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1.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404946

RESUMO

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A-D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.


Assuntos
Amidas/uso terapêutico , Cardiomiopatia Dilatada/tratamento farmacológico , Fumaratos/uso terapêutico , Renina/antagonistas & inibidores , Renina/sangue , Animais , Caquexia/sangue , Caquexia/complicações , Caquexia/tratamento farmacológico , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/complicações , Modelos Animais de Doenças , Edema/sangue , Edema/complicações , Edema/tratamento farmacológico , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL
2.
Plant Foods Hum Nutr ; 74(3): 405-413, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273642

RESUMO

The aim of this work was to evaluate the ability of broken rice, an underutilized industrial by-product, as a potential functional and health promoting ingredient. With this purpose, the ability to inhibit the angiotensin converting enzyme and renin of a rice protein hydrolyzate (RPH) obtained from a high-protein variety of broken rice (var. Nutriar FCAyF) was analyzed (IC50 = 0.87 and 2.7 mg/mL, respectively). RPH was separated by gel permeation chromatography and in a second purification step by RP-HPLC. The sequence of antihypertensive peptides presented in two RP-HPLC fractions was analyzed. Peptides capable of interacting with the active sites of both enzymes were identified. In this study, we demonstrate that the hydrolysis treatment improves functional and biological properties of rice proteins. Protein preparations obtained from a by-product of rice industry, such as broken rice, are a promising ingredient with potentially good biological properties.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/isolamento & purificação , Oryza/química , Peptídeos/isolamento & purificação , Renina/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão , Promoção da Saúde , Hidrólise , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Renina/metabolismo
3.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261774

RESUMO

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin-angiotensin-aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.


Assuntos
Insuficiência Cardíaca/sangue , Renina/sangue , Animais , Biomarcadores/sangue , Débito Cardíaco , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Renina/antagonistas & inibidores , Sístole
4.
BMC Pharmacol Toxicol ; 20(1): 23, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053170

RESUMO

BACKGROUND: The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure. METHOD: Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks. RESULTS: Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate. CONCLUSION: Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.


Assuntos
Amidas/farmacologia , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Creatina Quinase Forma MB/sangue , Fumaratos/farmacologia , Insuficiência Cardíaca/sangue , Metaloproteinase 9 da Matriz/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Ramipril/farmacologia , Tetrazóis/farmacologia , Angiotensinas/antagonistas & inibidores , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiologia , Neprilisina/antagonistas & inibidores , Ratos Wistar , Renina/antagonistas & inibidores , Renina/sangue , Troponina I/sangue
5.
Am J Cardiovasc Drugs ; 19(3): 259-286, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737754

RESUMO

INTRODUCTION: Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES: Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS: Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION: Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Biomed Res Int ; 2019: 3027036, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809535

RESUMO

Aim: Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP). Methods: The behaviors of 1α (OH)-ase knockout mice and wild type mice were observed before analysis. The ICR mice were treated with vehicle or paricalcitol, a vitamin D analogue, followed by animals receiving a standard diet and free access to drinking water either with aliskiren (renin blocker; 37.5 mg aliskiren in 100 ml water), or telmisartan (a angiotensin II type I receptor blocker; 40 mg telmisartan in 100 ml water) a week before study. The expressions of AQP-1, AQP-4, and renin in mice kidneys were detected by western bolting, immunohistochemistry, and immunofluorescence. Results: Diuresis and polydipsia were observed in 1α (OH)-ase knockout mice, and a decreased water intake and urine output in ICR mice was observed after paricalcitol treatment. Compared with wild type, the AQP-1 expressions were increased in renal papilla and AQP-4 expressions were decreased in renal proximal tubule of 1α(OH) ase knockout mice. In addition, AQP-1 was decreased in renal papilla and AQP-4 expressions were increased in proximal tubule by suppressing renin activity or supplement of Vitamin D analogue. After injecting renin into the lateral ventricle of the 1α(OH)ase knockout mice, the renin expression level was decreased in the kidney, followed by the decrease of AQP-1 in renal papilla and increase of AQP-4 in proximal tubule. Conclusions: Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.


