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1.
Life Sci ; 239: 117062, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734261

RESUMO

AIMS: Endothelin has been implicated in various processes in the brain, including the modulation of sympathetic responses. The present study examined the pathophysiologic role of brain endothelin-receptors in the setting of acute myocardial infarction, characterized by high incidence of ventricular tachyarrhythmias. MAIN METHODS: We investigated the effects of intracerebroventricular administration of antagonists of endothelin-receptors ETA, ETB, or both, during a 24 h-observation period post-coronary ligation in (n = 70) rats. Continuous recording was performed via implanted telemetry transmitters, followed by arrhythmia-analysis and calculation of autonomic indices derived from heart rate variability. The regional myocardial electrophysiologic properties were assessed by monophasic action potentials and multi-electrode recordings. KEY FINDINGS: Sympathetic-activity was decreased and vagal-activity was enhanced after intracerebroventricular ETA-receptor blockade, thus attenuating regional myocardial repolarization inhomogeneity. As a result, the incidence of ventricular tachyarrhythmias was markedly lower in this group. Such effects were also observed after intracerebroventricular blockade of ETB-, or both, ETA- and ETB-receptors, although to a lesser extent. SIGNIFICANCE: ETA-receptors in the brain modulate sympathetic and vagal responses and alter arrhythmogenesis during evolving myocardial necrosis in rats. These findings provide insights into arrhythmogenic mechanisms during acute myocardial infarction and call for further investigation on the role of endothelin in the central autonomic network.


Assuntos
Endotelinas/farmacologia , Infarto do Miocárdio/fisiopatologia , Receptores de Endotelina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/metabolismo , Sistema Nervoso Autônomo/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Antagonistas dos Receptores de Endotelina/metabolismo , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/farmacologia , Endotelinas/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Receptores de Endotelina/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
3.
Eur J Pharmacol ; 850: 126-134, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753868

RESUMO

Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC50 = 10 ±â€¯3.1 and 7.8 ±â€¯0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC50 = 51.7 ±â€¯9.1 nM) as well as in aortic rings (IC50 = 45.5 ±â€¯1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (>400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos , Distribuição Tecidual , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases Associadas a rho/química , Quinases Associadas a rho/metabolismo
4.
Ther Adv Respir Dis ; 13: 1753466618823440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30736726

RESUMO

Macitentan (10 mg once daily orally), a dual endothelin receptor antagonist (ERA) developed by modifying the structure of bosentan to increase the efficacity and safety, is approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal SERAPHIN trial, (a landmark trial in the history of PAH trials because of the large number of included patients, the long-term follow up and the first trial with morbidity/mortality as the primary endpoint) showed a reduction of the risk of a morbidity or mortality event by 45% over the treatment time compared with placebo. The positive effect on the primary endpoint was observed whether or not the patient was already on PAH therapy. There has been no direct comparison between macitentan and other ERAs, which were approved based on improved exercise capacity, but preclinical and clinical data suggest better pharmacological and safety profiles. Further analyses of the SERAPHIN trial investigated the predictive value of different indices and events on long-term outcome and mortality. The efficacy in children, the long-term effects and safety of macitentan and its place in combination therapy compared with other ERAs are still under investigation. This review presents the preclinical evidence of superiority of macitentan compared with other ERAs, and the available clinical trial data. The place of macitentan in the therapeutic algorithm for PAH treatment, post-marketing experience and future perspectives are discussed.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacologia , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Resultado do Tratamento
5.
J Pharmacol Exp Ther ; 368(3): 462-473, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30622171

RESUMO

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.


