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INTRODUCTION: Cerebral blood flow (CBF) is reduced in patients with Alzheimer's disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD. METHODS: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan). RESULTS: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 ± 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (-11.4 ± 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 ± 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 µmol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT. CONCLUSION: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.
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Enfermedad de Alzheimer , Humanos , Masculino , Ratones , Animales , Lactante , Enfermedad de Alzheimer/tratamiento farmacológico , Bosentán , Receptores de Endotelina , Dilatación , Hipercapnia , Modelos Animales de Enfermedad , Circulación Cerebrovascular , Ratones Transgénicos , Endotelina-1RESUMEN
Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.
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Agua Corporal/metabolismo , Antagonistas de los Receptores de Endotelina/administración & dosificación , Pirimidinas/administración & dosificación , Sodio en la Dieta/efectos adversos , Sulfonamidas/administración & dosificación , Equilibrio Hidroelectrolítico/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Administración Oral , Adulto , Aldosterona/sangre , Estudios Cruzados , Método Doble Ciego , Antagonistas de los Receptores de Endotelina/efectos adversos , Glicopéptidos/sangre , Voluntarios Sanos , Homeostasis , Humanos , Masculino , Persona de Mediana Edad , Natriuresis/efectos de los fármacos , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Suiza , Ácido Úrico/sangre , Adulto JovenRESUMEN
Pulmonary arterial hypertension is a severe respiratory disease characterized by pulmonary artery remodeling. RV dysfunction and dysregulated circulating metabolomics are associated with adverse outcomes in pulmonary arterial hypertension. We investigated effects of tadalafil and macitentan alone or in combination on the RV and plasma metabolomics in SuHx and PAB models. For SuHx model, rats were injected with SU5416 and exposed to hypoxia for three weeks and then were returned to normoxia and treated with either tadalafil (10 mg/kg in chow) or macitentan (10 mg/kg in chow) or their combination (both 10 mg/kg in chow) for two weeks. For PAB model, rats were subjected to either sham or PAB surgery for three weeks and treated with above-mentioned drugs from week 1 to week 3. Following terminal echocardiographic and hemodynamic measurements, tissue samples were collected for metabolomic, histological and gene expression analysis. Both SuHx and PAB rats developed RV remodeling/dysfunction with severe and mild plasma metabolomic alterations, respectively. In SuHx rats, tadalafil and macitentan alone or in combination improved RV remodeling/function with the effects of macitentan and combination therapy being superior to tadalafil. All therapies similarly attenuated SuHx-induced changes in plasma metabolomics. In PAB rats, only macitentan improved RV remodeling/function, while only tadalafil attenuated PAB-induced changes in plasma metabolomics.
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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.
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Antihipertensivos/administración & dosificación , Antagonistas de los Receptores de Endotelina/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Pirimidinas/administración & dosificación , Sistema Renina-Angiotensina/efectos de los fármacos , Sulfonamidas/administración & dosificación , Animales , Antihipertensivos/farmacología , Acetato de Desoxicorticosterona/toxicidad , Quimioterapia Combinada , Antagonistas de los Receptores de Endotelina/farmacología , Hipertensión/inducido químicamente , Masculino , Pirimidinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Sistema Renina-Angiotensina/fisiología , Sulfonamidas/farmacologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an unknown cause. Two drugs, nintedanib and pirfenidone, have been shown to slow, but not stop, disease progression. Pulmonary hypertension (PH) is a frequent complication in IPF patients and is associated with poor prognosis. Macitentan is a dual endothelin receptor antagonist that is approved for pulmonary arterial hypertension treatment. We hypothesised that using macitentan to treat animals with pulmonary fibrosis induced by adenoviral vector encoding biologically active transforming growth factor-ß1 (AdTGF-ß1) would improve the PH caused by chronic lung disease and would limit the progression of fibrosis.Rats (Sprague Dawley) which received AdTGF-ß1 were treated by daily gavage of macitentan (100â mg·kg-1·day-1), pirfenidone (0.5% food admix) or a combination from day 14 to day 28. Pulmonary artery pressure (PAP) was measured before the rats were killed, and fibrosis was subsequently evaluated by morphometric measurements and hydroxyproline analysis.AdTGF-ß1 induced pulmonary fibrosis associated with significant PH. Macitentan reduced the increase in PAP and both macitentan and pirfenidone stopped fibrosis progression from day 14 to day 28. Macitentan protected endothelial cells from myofibroblast differentiation and apoptosis whereas pirfenidone only protected against fibroblast-to-myofibroblast differentiation. Both drugs induced apoptosis of differentiated myofibroblasts in vitro and in vivoOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis.