Assuntos
Aquaporina 1/genética , Aquaporina 4/genética , Renina/genética , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Amidas/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Fumaratos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Camundongos , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Renina/administração & dosagem , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Telmisartan/administração & dosagem , Vitamina D/genética , Água/química
7.
Curr Diab Rep ; 19(1): 4, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673886

RESUMO

PURPOSE OF REVIEW: Type 2 diabetes (T2D) is associated with an increased risk of diabetic kidney disease (DKD), cardiovascular disease, and heart failure, in part through activation of the renin-angiotensin-aldosterone system (RAAS). Although recent cardiovascular outcome trials have identified newer therapeutic agents such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists that reduce the risk of these complications, patients still exhibit residual cardiorenal morbidity and mortality. Accordingly, the identification of pharmacological agents that attenuate micro- and macrovascular complications related to T2D is a major priority. Our aim was to review evidence for the role of novel mineralocorticoid receptor antagonists (MRAs) that are being developed as adjunctive therapies to reduce the risk of DKD and cardiovascular disease in the setting of T2D. RECENT FINDINGS: Dual RAAS blockade with angiotensin-converting enzyme (ACE) inhibitor plus angiotensin receptor blockade (ARB) or ARB plus renin inhibition increases serious adverse events such as acute kidney injury and stroke. Due to the potential for these serious side effects, more recent interest has focused on newer, more selective non-steroidal MRAs such as finerenone as cardiorenal protective therapies. Finerenone reduces albuminuria in the setting of DKD in patients with T2D and has a lower risk of hyperkalemia compared to currently available MRAs. Novel MRAs such as finerenone have the potential to reduce the risk of DKD progression in patients with T2D. The impact of finerenone on hard, long-term cardiorenal endpoints is being examined in the FIGARO and FIDELIO trials in patients with DKD.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico , Adulto , Albuminúria/tratamento farmacológico , Aldosterona/metabolismo , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Humanos , Hiperpotassemia/etiologia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Naftiridinas/efeitos adversos , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos
8.
Xenobiotica ; 49(5): 584-590, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29790816

RESUMO

The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α1-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels.


Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Morfolinas/farmacologia , Morfolinas/farmacocinética , Orosomucoide/metabolismo , Piperidinas/farmacologia , Piperidinas/farmacocinética , Renina/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/efeitos adversos , Masculino , Morfolinas/efeitos adversos , Piperidinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Terebintina/farmacocinética , Terebintina/farmacologia
9.
Fundam Clin Pharmacol ; 33(2): 191-198, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30312501

RESUMO

It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50-100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary.


Assuntos
Amidas/farmacologia , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Fumaratos/farmacologia , Pentilenotetrazol , Renina/antagonistas & inibidores , Convulsões/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Interações de Medicamentos , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores de Tempo
10.
Eur J Pharmacol ; 845: 74-84, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30586551

RESUMO

Nicousamide has been shown to exert renal protective effects against diabetic nephropathy and has moved to a phase II clinical trial in China for diabetic nephropathy indication. To expand its clinical indications, 5/6-nephrectomised rats were used to mimic glomerular and vascular sclerosis and tubulointerstitial scarring, with subsequent progression towards end-stage renal disease. Adult Wistar rats underwent 5/6 nephrectomy to induce the development of chronic kidney disease, with a sham operation performed as a control. The nephrectomised animals were treated orally with either saline, nicousamide (7.5,15, or 45 mg/kg), benazepril (4 mg/kg), or losartan (10 mg/kg) daily for 20 weeks. At 8, 16, and 20 weeks of treatment, blood pressure was measured in each animal, and blood and urine samples were collected for biochemical analysis, while kidney remnants were collected for histological examination. Levels of fibronectin and transforming growth factor beta 1 (TGF-ß1) were measured in kidneys by immunohistochemistry. Renin activity in the plasma was measured by an enzyme-linked immunosorbent assay. The results showed that nicousamide treatment significantly reduced systemic hypertension, proteinuria, and blood urea nitrogen (P < 0.05), effectively alleviated glomerular sclerosis scores and tubulointerstitial injuries in a dose-dependent manner (P < 0.01), and markedly decreased fibronectin and TGF-ß1 levels in kidney tissues of the 5/6-nephrectomised animals. In vitro studies suggested that nicousamide could moderately inhibit the renin activity and strongly block the TGF-ß1 internalisation into fibroblast cells. In summary, nicousamide may protect from renal failure through dual targeting, which involves a TGF-ß1-dependent mechanism and inhibition of renin activity.


Assuntos
Compostos de Anilina/uso terapêutico , Cumarínicos/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Glomérulos Renais/lesões , Renina/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , China , Cumarínicos/administração & dosagem , Cumarínicos/farmacologia , Fibronectinas/metabolismo , Hipertensão , Nefrectomia , Proteinúria , Ratos , Ratos Wistar
12.
Cell Physiol Biochem ; 50(2): 654-667, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308499

RESUMO

BACKGROUND/AIMS: Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. METHODS: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. RESULTS: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. CONCLUSION: C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzofuranos/farmacologia , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Renina/metabolismo , Animais , Benzofuranos/metabolismo , Benzofuranos/uso terapêutico , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Medicina Tradicional Chinesa , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , Simulação de Acoplamento Molecular , Nefrectomia , Fosfoproteínas/metabolismo , Ratos , Ratos Endogâmicos SHR , Renina/antagonistas & inibidores
13.
PLoS One ; 13(8): e0202176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30092100

RESUMO

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.