Assuntos
Anti-Hipertensivos/administração & dosagem , Antagonistas dos Receptores de Endotelina/administração & dosagem , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Pirimidinas/administração & dosagem , Sistema Renina-Angiotensina/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Animais , Anti-Hipertensivos/farmacologia , Acetato de Desoxicorticosterona/toxicidade , Quimioterapia Combinada , Antagonistas dos Receptores de Endotelina/farmacologia , Hipertensão/induzido quimicamente , Masculino , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sistema Renina-Angiotensina/fisiologia , Sulfonamidas/farmacologia
6.
Arch Oral Biol ; 97: 231-237, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30408737

RESUMO

OBJECTIVE: To improve understanding of the pathophysiology of cancer-induced facial nociception, by evaluating the contribution of peripheral endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception in a rat model of facial cancer. DESIGN: The study was conducted using 396 rats. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rats' right vibrissal pad. Facial heat hyperalgesia and spontaneous grooming were assessed on day 6, while the conditioned place preference (CPP) test was performed on days 3-6 after tumor cells inoculation. Rats received local injections of the non-peptidic dual ETA/ETB endothelin receptors antagonist, bosentan (10 and 30 µg/50 µL), single or combined injections of peptidic ETA and ETB endothelin receptors antagonists (BQ-123 and BQ-788, at 20 ug/50 µL, each), or of lidocaine (1 mg/50 µl) and morphine (30 µg/50 µL). RESULTS: Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (p < 0.05) and spontaneous facial grooming (p < 0.05). However, BQ-123 and BQ-788 did not modify tumor-induced heat hyperalgesia or the spontaneous facial grooming (p > 0.05). Whether this difference in effectiveness is due to receptor affinity or to pharmacokinetic factors still needs to be explored. Local injection of bosentan, lidocaine or morphine failed to control ongoing nociception, as evidenced by the absence of CPP in tumor-bearing rats (p > 0.05). CONCLUSION: Endothelins, acting through peripheral ETA and ETB receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.


Assuntos
Dor do Câncer/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/farmacologia , Neoplasias Faciais/fisiopatologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Receptores de Endotelina/metabolismo , Animais , Bosentana/farmacologia , Modelos Animais de Doenças , Temperatura Alta , Lidocaína/farmacologia , Masculino , Morfina/farmacologia , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Ratos
7.
Curr Med Chem ; 26(16): 2844-2864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29421995

RESUMO

Despite recent advances in Pulmonary Arterial Hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signaling pathways and investigational drugs with promising role in the treatment of PAH.


Assuntos
Hipertensão Pulmonar/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Antagonistas dos Receptores de Endotelina/farmacologia , Terapia Genética , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Imunoterapia , Inibidores da Fosfodiesterase 5/farmacologia
8.
Invest Ophthalmol Vis Sci ; 59(12): 5167-5175, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30372743

RESUMO

Purpose: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in retinal venous pathologies such as diabetic retinopathy and retinal vein occlusion. However, underlying mechanisms contributing to venular constriction remain unknown. Thus, we examined the roles of ET-1 receptors, extracellular calcium (Ca2+), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) in ET-1-induced constriction of retinal venules. Methods: Porcine retinal venules were isolated and pressurized for vasoreactivity study using videomicroscopic techniques. Protein and mRNA were analyzed using molecular tools. Results: Retinal venules developed basal tone and constricted concentration-dependently to ET-1. The ETA receptor (ETAR) antagonist BQ123 abolished venular constriction to ET-1, but ETB receptor (ETBR) antagonist BQ788 had no effect on vasoconstriction. The ETBR agonist sarafotoxin S6c did not elicit vasomotor activity. In the absence of extracellular Ca2+, venules lost basal tone and ET-1-induced constriction was nearly abolished. Although L-VOCC inhibitor nifedipine also reduced basal tone and blocked vasoconstriction to L-VOCC activator Bay K8644, constriction of venules to ET-1 remained. The ROCK inhibitor H-1152 but not PKC inhibitor Gö 6983 prevented ET-1-induced vasoconstriction. Protein and mRNA expressions of ETARs and ETBRs, along with ROCK1 and ROCK2 isoforms, were detected in retinal venules. Conclusions: Extracellular Ca2+ entry via L-VOCCs is essential for developing and maintaining basal tone of porcine retinal venules. ET-1 causes significant constriction of retinal venules by activating ETARs and extracellular Ca2+ entry independent of L-VOCCs. Activation of ROCK signaling, without involvement of PKC, appears to mediate venular constriction to ET-1 in the porcine retina.