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Hipertensión Pulmonar/tratamiento farmacológico , Miofibroblastos/efectos de los fármacos , Fibrosis Pulmonar/patología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/inducido químicamente , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Masculino , Miofibroblastos/metabolismo , Fibrosis Pulmonar/inducido químicamente , Piridonas/farmacología , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is a selective nonprostanoid prostacyclin (PGI2) receptor (IP receptor) agonist that is approved for the treatment of pulmonary arterial hypertension (PAH). In contrast to selexipag, PGI2 analogs used in the clinic are nonselective agonists at prostanoid receptors and can also activate contractile prostaglandin E receptor 3 (EP3) receptors. Leg pain is a common side effect in patients receiving treatment with PGI2 analogs and peripheral vasoconstriction can be responsible for side effects related to muscular ischemia. This study tested the hypothesis that PGI2 analogs could cause paradoxical vasoconstriction of the femoral artery via EP3 receptor activation but that only vasorelaxation would be observed in response to selexipag and its active metabolite ACT-333679 [{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid]. Selexipag and ACT-333679 relaxed rings of the isolated rat femoral artery contracted with either prostaglandin F2α (PGF2α ) or the α1 adrenoceptor (α1AR) agonist phenylephrine. ACT-333679 also inhibited contraction of the femoral artery to sympathetic nerve stimulation. In contrast, PGI2 analogs (iloprost, beraprost, and treprostinil) caused additional contraction of arterial rings precontracted with phenylephrine, which was reverted to relaxation by antagonism of EP3 receptors. Treprostinil augmented contraction of the femoral artery to sympathetic nerve stimulation in an EP3 receptor-dependent manner. Mechanistically, concomitant EP3 and α1AR receptor activation synergistically constricted femoral arteries. It is concluded that selexipag and ACT-333679 are vasorelaxants of the rat femoral artery and, unlike PGI2 analogs, do not cause paradoxical vasoconstriction via activation of EP3 receptors. EP3 receptor-mediated vasoconstriction may contribute to the well documented peripheral muscle pain reported in patients with PAH receiving PGI2 analogs. Leg pain may be less in patients treated with selexipag.
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Acetamidas/farmacología , Epoprostenol/química , Epoprostenol/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/fisiología , Pirazinas/farmacología , Receptores de Epoprostenol/agonistas , Vasoconstricción/efectos de los fármacos , Animales , Arteria Femoral/metabolismo , Masculino , Ratas , Ratas Wistar , Subtipo EP3 de Receptores de Prostaglandina E/metabolismoRESUMEN
BACKGROUND: Nanoparticles are increasingly suspected as a strong etiologic factor of granuloma formation. AIM OF THE STUDY: The aim of our study was to compare lung inflammatory response and histology changes following exposure of mice to two widely used nanoparticles: carbon nanotubes (MWCNT) and cadmium-based nanoparticles (QDOT705) in an attempt to better our understanding of granulomatous inflammation. MATERIALS AND METHODS: Various groups of mice were included: control mice and mice that were intranasally instilled with QDOT or MWCNT. At defined time points post-challenge, bronchoalveolar lavages (BALs) and lung tissues were collected to study inflammatory and histologic changes. RESULTS: Analyses of lung BAL fluids and tissues of nanoparticles-challenged mice in comparison to controls found: (1) increased cellularity in BALs, (2) increase of total protein concentration, LDH activity and proteolytic activity in BALs; (3) patchy granulomas, (4) macrophages, CD3 ± T, Treg and B cell infiltration in granulomatous areas; and (5) altered regulation of key inflammatory mediators and receptors. Importantly, these changes were nanoparticle type-dependent. CONCLUSION: Our work enhances understanding of nanoparticles-induced lung inflammatory and histological changes that result in granuloma formation. We provide compelling evidence that not only exposure to nanoparticles leads to granulomatous lung inflammation, but the severity of this latter is nanostructure type-dependent. Of importance, while nanotechnology has the potential to revolutionize various fields including medicine, nanoparticles form the potential for an entirely new lung health risk that it is necessary to take seriously into consideration by setting up and/or reinforcing adequate safety measures.
