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1.
Life Sci ; 240: 117085, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31759042

RESUMEN

AIMS: Our study was designed to explore the function and mechanism of Tanshinone IIA in alleviating pain syndrome caused by endometriosis (EMs). MAIN METHODS: Female Sprague-Dawley rats went through autotransplantation operation to establish EMs model. The rats were randomly divided into five groups: sham, model, positive, Tanshinone IIA (L) (3 mg/kg/d) and Tanshinone IIA (H) (12 mg/kg/d) group. Volume of ectopic endometrium was measured after 21 days of continuous administration. Serum estradiol (E2) was detected by enzyme linked immunosorbent assay (Elisa). The protein expression of angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), angiotensin II (ANGII) and angiotensin II type 2 receptor (AT2) in the dorsal root ganglion (DRG) neurons were measured by immunohistochemistry and Western Blotting. The mRNA expression levels of AGT and ANGII were measured by Real-time polymerase chain reaction (PCR). KEY FINDINGS: Tissue measurements showed that tanshinone IIA significantly inhibited the growth of ectopic endometrium. Tanshinone IIA could improve the paw withdrawal threshold thus reducing the mechanical hyperalgesia of EMs rats. Moreover, Tanshinone IIA regulated the DRG renin angiotensin system (RAS) by reducing the protein expression of AGT, REN, ACE, ANGII and AT2 in DRG neurons. Furthermore, Real-time PCR results also showed that the mRNA expression levels of AGT and ANGII in the DRG neurons were decreased. SIGNIFICANCE: The Tanshinone IIA inhibitory effect on the EMs associated pain in EMs rats might occur through decreasing the expression of E2, ANGII and AT2, thus halting DRG sprouting and promoting hyperalgesia threshold.


Asunto(s)
/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Axones/patología , Endometriosis/tratamiento farmacológico , Ganglios Espinales/patología , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina II/metabolismo , Animales , Endometriosis/patología , Estradiol/metabolismo , Femenino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Ratas , Ratas Sprague-Dawley
2.
Food Chem ; 308: 125601, 2020 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-31670190

RESUMEN

The aim of this work was to analyse the hypotensive effect of amaranth protein/peptides on spontaneously hypertensive rats (SHR). The mechanism of action of these peptides was studied in vivo and ex vivo. We also tested the effect of protection against gastrointestinal digestion (GID) exerted by an O:W emulsion on the integrity of the antihypertensive peptides. All samples tested produced a decrease in blood pressure (SBP). The animals treated with emulsion (GE) and emulsion + peptide (GE+VIKP) showed the most significant reduction in the SBP (42 ±â€¯2 mmHg and 35 ±â€¯2 mmHg, respectively). The results presented suggest that after GID, a variety of peptides with biological activities were released or were resistant to this process. These peptides play a role in the regulation of the SBP by acting on plasma ACE, plasma renin and the vascular system. These results support the use of amaranth protein/peptides in the elaboration of functional foods for hypertensive individuals.


Asunto(s)
Amaranthus/química , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Péptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Masculino , Péptidos/uso terapéutico , Proteínas de Plantas/farmacología , Proteínas de Plantas/uso terapéutico , Ratas , Ratas Endogámicas SHR
3.
Medicine (Baltimore) ; 98(49): e17963, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31804307