Assuntos
Cálcio/metabolismo , Endotelina-1/farmacologia , Receptor de Endotelina A/metabolismo , Veia Retiniana/fisiologia , Vasoconstrição/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Animais , Western Blotting , Canais de Cálcio Tipo L/metabolismo , Antagonistas do Receptor de Endotelina B/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Feminino , Masculino , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Proteína Quinase C/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Endotelina A/genética , Sus scrofa , Vênulas/fisiologia
9.
Curr Hypertens Rep ; 20(10): 90, 2018 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-30145617

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent data available on advances in development of novel medical treatments for hypertension and related comorbidities. RECENT FINDINGS: Approximately half of all hypertensive patients have not achieved goal blood pressure with current available antihypertensive medications. Recent landmark studies and new hypertension guidelines have called for stricter blood pressure control, creating a need for better strategies for lowering blood pressure. This has led to a shift in focus, in recent years, to the development of combination pills as a means of achieving improved blood pressure control by increasing adherence to prescribed medications along with further research and development of promising novel drugs based on discovery of new molecular targets such as the counter-regulatory renin-angiotensin system. Fixed-dose combination pills and novel treatments based on recently discovered pathogenic mechanisms of hypertension that have demonstrated promising results as treatments for hypertension and related comorbidities will be discussed in this review.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Aminopeptidases/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/farmacologia , Combinação de Medicamentos , Antagonistas dos Receptores de Endotelina/farmacologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ouabaína/antagonistas & inibidores , Receptores de Peptídeo Intestinal Vasoativo/agonistas , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Vacinas/farmacologia , Proteínas ras/antagonistas & inibidores
10.
Physiol Res ; 67(Suppl 1): S227-S236, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947542

RESUMO

Over activation of the endothelin-1 (ET-1) system in disease states contributes to endothelial dysfunction. On the other hand, ET-1 promotes proliferation and survival of endothelial cells. Regulation of programmed cell death (PCD) pathways is critical for cell survival. Recently discovered necroptosis (regulated necrosis) is a pathological PCD mechanism mediated by the activation of toll like receptor 4 (TLR4), which also happens to stimulate ET-1 production in dendritic cells. To establish the effect of ET-1 on PCD and survival of human brain microvascular endothelial cells (BMVECs) under control and inflammatory conditions, BMVECs were treated with ET-1 (10 nM, 100 nM and 1 microM) or lipopolysaccharide (LPS, 100 ng/ml). ET receptors were blocked with bosentan (10 microM). Under normal growth conditions, exogenous ET-1 reduced BMVEC viability and migration at a relatively high concentration (1 microM). This was accompanied with activation of necroptosis and apoptosis marker genes. LPS decreased endogenous ET-1 secretion, increased ET(B) receptor expression and activated necroptosis. Even though ET-1 levels were low (less than 10 nM levels used under normal growth conditions), blocking of ET receptors with bosentan inhibited the necroptosis pathway and improved the cell migration ability of BMVECs, suggesting that under inflammatory conditions, ET-1 activates PCD pathways in BMVECs even at physiological levels.


Assuntos
Encéfalo/metabolismo , Células Endoteliais/metabolismo , Antagonistas dos Receptores de Endotelina/farmacologia , Lipopolissacarídeos/toxicidade , Microvasos/metabolismo , Receptores de Endotelina/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/efeitos dos fármacos , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Humanos , Microvasos/efeitos dos fármacos , Necrose/induzido quimicamente , Necrose/metabolismo
11.
Spine J ; 18(9): 1669-1677, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29886166