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Granuloma/patología , Nanopartículas/efectos adversos , Neumonía/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Cadmio/efectos adversos , Granuloma/etiología , Ratones , Nanopartículas/química , Nanotubos de Carbono/efectos adversos , Neumonía/etiologíaRESUMEN
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.
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Endotelio Vascular/efectos de los fármacos , Inflamación/prevención & control , Dinitrato de Isosorbide/análogos & derivados , Dinitrato de Isosorbide/toxicidad , Estrés Oxidativo/efectos de los fármacos , Pirimidinas/farmacología , Sulfonamidas/farmacología , Enfermedades Vasculares/prevención & control , Animales , Células Cultivadas , Antagonistas de los Receptores de Endotelina/farmacología , Endotelio Vascular/patología , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Wistar , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/patología , Vasodilatadores/toxicidadRESUMEN
Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH-PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs' proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles.
RESUMEN
Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE-/- mice with macitentan, a dual ETA/ETB receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE-/- mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ETA/ETB antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE-/- mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ETA/ETB receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis.
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Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation, and extracellular matrix synthesis. Selexipag (Uptravi, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide) is the first nonprostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy ACT-333679 (previously known as MRE-269) behaved as a full agonist in multiple PAH-relevant receptor-distal-or downstream-cellular assays with a maximal efficacy (Emax) comparable to that of the prototypic PGI2 analog iloprost. In PASMC, ACT-333679 potently induced cellular relaxation (EC50 4.3 nM) and inhibited cell proliferation (IC50 4.0 nM) as well as extracellular matrix synthesis (IC50 8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal-or upstream-cAMP accumulation assays (Emax 56%) when compared with iloprost and the PGI2 analogs beraprost and treprostinil (Emax â¼100%). Partial agonism of ACT-333679 also resulted in limited ß-arrestin recruitment (Emax 40%) and lack of sustained IP receptor internalization, whereas all tested PGI2 analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.
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Acetamidas/farmacología , Acetatos/farmacología , Proteínas Contráctiles/antagonistas & inhibidores , Contracción Muscular/efectos de los fármacos , Pirazinas/farmacología , beta-Arrestinas/metabolismo , Animales , Células CHO , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Epoprostenol/análogos & derivados , Epoprostenol/farmacología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Iloprost/farmacología , Masculino , Relajación Muscular/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Receptores de Epoprostenol/agonistasRESUMEN
Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ETB receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ETA-selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ETA-selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ETA-selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ETB-selective receptor antagonism. ETA-selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ETA-selective antagonism increased vascular permeability via ETB receptor overstimulation. Acutely, ETA-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ETA-selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ETB receptors, endothelin receptor antagonists (particularly ETA-selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention.