RESUMEN

Renin angiotensin aldosterone system inhibitors (RAASi) and diuretics are among the most frequently prescribed anti-hypertensives. Individuals with chronic kidney disease (CKD) are particularly at risk for electrolyte disturbances and kidney injury but the appropriate use of lab monitoring following RAASi or diuretic initiation is uncertain in CKD.We describe the frequency and time interval of lab monitoring during initiation of RAASi and diuretics in CKD and assess whether close lab monitoring associates with one-year risk of emergency department (ED) visit or hospitalization.We evaluated an observational cohort of 8,217 individuals with stage 3-5 non-dialysis CKD newly prescribed a RAASi (52.3%) or diuretic (47.7%) from thirty-six primary care offices affiliated with Brigham and Women's Hospital and Massachusetts General Hospital between 2009 and 2011.Overall, 3306 (40.2%) individuals did not have pre-prescription labs done within 2 weeks, and 5957 (72.5%) did not have post-prescription labs done within 2 weeks which includes 524 (6.4%) individuals without post-prescription within 1 year. Close monitoring occurred in only 1547 (20.1%) and was more likely in individuals prescribed diuretics compared to RAASi (adjusted OR 1.39; 95%CI 1.20-1.62), with CKD stage 4,5 compared with stage 3 (adjusted OR 1.47; 95%CI 1.16-1.86) and with cardiovascular disease (adjusted OR 1.42; 95%CI 1.21-1.66). Close monitoring was not associated with decreased risk of ED visit or hospitalization.Close lab monitoring during initiation of RAASi or diuretics was more common in participants with cardiovascular disease and advanced CKD suggesting physicians selected high-risk individuals for close monitoring. As nearly 80% of individuals did not receive close lab monitoring there may be value in future research on electronic physician decision tools targeted at lab monitoring.


Asunto(s)
Atención Ambulatoria/estadística & datos numéricos , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Pruebas de Función Renal/estadística & datos numéricos , Insuficiencia Renal Crónica/epidemiología , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Boston , Comorbilidad , Diuréticos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Potasio/sangre , Sistema Renina-Angiotensina/efectos de los fármacos , Índice de Severidad de la Enfermedad , Factores Socioeconómicos
4.
Rev Cardiovasc Med ; 20(3): 111-120, 2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31601085

RESUMEN

Randomized controlled trials have demonstrated the benefits of guideline-directed medical therapy in the outpatient setting for treatment of chronic heart failure. However, the benefits of continuation (or discontinuation) of major chronic heart failure therapies when treating acute heart failure during hospitalization are less clear. Real and anticipated worsening renal function, hyperkalemia and hypotension are the three major reasons for discontinuation of renin-angiotensin-aldosterone system inhibitors during hospitalization, and a failure to resume renin-angiotensin-aldosterone system inhibitors before discharge could worsen cardiovascular outcomes. Available data, mostly observational, shows that continuation or initiation of renin-angiotensin-aldosterone system inhibitors appears efficacious, safe, and well tolerated in majority of acute heart failure patients during hospitalization. Worsening renal function portends poor prognosis only if associated with congestion in acute heart failure, and clinicians should not de-escalate diuretic therapy routinely for worsening renal function.


Asunto(s)
Antagonistas de Receptores de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Síndrome Cardiorrenal/tratamiento farmacológico , Diuréticos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Admisión del Paciente , Sistema Renina-Angiotensina/efectos de los fármacos , Antagonistas de Receptores de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/mortalidad , Síndrome Cardiorrenal/fisiopatología , Toma de Decisiones Clínicas , Diuréticos/efectos adversos , Esquema de Medicación , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Humanos , Factores de Riesgo , Resultado del Tratamiento
5.
Hypertension ; 74(5): 1181-1191, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31564162

RESUMEN

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.


Asunto(s)
Proteína ADAM17/metabolismo , Angiotensina II/farmacología , Hipertensión/fisiopatología , Núcleo Hipotalámico Paraventricular/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina/genética , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiopatología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Hipertensión/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Optogenética/métodos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/patología , Distribución Aleatoria , Sistema Renina-Angiotensina/efectos de los fármacos
6.
Endocrinology ; 160(12): 2787-2799, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31593246

RESUMEN

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.