RESUMO

BACKGROUND CONTEXT: Endothelin-1 (ET-1) is an inflammatory mediator associated with cartilage end plate (CEP) degeneration in the intervertebral disc (IVD). SOX9 is downregulated during CEP degeneration, along with its targets, collagen II and aggrecan. Wnt/ß-catenin signaling is associated with CEP degeneration and a downstream target of SOX9; however, the precise mechanism of CEP degeneration and the role of ET-1 are largely unknown. PURPOSE: The purpose of the study was to evaluate the influence of the endothelin-A receptor antagonist, BQ-123, on ET-1-induced effects on cartilaginous end plate cells (CECs) associated with CEP degeneration via the Wnt/ß-catenin signaling pathway. STUDY DESIGN/SETTING: The influence of ET-1 on the expression levels of collagen II, aggrecan, and SOX9 in CECs and the effect of BQ-123 in this context were investigated. METHODS: To establish a model for CEP degeneration, three lumbar discs (L3-L4, L4-L5, and L5-L6 levels) in New Zealand white rabbits were punctured close to the vertebral end plate using a 14G needle. Intervertebral disc degeneration was evaluated by magnetic resonance imaging 4 weeks after vertebral end plate injury. CECs were then isolated from the degenerated CEPs to allow evaluation of the role of ET-1 and BQ-123 and to investigate their effects on the Wnt/ß-catenin signaling pathway. The expression of ET-1 in CECs from degenerated CEPs was analyzed by immunofluorescent staining. Changes in the levels of collagen II, aggrecan, and SOX9 were evaluated in CECs by real-time polymerase chain reaction and by Western blotting. The Wnt/ß-catenin signaling pathway was also investigated by Western blotting. RESULTS: After 4 weeks, IVDs with vertebral end plate injury exhibited clear signs of disc degeneration. Immunofluorescent staining showed that ET-1 was expressed in the cytoplasm of CECs. Endothelin-1 stimulation significantly inhibited the expression of collagen II, aggrecan, and SOX9 in CECs, whereas BQ-123 increased the levels of these three molecules. In addition, ET-1 stimulation increased the expression of ß-catenin, cyclin D1, and Dvl1 in the Wnt/ß-catenin signaling pathway of CECs from degenerated discs and reduced the expression of GSK-3ß, whereas BQ-123 had the opposite effect. CONCLUSIONS: Endothelin-1 can reduce levels of collagen II, aggrecan, and SOX9 in CECs through activation of the Wnt/ß-catenin signaling pathway, whereas BQ-123 attenuates these negative effects, highlighting a new molecular mechanism with potential for exploitation for treatment of CEP degeneration.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/farmacologia , Degeneração do Disco Intervertebral/metabolismo , Disco Intervertebral/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Via de Sinalização Wnt , Agrecanas/metabolismo , Animais , Colágeno/metabolismo , Disco Intervertebral/metabolismo , Coelhos , beta Catenina/metabolismo
12.
Basic Clin Pharmacol Toxicol ; 123(2): 103-113, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29719121

RESUMO

The approval of macitentan has increased the number of pharmacological treatments of pulmonary arterial hypertension (PAH). Here, we review the effect on PAH of macitentan compared to other endothelin receptor antagonists. Drugs targeting the endothelin (ET) pathway include the selective ETA receptor antagonist ambrisentan, the ETA /ETB receptor antagonists, bosentan and macitentan, which were recently approved for PAH treatment. Macitentan exhibits higher antagonistic potency than bosentan and ambrisentan in pulmonary smooth muscle cells. Compared to ambrisentan and bosentan, macitentan has a longer duration of action, reflected by the longer half-life, as well as pharmacodynamics attributed to its active metabolite, ACT-132577. The efficacy of macitentan on PAH was investigated in the phase III SERAPHIN trial (NCT00660179). Macitentan significantly reduced morbidity and mortality. It improved the 6-min. walk distance (6MWD) among PAH patients. In the AMB-320/321-E (NCT00578786) study, ambrisentan improved exercise capacity. In the EARLY study (NCT00091715), bosentan showed improvements in 6MWD which were not statistically significant. Bosentan had an effect on PAH in patients with Eisenmenger syndrome (ES) in the BREATHE-5 study (NCT00367770), while macitentan did not improve 6MWD in these patients, but there are differences regarding study size and functional class, and that 30% of the patients treated with macitentan were already in treatment with a phosphodiesterase type 5 inhibitor. Macitentan revealed a lower risk of developing peripheral oedema and hepatotoxicity in the SERAPHIN study. In summary, macitentan has an efficiency comparable to bosentan and ambrisentan in the treatment of PAH. Patients treated with macitentan exhibited less adverse effects compared to bosentan and ambrisentan. In patients with PAH associated with ES, the trials with bosentan and macitentan do not seem comparable, and it needs to be clarified whether these drugs are effective when administered as part of a combination treatment in this condition.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Bosentana , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada/métodos , Antagonistas dos Receptores de Endotelina/farmacologia , Meia-Vida , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fenilpropionatos/farmacologia , Fenilpropionatos/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Resultado do Tratamento , Teste de Caminhada
13.
Medicine (Baltimore) ; 97(11): e0122, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29538209