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Permeabilidad Capilar/efectos de los fármacos , Antagonistas de los Receptores de Endotelina/farmacología , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Aldosterona/metabolismo , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Arginina Vasopresina/metabolismo , Bosentán , Endotelinas/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hematócrito/métodos , Hemoglobinas/metabolismo , Masculino , Fenilpropionatos/farmacología , Piridazinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Brattleboro , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Sulfonamidas/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. METHODS AND RESULTS: In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. CONCLUSIONS: These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF.
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Antagonistas de los Receptores de la Endotelina A/uso terapéutico , Antagonistas de los Receptores de la Endotelina B/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Pirimidinas/uso terapéutico , Volumen Sistólico , Sulfonamidas/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Anciano , Animales , Estudios de Casos y Controles , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo I/genética , Conectina/efectos de los fármacos , Conectina/genética , Diástole , Ecocardiografía , Antagonistas de los Receptores de la Endotelina A/farmacología , Antagonistas de los Receptores de la Endotelina B/farmacología , Endotelina-1/sangre , Femenino , Corazón/efectos de los fármacos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertrofia , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Técnicas In Vitro , Factores de Transcripción MEF2/efectos de los fármacos , Factores de Transcripción MEF2/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Miocitos Cardíacos/efectos de los fármacos , Pirimidinas/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Sulfonamidas/farmacología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/efectos de los fármacosRESUMEN
AIMS: To determine the impact of mixed endothelin receptor antagonist and mouse mast cell protease-4 (mMCP-4) in the development of atherosclerosis in the mouse model. MATERIALS AND METHODS: Apolipoprotein E (ApoE) KO mice were crossed with mMCP-4 KO mice to generate ApoE/mMCP-4 double KO mice. Atherosclerosis was induced with a normal- or high-fat diet for 12, 27 or 52weeks. Macitentan (30mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6weeks (27week protocol). At sacrifice, aortas and brachiocephalic arteries (BCAs) were collected. En face Sudan IV staining was performed on aortas and BCA sections were subjected to Masson's trichrome stain and α-smooth muscle actin labeling. KEY FINDINGS: Under normal diet, both macitentan treatment and the absence of mMCP-4 reduced the development of aortic atherosclerotic lesions in 27-week old ApoE KO mice, but mMCP-4 deletion failed to maintain this effect on 52-week old mice. Under high-fat diet (WD), macitentan, but not the absence of mMCP-4, reduced aortic lesion development in ApoE KO mice. On BCA lesions of 27-week old WD mice, macitentan treatment had a small impact while mMCP-4 deletion showed improved features of plaque stability. SIGNIFICANCE: These results suggest that the inhibition of mMCP-4 reduces lesion spreading in the earlier phases of atherosclerosis development and can help stabilise the more advanced plaque. Macitentan treatment was more effective to prevent lesion spreading but did not improve plaque features to the same extent.
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Aorta/patología , Aterosclerosis/patología , Antagonistas de los Receptores de Endotelina/farmacología , Pirimidinas/farmacología , Serina Endopeptidasas/metabolismo , Sulfonamidas/farmacología , Animales , Ratones , Ratones Noqueados , Serina Endopeptidasas/genéticaRESUMEN
OBJECTIVE: High endothelin-1 (ET-1) and transforming growth factor-ß (TGF-ß) levels may induce in healthy endothelial cells (EC) an endothelial-to-mesenchymal transition (EndMT). The same cytokines are associated with fibrosis development in systemic sclerosis (SSc). Although EndMT has not been definitively shown in SSc, this process, potentially induced by a stimulatory loop involving these 2 cytokines, overexpressed in this disease might contribute to fibroblast accumulation in affected tissues. Macitentan (MAC), an ET-1 receptor antagonist interfering with this loop, might prevent EndMT and fibroblast accumulation. METHODS: EC, isolated from healthy controls (HC) and patients with SSc, were treated with ET-1 and TGF-ß and successively analyzed for gene and protein expressions of endothelial and mesenchymal markers, and for Sma- and Mad-related (SMAD) phosphorylation. Further, in the supernatants, we evaluated ET-1 and TGF-ß production by ELISA assay. In each assay we evaluated the ability of MAC to inhibit both the TGF-ß and ET-1 effects. RESULTS: We showed that both TGF-ß and ET-1 treatments induced an activation of the EndMT process in SSc-EC as reported in HC cells. The ELISA assays showed a mutual TGF-ß and ET-1 induction in both SSc-EC and HC-EC. A statistically significant increase of SMAD phosphorylation after treatment was observed in SSc-EC. In each assay, MAC inhibited both TGF-ß and ET-1 effects. CONCLUSION: Our work is the first demonstration in literature that SSc-EC, under the synergistic effect of TGF-ß and ET-1, may transdifferentiate toward myofibroblasts, thus contributing to fibroblast accumulation. MAC, interfering with this process in vitro, may offer a new potential therapeutic strategy against fibrosis.