Asunto(s)
Receptor del Péptido 1 Similar al Glucagón/agonistas , Hiperandrogenismo/complicaciones , Liraglutida/uso terapéutico , Síndrome Metabólico/prevención & control , Síndrome del Ovario Poliquístico/complicaciones , Animales , Presión Sanguínea/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Resistencia a la Insulina , Leptina/sangre , Lípidos/sangre , Liraglutida/farmacología , Síndrome Metabólico/etiología , Posmenopausia , Distribución Aleatoria , Ratas Sprague-Dawley , Sistema Renina-Angiotensina/efectos de los fármacos
7.
Anticancer Res ; 39(9): 4597-4602, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31519556

RESUMEN

Our previous review of the literature assessed the existing knowledge (until 2000) about the possible link between angiotensin-converting enzyme inhibitors (ACEIs) and factors influencing the development of malignancies. We reviewed the literature for reports of statistical associations (or lack thereof) between ACEi treatment and incidence of specific cancers (e.g. breast, gastrointestinal, and skin). We concluded then that results from the epidemiological studies are conflicting, even taking the different methodology and endpoints into consideration, and thus inconclusive. Further investigation is needed beyond the observation period of most of these studies, and additional experimental studies are needed also to study the mechanisms by which agents blocking the renin-angiotensin system may obtain their inhibitory effect on tumor growth and metastasis. The present review elaborates further with more recent evidence from numerous human clinical studies from the past two decades (including large epidemiological studies, and long-term prospective and retrospective studies) on a protective association between ACEi treatment and the prognosis of patients with specific cancer types, malignancy characteristics or stage. Moreover, treatment with ACEI/angiotensin receptor blockers represents an adjuvant therapy with synergistic effects to chemotherapy and may improve patient outcomes (i.e. progression-free survival, and prolonged overall survival) in different types of cancers.


Asunto(s)
Neoplasias/metabolismo , Neoplasias/mortalidad , Sistema Renina-Angiotensina/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Clínicos como Asunto , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/etiología , Pronóstico , Resultado del Tratamiento
8.
Nat Commun ; 10(1): 4202, 2019 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-31519895

RESUMEN

It remains disputable about perioperative use of renin-angiotensin system inhibitors (RASi) and their outcome effects. This multicenter retrospective cohort study examines association between use of perioperative RASi and outcomes in patients undergoing coronary artery bypass graft and/or valve surgery. After the exclusion, the patients are divided into 2 groups with or without preoperative RASi (PreRASi, n = 8581), or 2 groups with or without postoperative RASi (PostRASi, n = 8130). With using of propensity scores matching to reduce treatment selection bias, the study shows that PreRASi is associated with a significant reduction in postoperative 30-day mortality compared with without one (3.41% vs. 5.02%); PostRASi is associated with reduced long-term mortality rate compared with without one (6.62% vs. 7.70% at 2-year; 17.09% vs. 19.95% at 6-year). The results suggest that perioperative use of RASi has a significant benefit for the postoperative and long-term survival among patients undergoing cardiac surgery.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Atención Perioperativa , Sistema Renina-Angiotensina/efectos de los fármacos , Anciano , Antagonistas de Receptores de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Puente de Arteria Coronaria , Femenino , Válvulas Cardíacas/cirugía , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
9.
Cell Physiol Biochem ; 53(4): 587-605, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31535830

RESUMEN

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.


Asunto(s)
Riñón/metabolismo , Miocardio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervioso Simpático/metabolismo , Animales , Atenolol/farmacología , Atenolol/uso terapéutico , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacología , Enalapril/uso terapéutico , Interleucina-6/metabolismo , Losartán/farmacología , Losartán/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Sistema Nervioso Simpático/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Vimentina/genética , Vimentina/metabolismo
10.
Pharmacol Rev ; 71(4): 539-570, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31537750

RESUMEN

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure-regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión/fisiopatología , Terapia Molecular Dirigida
11.
Biol Pharm Bull ; 42(9): 1482-1490, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31474709