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease and ultimately leads to right heart failure. Endothelin receptor antagonists (ERAs) have been demonstrated to significantly improve prognosis in PAH. However, ERAs-induced side effects can result in poor patient tolerance. Thus, we aim to evaluate current safety evidence of ERAs in PAH. METHODS: An electronic search will be performed for randomized controlled trials (RCTs) that reported the interested safety data (abnormal liver function, peripheral edema, and anemia) of ERAs in PAH. Risk ratios (RRs) with their confidence intervals (CIs) and the surface under the cumulative ranking curve (SUCRA) will be calculated using a network analysis. RESULTS: This study will provide the safety evidence of ERAs in PAH by combining the results of individual studies based on direct- and network comparison, and to rank ERAs in the evidence network. CONCLUSIONS: The results will supplement missing evidence of head-to-head comparisons between different ERAs and guide both clinical decision-making and future research.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacologia , Insuficiência Cardíaca/prevenção & controle , Hipertensão Pulmonar/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão Pulmonar/complicações , Metanálise em Rede , Projetos de Pesquisa , Resultado do Tratamento
14.
Lung ; 196(3): 321-327, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29516177

RESUMO

INTRODUCTION: A number of studies indicate that endothelin-1 (ET-1) may act as an inflammatory cell "gatekeeper," by regulating the influx of neutrophils following pulmonary injury. To further examine the role of ET-1 in modulating lung inflammation, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of amiodarone (AM) or 24 h afterwards. METHODS: In both cases, the extent of lung injury and repair was determined by (1) histopathological changes; (2) neutrophil content in bronchoalveolar lavage fluid (BALF); (3) lung collagen content; (4) tumor necrosis factor receptor 1 expression by BALF macrophages; (5) BALF levels of (a) transforming growth factor beta-1, (b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and (c) platelet-derived growth factor BB; (6) alveolar septal cell apoptosis. RESULTS: For each parameter, pretreatment with HJP272 resulted in a significant reduction compared to AM alone, whereas post-treatment was either ineffective or produced only a marginally significant change, suggesting that the course of lung inflammation and repair is programmed at a very early stage. CONCLUSIONS: This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential.


Assuntos
Amiodarona/toxicidade , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/antagonistas & inibidores , Hidroxiquinolinas/farmacologia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Vasodilatadores/toxicidade , Animais , Apoptose/efeitos dos fármacos , Becaplermina/efeitos dos fármacos , Becaplermina/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CXCL12/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Feminino , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Mesocricetus , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
15.
Oxid Med Cell Longev ; 2018: 7845629, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30687454