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Transdiferenciación Celular/fisiología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelina-1/metabolismo , Pirimidinas/farmacología , Sulfonamidas/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Italia , Masculino , Valores de Referencia , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/tratamiento farmacológico , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.
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Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Descubrimiento de Drogas , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Conformación Molecular , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis químicaRESUMEN
AIMS: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. METHODS AND RESULTS: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. CONCLUSIONS: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.
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Antagonistas de los Receptores de Endotelina/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Pirimidinas/farmacología , Sulfonamidas/farmacología , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Bleomicina , Bosentán , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas Wistar , Factores de Tiempo , Remodelación Vascular/efectos de los fármacosRESUMEN
Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor ß1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.
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Quimasas/metabolismo , Quimasas/fisiología , Hipertensión Pulmonar/fisiopatología , Pulmón/fisiopatología , Fibrosis Pulmonar/fisiopatología , Animales , Bleomicina/química , Quimasas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Endotelina-1/metabolismo , Ensayo de Inmunoadsorción Enzimática , Hemodinámica , Humanos , Hipertrofia Ventricular Derecha/enzimología , Inmunohistoquímica , Pulmón/enzimología , Pulmón/metabolismo , Mastocitos/enzimología , Metaloproteinasa 2 de la Matriz/metabolismo , Mesocricetus , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Radioinmunoensayo , Distribución Aleatoria , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Prostaglandins display a wide array of pharmacological effects and prostaglandin analogs are already used in the treatment of pulmonary arterial hypertension (PAH). After synthesis and release from cells, prostaglandins undergo reuptake by the prostaglandin transporter (PGT). WO2014/204895 claims the use of a series of trisubstituted triazine derivatives for the treatment of obesity and PAH. Composition of matter of these triazines has been claimed in WO2011/037610 and the compounds are described as potent inhibitors of the PGT. One compound (nr 146) was shown to improve high fat diet-induced glucose tolerance in a mouse model. In addition, this compound has been explored in the rat monocrotaline model of PAH and reduced characteristic features of the pathology. This class of compounds presents a potential new treatment paradigm in the treatment of obesity-related disorders and PAH.
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Hipertensión Pulmonar/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Transportadores de Anión Orgánico/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacología , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Hipertensión Pulmonar/fisiopatología , Ratones , Patentes como Asunto , Prostaglandinas/metabolismo , Prostaglandinas/farmacología , Prostaglandinas Sintéticas/farmacología , RatasRESUMEN
INTRODUCTION: The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs). METHODS: The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry. RESULTS: In healthy vessels, ETB receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ETB-mediated relaxation was lost while vasoconstriction on stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ETA/ETB ERA macitentan on top of a maximal effective dose of the ETA-selective ERA ambrisentan further reduced blood pressure, indicating that ETB receptors blockade provides additional benefit. CONCLUSIONS: Taken together, these data suggest that in pathology, dual ETA/ETB receptor antagonism can provide superior vascular effects compared with ETA-selective receptor blockade.