RESUMEN

Zhengganxifeng decoction (ZGXFD) is a traditional Chinese medicinal formula, from "Medical Zhong parameter West recorded" by Xichun Zhang, which has been applied to the treatment of clinical essential hypertension. Besides its effect in blood pressure reduction, ZGXFD is also known to be a radical therapy with little or no side effects. Compared with western medicines, Chinese medicinal formulas have the advantage of simultaneously attacking multiple targets. However, such a property brings trouble to the pharmacological studies of Chinese medicines. This study investigated the composition of gut microbiota in spontaneously hypertensive rats (SHR) treated with ZGXFD. ZGXFD was shown to cause similar effects in the treatment group as benazepril: both were able to reduce in SHR the microbial diversity, Firmicutes to Bacteroidetes (F/B) ratio and coccus to bacillus (C/B) ratio. Meanwhile, ZGXFD can maintain the integrity of intestinal mechanistic barrier and elevate the percentage of bacteria producing short chain fatty acids (SCFA). By investigating renin-angiotensin system (RAS) system, we found that ZGXFD can decrease the expression of angiotensin-converting-enzyme (ACE) in lungs, which in turn causes a increase in AngI produces angiotensin1-7 (Ang1-7) and decrease in AngII. ZGXFD regulate blood pressure in SHR via RAS.


Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal/fisiología , Hipertensión/microbiología , Ratas Endogámicas SHR , Ratas Endogámicas WKY
12.
Ther Adv Cardiovasc Dis ; 13: 1753944719868134, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31401939

RESUMEN

Since the launch of the first orally available angiotensin II (AngII) type 1 receptor (AT1R) blocker (ARB) losartan (Cozaar) in the late 1990s, the class of ARBs (or 'sartans', short for Angiotensin-RecepTor-ANtagonistS) quickly expanded to include candesartan, eprosartan, irbesartan, valsartan, telmisartan, and olmesartan. All ARBs have high affinity for the AT1 receptor, expressed in various tissues, including smooth muscle cells, heart, kidney, and brain. Since activation of AT1R, the target of these drugs, leads, among other effects, to vascular smooth muscle cell growth, proliferation and contraction, activation of fibroblasts, cardiac hypertrophy, aldosterone secretion from the adrenal cortex, thirst-fluid intake (hypervolemia), etc., the ARBs are nowadays one of the most useful cardiovascular drug classes used in clinical practice. However, significant differences in their pharmacological and clinical properties exist that may favor use of particular agents over others within the class, and, in fact, two of these drugs, candesartan and valsartan, continuously appear to distinguish themselves from the rest of the 'pack' in recent clinical trials. The reason(s) for the potential superiority of these two agents within the ARB class are currently unclear but under intense investigation. The present short review gives an overview of the clinical properties of the ARBs currently approved by the United States Food and Drug Administration, with a particular focus on candesartan and valsartan and the areas where these two drugs seem to have a therapeutic edge. In the second part of our review, we outline recent data from our laboratory (mainly) on the molecular effects of the ARB drugs on aldosterone production and on circulating aldosterone levels, which may underlie (at least in part) the apparent clinical superiority of candesartan (and valsartan) over most other ARBs currently in clinical use.


Asunto(s)
Aldosterona/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bencimidazoles/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Tetrazoles/uso terapéutico , Valsartán/uso terapéutico , Animales , Biomarcadores/sangre , Regulación hacia Abajo , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Recuperación de la Función , Resultado del Tratamiento
13.
Oxid Med Cell Longev ; 2019: 5868935, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31396301

RESUMEN

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPßCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPßCD) or HPßCD/Ang-(1-7) in the last 6 weeks. FAT-HPßCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPßCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPßCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.


Asunto(s)
Angiotensina I/farmacología , Antioxidantes/farmacología , Síndrome Metabólico/patología , Fragmentos de Péptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Catalasa/genética , Catalasa/metabolismo , Ciclodextrinas/farmacología , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Insulina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/veterinaria , Músculo Esquelético/metabolismo , Estrés Oxidativo/efectos de los fármacos , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Ratas , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo
14.
Curr Top Med Chem ; 19(20): 1850-1866, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31448711