RESUMO

Objective: Organic nitrates such as isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) are used for the treatment of patients with chronic symptomatic stable coronary artery disease and chronic congestive heart failure. Limiting side effects of these nitrovasodilators include nitrate tolerance and/or endothelial dysfunction mediated by oxidative stress. Here, we tested the therapeutic effects of the dual endothelin (ET) receptor antagonist macitentan in ISMN- and ISDN-treated animals. Methods and Results: Organic nitrates (ISMN, ISDN, and nitroglycerin (GTN)) augmented the oxidative burst and interleukin-6 release in cultured macrophages, whereas macitentan decreased the oxidative burst in isolated human leukocytes. Male C57BL/6j mice were treated with ISMN (75 mg/kg/d) or ISDN (25 mg/kg/d) via s.c. infusion for 7 days and some mice in addition with 30 mg/kg/d of macitentan (gavage, once daily). ISMN and ISDN in vivo therapy caused endothelial dysfunction but no nitrate (or cross-)tolerance to the organic nitrates, respectively. ISMN/ISDN increased blood nitrosative stress, vascular/cardiac oxidative stress via NOX-2 (fluorescence and chemiluminescence methods), ET1 expression, ET receptor signaling, and markers of inflammation (protein and mRNA level). ET receptor signaling blockade by macitentan normalized endothelial function, vascular/cardiac oxidative stress, and inflammatory phenotype in both nitrate therapy groups. Conclusion: ISMN/ISDN treatment caused activation of the NOX-2/ET receptor signaling axis leading to increased vascular oxidative stress and inflammation as well as endothelial dysfunction. Our study demonstrates for the first time that blockade of ET receptor signaling by the dual endothelin receptor blocker macitentan improves adverse side effects of the organic nitrates ISMN and ISDN.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Inflamação/prevenção & controle , Dinitrato de Isossorbida/análogos & derivados , Dinitrato de Isossorbida/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Doenças Vasculares/prevenção & controle , Animais , Células Cultivadas , Antagonistas dos Receptores de Endotelina/farmacologia , Endotélio Vascular/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/patologia , Vasodilatadores/toxicidade
16.
Transplantation ; 102(4): 601-608, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29189484

RESUMO

BACKGROUND: The optimal vasodilator to avoid hepatic artery vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), epoprostenol (prostacyclin analogue), and verapamil (calcium channel antagonist). METHODS: Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: group 1, livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion; group 2, epoprostenol at a continuous infusion of 4 mg/h; group 3, verapamil 2.5 mg at baseline and at 2 hours of perfusion; group 4, no vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily posttransplantation until postoperative day (POD) 3. All groups were compared with a cold storage group for postoperative graft function. RESULTS: Hepatic artery flow during NEVLP was significantly higher in BQ123 compared with verapamil, epoprostenol, and no vasodilator-treated livers. Aspartate aminotransferase levels were significantly lower with BQ123 and verapamil compared with epoprostenol and control group during perfusion. Peak aspartate aminotransferase levels were lower in pigs receiving BQ123 and verapamil perfused grafts compared with epoprostenol and control group. International Normalized Ratio, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and verapamil groups compared to epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. CONCLUSION: The use of BQ123, epoprostenol, and verapamil during NEVLP is safe. Livers perfused with BQ123 and verapamil have higher hepatic artery flow and reduced hepatocyte injury during perfusion compared with epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Epoprostenol/farmacologia , Artéria Hepática/efeitos dos fármacos , Transplante de Fígado/métodos , Fígado/irrigação sanguínea , Peptídeos Cíclicos/farmacologia , Perfusão/métodos , Traumatismo por Reperfusão/prevenção & controle , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Verapamil/farmacologia , Animais , Apoptose/efeitos dos fármacos , Artéria Hepática/fisiopatologia , Fígado/patologia , Circulação Hepática/efeitos dos fármacos , Masculino , Necrose , Perfusão/efeitos adversos , Perfusão/instrumentação , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Sus scrofa
17.
Hypertension ; 71(1): 208-216, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133362

