases associated with sympathetic activation prior to AKI or it may be induced by stressors that ultimately lead to AKI such as endotoxins and arterial hypotension in circulatory shock. Conversely, sympathetic activation may also result from acute renal injury. Focusing on studies in experimental renal ischaemia and reperfusion (IR), this review summarizes the current knowledge on how the SNS is activated in IR-induced AKI and on the consequences of sympathetic activation for the development of acute renal damage. Experimental studies show beneficial effects of sympathoinhibitory interventions on renal structure and function in response to IR. However, few clinical trials obtained in scenarios that correspond to experimental IR, namely major elective surgery, showed that peri-operative treatment with centrally acting sympatholytics reduced the incidence of AKI. Apparently, discrepant findings on how sympathetic activation influences renal responses to acute IR-induced injury are discussed and future areas of research in this field are identified.


Assuntos
Injúria Renal Aguda/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Simpatolíticos/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Animais , Humanos
16.
Hypertens Res ; 42(12): 1872-1882, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31527789

RESUMO

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Hipertensão/fisiopatologia , Simpatolíticos/farmacologia , Vasoconstritores/farmacologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Barorreflexo/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiopatologia , Catecolaminas/metabolismo , Guanetidina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Restrição Física , Estresse Psicológico
17.
Chin J Physiol ; 62(2): 86-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31243179

RESUMO

Cold stress-elicited hemodynamic perturbations (CEHP) its underlying mechanisms still not clear. We examined the difference of two effector arms of sympathetic outflows, the sympathoadrenal system, and postganglionic sympathetic neurons, their role in CEHP genesis by using two sympatholytic agents, fusaric acid (FA, dopamine-ß-hydroxylase inhibitor) and guanethidine (GUA, norepinephrine-depleting drug). Adult male Sprague-Dawley rats were divided into three groups (n = 6, each), an intraperitoneal injection of control vehicle saline or FA or GUA and then all rats were subjected to a 10-min CS trial. Systolic blood pressure (SBP), heart rate (HR), dicrotic notch (Dn), power spectrum of blood pressure variability and HR variability (BPV, HRV), and coherence spectrum at very-low, low, and high frequency regions (VLF: 0.02-0.2 Hz, LF: 0.2-0.6 Hz, and HF: 0.6-3.0 Hz) were monitored using telemetry throughout the experiment course. We observed both FA and GUA attenuated SBP and HR and the spectral powers of BPV at VLF, LF, and HF in both baseline (PreCS) and cold stimuli (CS) conditions, but apparently, FA exerted stronger effects than GUA did. Both FA and GUA generally attenuated the responses of CS-induced pressor and tachycardia and the CS-increased VLFBPV, LFBPV, and HFBPV, but different effects between FA and GUA, when compared with control vehicle under CS. FA reduced the CS-reduced VLFHRV and the CS-increased LFBPV and HFBPV more than GUA did. We further observed in both PreCS and CS, GUA but not FA increased HFHRV; FA reduced but apparently, GUA increased the occurrence of Dn. Finally, we observed FA weakened, but GUA strengthened the coherence between BPV and HRV at both LF and HF regions. Taken together, the different effects between FA and GUA on CEHP indicate a role of the sympathoadrenal mechanism in response to CS.


Assuntos
Hemodinâmica , Animais , Pressão Sanguínea , Frequência Cardíaca , Masculino , Ratos , Ratos Sprague-Dawley , Simpatolíticos
18.
J. bras. nefrol ; 41(2): 266-274, Apr.-June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1012534

RESUMO

Abstract Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.


Resumo A Hipertensão Arterial Refratária (HARf) representa um fenótipo extremo da hipertensão arterial resistente (HAR), sendo considerada a falência ao tratamento apesar do uso de 5 ou mais classes de anti-hipertensivos, incluindo um diurético tiazídico de longa ação e um antagonista mineralocorticoide. A HAR é comum (10-20%) entre os hipertensos em geral, sendo decorrente de hiperatividade do Sistema Renina Angiotensina Aldosterona e retenção hidrossalina. Aqueles com HARf correspondem a 5-8% dos resistentes e parecem sofrer maior influência catecolaminérgica. Os resistentes tendem a ter maior idade, ao sobrepeso e à obesidade. Comorbidades incluem diabetes, apneia obstrutiva do sono e status de hiperaldosteronismo. Refratários são afro-americanos em maior proporção, mais jovens e, predominantemente, mulheres. Ambos são fortemente associados à elevada albuminúria, HVE, doenças cardio e cerebrovasculares, além da doença renal crônica. O fenômeno do jaleco branco parece ser mais evidente nos resistentes. Quanto ao tratamento, a intensificação da terapia diurética está indicada nos resistentes, enquanto na HARf, a falência à terapia impôs novas alternativas de tratamento ("simpaticolíticas"). Em conclusão, tanto a HAR quanto a HARf constituem-se desafios na prática clínica e devem ser abordadas como entidades clínicas distintas por profissionais especialistas que identifiquem comorbidades e venham a prover um tratamento específico, diversificado e individualizado.