RESUMEN

Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin-Angiotensin-Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Péptidos Natriuréticos/farmacología , Animales , Inhibidores Enzimáticos/metabolismo , Insuficiencia Cardíaca/metabolismo , Humanos , Péptidos Natriuréticos/metabolismo , Neprilisina/antagonistas & inhibidores , Neprilisina/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos
15.
Eur J Pharmacol ; 860: 172585, 2019 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-31376367

RESUMEN

We previously reported that neonatal blockade of angiotensin II AT1 receptor prevents cardiac changes in 4 weeks rats with neonatal hyperoxia-induced cardiomyopathy, a recognized model of prematurity-related deleterious conditions. Considering the importance of AT1 receptor and the renin angiotensin system (RAS) in normal development, the present study aimed to investigate the adult effects of neonatal AT1 blockade on left ventricle (LV) in rats exposed to neonatal hyperoxia. Sprague-Dawley pups were exposed to 80% O2 or room air from days 3-10. AT1 blocker (losartan) or H2O were given by gavage from day 8-10. LV function (echo and intraventricular pressure), histology and expression of RAS components were examined in 15-16 weeks old adult males. Losartan treatment prevented myocardial fibrosis, LV wall thickening and stroke volume reduction in rats exposed to high O2 in the neonatal period. However, Losartan treatment of O2-exposed pups led to reduced ejection fraction (EF) and fractional shortening (FS), and did not prevent changes in diastolic function. Losartan also did not prevent increased LV AT2 and decreased angiotensin-(1-7) Mas receptors expression observed in high O2-exposed rats. Neonatal Losartan attenuated long-term impact of neonatal hyperoxia but also led to decreased EF and FS. Increased AT2 and decreased Mas receptor expression observed in O2-exposed group were unaffected by Losartan treatment. Our results show that early life Losartan treatment aimed at preventing cardiac consequences of neonatal deleterious conditions may also comprise detrimental effects that require further investigation prior to clinical translation in developing children.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Corazón/efectos de los fármacos , Oxígeno/efectos adversos , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Diástole/efectos de los fármacos , Modelos Animales de Enfermedad , Fibrosis , Corazón/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Losartán/farmacología , Miocardio/patología , Ratas , Ratas Sprague-Dawley , Sístole/efectos de los fármacos , Factores de Tiempo
16.
Adv Exp Med Biol ; 1165: 671-691, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31399990

RESUMEN

The rennin-angiotensin-aldosterone system (RAAS) has been well documented in regulating blood pressure, fluid volume, and sodium balance. Overactivity of RAAS promotes both systemic and regional glomerular capillary hypertension, which could induce hemodynamic injury to the glomerulus, leading to kidney damage and renal fibrosis via profibrotic and proinflammatory pathway. Therefore, the use of RAAS inhibitors (i.e., ACEIs, ARBs, and MRAs) as the optional therapy has been demonstrated to prevent proteinuria, and kidney fibrosis and slow the decline of renal function effectively in the process of kidney disease during the last few decades. Recently, several new components of the RAAS have been discovered, including ACE2 and the corresponding ACE2/Ang (1-7)/Mas axis, which are also present in the kidney. Besides the classic RAAS inhibitors target the angiotensin-AT1-aldosterone axis, with the expanding knowledge about RAAS, a number of potential therapeutic targets in this system is emerging. Newer agents that are more specific are being developed. The present chapter outlines the insights of the RAAS agents (classic RAAS antagonists/the new RAAS drugs), and discusses its clinical application in the combat of renal fibrosis.