RESUMO

Endothelium-derived endothelin (ET)-1 has been implicated in the development of hypertension and end-organ damage, but its exact role remains unclear. We have shown that tamoxifen-inducible endothelium-restricted human ET-1 overexpressing (ieET-1) mice exhibited blood pressure rise after a 3-week induction in an ET type A (ETA) receptor-dependent manner, in absence of vascular and renal injury. It is unknown whether long-term ET-1 overexpression results in sustained blood pressure elevation and vascular and renal injury. Adult male ieET-1 and control tamoxifen-inducible endothelium-restricted Cre recombinase (ieCre) mice were induced with tamoxifen and 2.5 months later, were treated with or without the ETA receptor blocker atrasentan for 2 weeks. Three-month induction of endothelial human ET-1 overexpression increased blood pressure (P<0.01), reduced renal artery flow (P<0.001), and caused mesenteric small artery stiffening (P<0.05) and endothelial dysfunction (P<0.01). These changes were accompanied by enhanced mesenteric small artery Col1A1 and Col3A1 expression, and perivascular adipose tissue oxidative stress (P<0.05) and monocyte/macrophage infiltration (P<0.05). Early renal injury was demonstrated by increased kidney injury molecule-1 expression in renal cortex tubules (P<0.05), with, however, undetectable lesions using histochemistry staining and unchanged urinary albumin. There was associated increased myeloid (CD11b+) and myeloid-derived suppressive cell (CD11b+Gr-1+) renal infiltration (P<0.01) and greater frequency of myeloid and renal cells expressing the proinflammatory marker CD36 (P<0.05). Atrasentan reversed or reduced all of the above changes (P<0.05) except the endothelial dysfunction and collagen expression and reduced renal artery flow. These results demonstrate that long-term exposure to endothelial human ET-1 overexpression causes sustained blood pressure elevation and vascular and renal injury via ETA receptors.


Assuntos
Pressão Sanguínea , Endotelina-1/metabolismo , Endotélio Vascular , Hipertensão , Rim , Pirrolidinas/farmacologia , Receptor de Endotelina A/metabolismo , Animais , Atrasentana , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/irrigação sanguínea , Rim/metabolismo , Camundongos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Resultado do Tratamento
18.
Eur J Pharmacol ; 818: 132-140, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29069579

RESUMO

Pain reported by patients with head and neck cancer is characterized as persistent pain with mechanical allodynia. Pain management is inadequate for many patients, highlighting the need for improved therapies. We examined the hypothesis that the mixed endothelin ETA and ETB receptor antagonist, bosentan, reduces tumor-induced ongoing pain and evoked hypersensitivity in a rat model of facial cancer pain. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rat's right vibrissal pad. Tumor-bearing rats developed heat and tactile hypersensitivity along with increased spontaneous grooming behavior. Systemic morphine (2.5mg/kg, s.c.) blocked tumor-induced thermal and tactile hypersensitivity, with a lower dose (0.625mg/kg, s.c.) effective only against thermal hypersensitivity. Systemic bosentan blocked tumor-induced thermal hypersensitivity only at a high (300mg/kg, p.o.) dose, but failed to modify tactile hypersensitivity. Co-administration of the low doses of bosentan and morphine resulted in improved reduction of the tumor-induced heat and tactile hypersensitivity compared to either dose alone. Bosentan (100mg/kg, p.o.) reduced spontaneous grooming and induced conditioned place preference (CPP) selectively in tumor-bearing rats, suggesting that bosentan reduces tumor-induced ongoing pain at a lower dose than required to block tumor-induced hypersensitivity. This study provides evidence that endothelins may mediate tumor-induced ongoing pain and thermal hypersensitivity. In addition, bosentan enhanced morphine's effects on blocking tumor-induced heat and tactile hypersensitivity indicating that endothelin antagonists may be beneficial therapeutic targets that can be used to manage cancer-induced facial pain with opioid-sparing effects.