Assuntos
Humanos , Resistência a Medicamentos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Fenótipo , Simpatolíticos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Terapias Complementares , Consumo de Bebidas Alcoólicas/efeitos adversos , Exercício Físico , Fumar/efeitos adversos , Prevalência , Monitorização Ambulatorial da Pressão Arterial , Dieta Hipossódica , Diuréticos/farmacologia , Abordagens Dietéticas para Conter a Hipertensão , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Anti-Hipertensivos/farmacologia
19.
Auton Neurosci ; 219: 42-48, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31122600

RESUMO

BACKGROUND: Frequent syncope is linked to poorer health-related quality of life (HRQoL). Recurrent syncope has been observed to reduce in all groups after seeing a syncope expert and enrolling in a clinical trial. It is unknown if HRQoL improves with this reduction in syncope recurrence. OBJECTIVES: We examined the change in HRQoL over time in vasovagal syncope (VVS) patients seen by a syncope expert and enrolled in a trial. We also explored whether change differed with treatment or the frequency of fainting during follow up. METHODS: The Short Form Health Survey (SF36) was completed at baseline (BL), 6 m, and 12 m post-enrollment by VVS patients in the 1st and 2nd Prevention of Syncope Trials, which were multi-centered, randomized, placebo-controlled trials of metoprolol (POST) and fludrocortisone (POST2). Differences in HRQoL at BL, 6 m, and 12 m were analyzed and compared by faints in follow-up and randomization group. RESULTS: Complete study data were available for 143 VVS patients (40 ±â€¯17 years, 62% F). Over 12 months, patients reported improvement in all SF36 dimensions except for bodily pain. Post hoc analyses indicated that differences first occurred between BL and 6 m for all but general health. Fainting in follow-up or drug randomization group did not diminish the improvements. The baseline syncope burden was not different whether patients' HRQoL improved or not. CONCLUSION: HRQoL of VVS patients improves over time after enrolling in a clinical trial, even with recurrent faints or randomization to placebo. Improvements may result from alternative factors, such as interaction with experts or patient adjustment.


Assuntos
Síncope Vasovagal/tratamento farmacológico , Adulto , Efeitos Psicossociais da Doença , Feminino , Fludrocortisona/uso terapêutico , Seguimentos , Humanos , Masculino , Metoprolol/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Simpatolíticos/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
20.
Hypertens Res ; 42(10): 1507-1517, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31138899

RESUMO

The sympathoinhibitory mechanism of azilsartan was investigated in an adenine-induced chronic renal failure model. Azilsartan exerted an antihypertensive effect, though BP elevation induced by adenine was marginal. The creatinine value was significantly lower in the azilsartan group (AZ) than in the vehicle group (VEH); furthermore, proteinuria was suppressed, and sodium excretion was augmented in the AZ group. The low frequency (LF) of systolic BP was suppressed (VEH: 4.07 ± 2.67 mmHg2 vs. AZ: 3.32 ± 1.93 mmHg2 P < 0.001), and the spontaneous baroreflex gain (sBRG) was augmented (VEH: 1.04 ± 0.62ms/mmHg vs. AZ: 1.38 ± 0.69 ms/mmHg, P < 0.001) in AZ. There were no significant differences in ACE1 and ACE2 expression between the groups, which indicated that the action of azilsartan on these components of the intrarenal renin-angiotensin-aldosterone system was comparatively small. Although NHE3, NKCC, and ENaC expression was similar between the groups, NaCl cotransporter (NCC) expression was markedly suppressed by azilsartan (P < 0.05). Thus, in a mild chronic kidney disease (CKD) model with slight BP elevation, the sympatholytic effect of ARB might be expected, and azilsartan might exert its natriuretic effect by NCC suppression achieved by sympathoinhibitory activity.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Natriurese/efeitos dos fármacos , Oxidiazóis/farmacologia , Insuficiência Renal Crônica/fisiopatologia , Simpatolíticos/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Sanguínea/efeitos dos fármacos , Creatinina/sangue , Rim/efeitos dos fármacos , Rim/enzimologia , Masculino , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos WKY , Sódio/urina
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