Assuntos
Benzimidazóis/farmacologia , Fármacos Cardiovasculares/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Morfolinas/farmacologia , Piperidinas/farmacologia , Substâncias Protetoras/farmacologia , Renina/antagonistas & inibidores , Amidas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Fumaratos/farmacologia , Coração/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Hipertrofia/mortalidade , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Pneumopatias/mortalidade , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Distribuição Aleatória , Renina/sangue
14.
Biomed Pharmacother ; 105: 899-906, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021383

RESUMO

Chios mastic gum (CMG) exerts robust anti-inflammatory and antioxidant properties and it affects pathways that are implicated in the pathophysiology of endothelial and vascular inflammation. Aim of this study was to test the hypothesis that CMG administration lowers blood pressure (BP) and improves hypertension-induced target organ damage. 2-kidney, 1-clip (2K1C) hypertensive rats were treated with CMG (40 mg/kg body weight/day) for 2-weeks after the establishment of hypertension. Acute CMG administration lowered systolic, diastolic and mean arterial BP, while these hemodynamic effects were sustained throughout the 2-week administration period. CMG group also exhibited alleviated target organ damage as proposed by amelioration of biomechanical properties of the aorta -including cross-sectional area (CSA), aortic wall stiffness and thickness-, reversal of myocardial small vessel hypertrophy and maintenance of serum albumin levels. The anti-hypertensive effects of CMG are likely to be mediated by the decrease in renin serum levels. Regression analysis indicated that the effect of CMG on organ damage was BP-lowering dependent and was not associated with direct effects of renin or with its anti-inflammatory properties. We suggest a BP lowering effect of CMG via down-regulation of renin excretion associated with attenuation of target organ damage and inflammatory status. These observations provide profound evidence for the beneficial role of CMG in hypertension, which could possibly translate to further clinical research.


Assuntos
Hipertensão Renovascular/tratamento farmacológico , Rim/efeitos dos fármacos , Resina Mástique/uso terapêutico , Renina/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Animais , Hipertensão Renovascular/metabolismo , Rim/metabolismo , Masculino , Resina Mástique/farmacologia , Ratos , Ratos Wistar , Renina/metabolismo , Remodelação Vascular/fisiologia
15.
Kidney Int ; 94(4): 689-700, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29884545

RESUMO

Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.


Assuntos
Amidas/farmacologia , Ativação do Complemento/efeitos dos fármacos , Complemento C3/química , Fumaratos/farmacologia , Glomerulonefrite Membranoproliferativa/metabolismo , Glomerulonefrite Membranoproliferativa/terapia , Renina/química , Amidas/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Criança , Complemento C3/metabolismo , Complemento C3a/química , Complemento C3a/metabolismo , Complemento C3b/química , Complemento C3b/metabolismo , Complemento C4/química , Complemento C5a/química , Complemento C5a/metabolismo , Complemento C5b/química , Complemento C5b/metabolismo , Fator B do Complemento/química , Fator D do Complemento/química , Feminino , Fumaratos/uso terapêutico , Membrana Basal Glomerular/patologia , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Mastócitos/fisiologia , Renina/antagonistas & inibidores , Renina/metabolismo
16.
Bioorg Med Chem ; 26(12): 3261-3286, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29754833

RESUMO

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.


Assuntos
Benzimidazóis/química , Piperidinas/química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Piperidinas/metabolismo , Piperidinas/farmacocinética , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Renina/metabolismo , Relação Estrutura-Atividade
17.
J Clin Pharmacol ; 58(11): 1516-1524, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29733435