Assuntos
Dor do Câncer/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/farmacologia , Neoplasias Faciais/complicações , Hiperalgesia/tratamento farmacológico , Receptores de Endotelina/metabolismo , Animais , Bosentana , Dor do Câncer/complicações , Dor do Câncer/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/uso terapêutico , Neoplasias Faciais/patologia , Masculino , Morfina/farmacologia , Morfina/uso terapêutico , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
19.
J Cell Biochem ; 119(4): 3118-3128, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29058764

RESUMO

This study aims to investigate the effects of PPAR-γ on rats with pregnancy-induced hypertension (PIH) by regulating endothelin receptor (ETR). A total of 60 pregnant Wistar rats were selected, and 50 rats were used to establish endotoxin induced PIH rat models. Rats were equally assigned into PIH-NS, PIH-5 mg/kg RM, PIH-10 mg/kg RM, PIH-100 mg/kg ETR, and PIH-200 mg/kg ETR groups, and the rest 10 rats were assigned to a the control group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used for determining mRNA and protein expressions of PPAR-γ and ETA R, respectively. Protein expression of ET-1 was detected by immunohistochemistry. Results show that On the 22nd day of pregnancy, compared with the PIH-NS group, SBP decreased in other groups, and platelet concentration increased most significantly in the PIH-10 mg/kg RM and PIH-200 mg/kg ETR groups. Compared with the control, PIH-10 mg/kg RM and PIH-200 mg/kg ETR groups, the increase in the expression of ET-1 and ETA R was most significant in the PIH-NS group. Compared with the control and PIH-10 mg/kg RM groups, expression of PPAR-γ was lower in the PIH-NS, PIH-5 mg/kg RM, PIH-100 mg/kg ETR, and PIH-200 mg/kg ETR groups. Compared with the PIH-NS, PIH-100 mg/kg ETR and PIH-200 mg/kg ETR groups, PPAR-γ expression was significantly higher in the PIH-5 mg/kg RM group (all P < 0.05). Based on our findings, we conclude that PPAR-γ activation inhibits ETR expression and reduces the effect of ET-1 on vascular contraction thereby delaying PIH progression.


Assuntos
Antagonistas dos Receptores de Endotelina/administração & dosagem , Endotoxinas/efeitos adversos , Hipertensão Induzida pela Gravidez/prevenção & controle , PPAR gama/metabolismo , Receptor de Endotelina A/metabolismo , Sulfonamidas/administração & dosagem , Animais , Bosentana , Antagonistas dos Receptores de Endotelina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Induzida pela Gravidez/induzido quimicamente , Hipertensão Induzida pela Gravidez/genética , Hipertensão Induzida pela Gravidez/metabolismo , Masculino , PPAR gama/genética , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor de Endotelina A/genética , Sulfonamidas/farmacologia
20.
Neurosurg Rev ; 41(2): 539-548, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28756589

RESUMO

Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B1 receptor (ET(B1)-receptor) antagonist. Also, an increased ET(B1)-receptor-dependent relaxation to sarafotoxin S6c (S6c; an ET(B1)-receptor agonist) was detected by preincubation with losartan. Investigations after experimental induced subarachnoid hemorrhage (SAH) are still missing. Therefore, we analyzed losartan in a further pathological setup. Cerebral vasospasm was induced by a modified double hemorrhage model. Rats were sacrificed on day 3 and isometric force of basilar artery ring segments was measured. Parallel to physiological conditions, after SAH, the ET-1-induced vasoconstriction was decreased by preincubation with losartan. This reduced contraction has been abolished after preincubation with BQ-788, an ET(B1)-receptor antagonist. In precontracted vessels, ET-1 induced a higher vasorelaxation under losartan and the endothelin A receptor (ET(A)-receptor) antagonist BQ-123. After SAH, losartan caused a modulatory effect on the ET(B1)-receptor-dependent vasorelaxation. It further induced an upregulation of the NO pathway. Under losartan, the formerly known loss of the ET(B1)-receptor vasomotor function was abolished and a significantly increased relaxation, accompanied with an enhanced sensitivity of the ET(B1)-receptor, has been detected. Also, the dose-dependent antagonistic effect to the ET-1-induced contraction can be effected by angiotensin II type 1 receptor (AT1-receptor) antagonism due to losartan directly via the ET(B1)-receptor.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Artéria Basilar/efeitos dos fármacos , Endotelina-1/farmacologia , Losartan/farmacologia , Hemorragia Subaracnóidea/etiologia , Angiotensinas , Animais , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Masculino , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasoespasmo Intracraniano/etiologia
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