RESUMO

Imarikiren hydrochloride (TAK-272/ SCO-272) is a novel direct renin inhibitor. This randomized, double-blind, phase I study evaluated the safety and pharmacokinetics/pharmacodynamics of multiple oral administrations of imarikiren in healthy nonelderly (aged 20-45 years) and elderly (aged 65-85 years) Japanese male subjects. Subjects were randomized within 1 of 3 cohorts to receive imarikiren or placebo: Cohort 1 (imarikiren 80 mg; nonelderly), Cohort 2 (imarikiren 160 mg; nonelderly), or Cohort 3 (imarikiren 80 mg; elderly). Imarikiren or placebo was administered orally, once daily, for 7 days. Accumulation of imarikiren did not occur during the 7-day treatment period. Area under the plasma-concentration time curve and maximum plasma concentration of imarikiren were higher in elderly than in nonelderly subjects (52% and 39% higher, respectively). Inhibition of plasma renin activity was observed for 7 days and was maintained for at least 71 hours after the last imarikiren administration at the 80-mg (nonelderly and elderly) and 160-mg (nonelderly) doses. Plasma active renin concentration increased in nonelderly and elderly subjects; peak concentrations were higher on day 7 than on day 1. Increase from baseline in plasma active renin concentration was smaller in elderly than in nonelderly subjects during the 7-day treatment period and until 71 hours after last imarikiren administration. Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity.


Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Morfolinas/farmacologia , Morfolinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/farmacocinética , Renina/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Benzimidazóis/sangue , Fármacos Cardiovasculares/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Morfolinas/sangue , Piperidinas/sangue
18.
Basic Clin Pharmacol Toxicol ; 123(5): 607-614, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29845723

RESUMO

Imarikiren hydrochloride (TAK-272/SCO-272) is a novel direct renin inhibitor with potential indications for cardiovascular and renal diseases. This phase I study evaluated the pharmacokinetics, pharmacodynamics and safety of a single oral administration of imarikiren in healthy Japanese male subjects. The Dose-Ascending part (double-blind, placebo-controlled, parallel-group design; n = 60) comprised six steps from 5 to 200 mg (n = 8 for imarikiren and n = 2 for placebo per step). The Food Effect part (n = 12) was an open-label, 2 × 2 crossover design with a dose of 50 mg to evaluate the effect of food on the pharmacokinetics and safety of imarikiren. There was a generally linear relationship between dose and area under the plasma concentration-time curve (0 to infinity) or maximum plasma concentration of imarikiren. Food had no clinically significant effect on the exposure of imarikiren. Inhibition of plasma renin activity was rapid and lasted up to 24 hr at all doses. Plasma active renin concentration increased, reaching a maximum at approximately 6 hr, in a nearly dose-dependent manner. Across both study parts, the number of subjects with treatment-emergent adverse events ranged from 0 to 3 per group with no dependency on dose. All treatment-emergent adverse events except two were mild in intensity; there were no serious adverse events or deaths. Single oral administration of imarikiren from 5 to 200 mg was safe and well tolerated. These findings suggest that further clinical development of a once-daily imarikiren regimen is warranted.


Assuntos
Benzimidazóis , Morfolinas , Piperidinas , Renina/antagonistas & inibidores , Administração Oral , Adulto , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Interações Alimento-Droga , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/farmacocinética
19.
Biopharm Drug Dispos ; 39(3): 175-183, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29474740

RESUMO

In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK-272 (SCO-272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK-272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK-272 was highly variable in monkeys. The results of mass balance studies in animals suggested that the absorbed TAK-272 was largely eliminated by metabolism. In vitro studies revealed that TAK-272 was mainly metabolized by CYP3A4/5 in humans, and it was a P-glycoprotein substrate. PK analysis suggested that the factors responsible for the low BA were different in rats and monkeys. First-pass hepatic extraction was high in rats, while the fraction absorbed from the gastrointestinal tract (Fa * Fg ) was low in monkeys. It was predicted that humans would have a higher BA and a longer half-life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and Fa * Fg in rats, which correlates relatively well with human values. TAK-272 was finally selected as a clinical candidate based on the result of human PK prediction. The actual human PK after oral administration of TAK-272 was comparable to the predicted profile and was preferable for clinical usage.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Benzimidazóis/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Morfolinas/farmacocinética , Piperidinas/farmacocinética , Renina/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Disponibilidade Biológica , Isótopos de Carbono/metabolismo , Humanos , Fígado/metabolismo , Macaca fascicularis , Masculino , Morfolinas/administração & dosagem , Morfolinas/metabolismo , Morfolinas/farmacologia , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Especificidade da Espécie
20.
Eur J Pharmacol ; 821: 97-104, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29331564

RESUMO

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.


Assuntos
Amidas/farmacologia , Fumaratos/farmacologia , Hipertensão Renovascular/metabolismo , Losartan/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Renina/antagonistas & inibidores , Angiotensina I/sangue , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Aorta/fisiologia , Sinergismo Farmacológico , Hipertensão Renovascular/sangue , Masculino , Nitritos/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Relaxamento/fisiologia
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