Asunto(s)
Sistema Renina-Angiotensina/efectos de los fármacos , Aldosterona , Angiotensina I , Presión Sanguínea , Humanos , Hipertensión , Antagonistas de Receptores de Mineralocorticoides
17.
Adv Exp Med Biol ; 1155: 45-59, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31468385

RESUMEN

Previous studies indicate that perinatal compromise of taurine causes cardiovascular disorders in adults via the influence of taurine on renin-angiotensin system (RAS). This study tested whether perinatal inhibition of the RAS would itself alter the adult cardiovascular system in a similar way. Female Sprague-Dawley rats were fed normal rat chow and given water alone (Control) or water containing captopril (400 mg/l) from conception until weaning. Then, the male offspring drank water or water containing captopril until 5 weeks of age followed by normal rat chow and water alone until 7 weeks of age. Thereafter, they drank water alone (Control, Captopril) or 1% NaCl solution (Control+1%, Captopril+1%). At 9 weeks of age, all animals were implanted with femoral arterial and venous catheters. Forty-eight hours later, blood chemistry, glucose tolerance, and hemodynamic parameters were determined in freely moving conscious rats. Then, the same experiments were repeated 2 days after captopril treatment. Body weights, kidney and heart to body weight ratios, fasting and non-fasting blood sugar, glucose tolerance, and heart rates were not significantly different among groups. Further, plasma sodium, mean arterial pressure, and sympathetic activity significantly increased whereas baroreflex sensitivity decreased in Captopril+1% compared to other groups. These changes were normalized by acute captopril treatment and the arterial pressure differences also by acute ganglionic and central adrenergic blockade. The present study suggests that inhibition of the RAS in the early life induces RAS overactivity, leading to salt-sensitive hypertension via sympathetic nervous system overactivity and depressed baroreflex sensitivity in adult male rats.


Asunto(s)
Captopril/farmacología , Hipertensión/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina II , Animales , Barorreflejo , Presión Sanguínea , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio Dietético
18.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31443094

RESUMEN

Urocortin 2 (Ucn2) - corticotropin-releasing hormone receptor 2 signalling has favourable effects in the cardiovascular system, including vasodilation, lowering of blood pressure and systemic peripheral resistance, increase in cardiac output and cardiac contractility, as well as cardioprotection against ischemia-reperfusion injury. Vasodilation and lowering of blood pressure seem to be very interesting and important effects, but their mechanism and interaction with the antihypertensive drugs have not been evaluated. The aim of the present study was to assess the relationship between Ucn2 concentration and antihypertensive therapy in patients with primary hypertension. We examined a group of 65 patients with primary hypertension receiving at least 3 antihypertensive drugs. In all of them plasma level of Ucn2, anthropometric measurements, biochemical tests, ambulatory blood pressure monitoring (ABPM), and echocardiography were performed. There were no differences in Ucn2 level related to beta-blockers, calcium channel blockers or diuretics, but we observed that in patients treated with angiotensin converting enzyme inhibitors (ACEI) (n = 52) serum Ucn2 levels were significantly higher than in patients treated with angiotensin-receptor blockers (ARBs) (n = 13) (10.93 versus 5.56 ng/mL; P < 0.05). Moreover, we did not observe any differences in terms of blood pressure on ABPM, biochemical measurements, left ventricular mass index, or presence of diabetes. In addition, in a small subgroup receiving alpha-blockers we also found a lower level of Ucn2, with coexisting higher systolic blood pressure at night, higher left ventricle mass index (LVMI) and more frequent occurrences of diabetes compared to non-alpha-blockers. Our findings suggest that the hypotensive action of renin-angiotensin-aldosterone system blockade may be related to the urocortin system. Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hormona Liberadora de Corticotropina/metabolismo , Hipertensión/tratamiento farmacológico , Urocortinas/metabolismo , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial/métodos , Bloqueadores de los Canales de Calcio/uso terapéutico , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos
19.
Curr Protein Pept Sci ; 20(10): 984-995, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31389312

RESUMEN

Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis. But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflammation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention. Hypertension is a disease with high incidence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vascular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with increased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly raise BP and promote target organ damage. Due to the high correlation between vitamin D and hypertension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage.


Asunto(s)
Antihipertensivos , Hipertensión/tratamiento farmacológico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacología , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inhibidores , Sistema Renina-Angiotensina/efectos de los fármacos
20.
Eur J Med Chem ; 179: 623-633, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31279295

RESUMEN

Fibrosis is a final pathological feature of many chronic diseases, but few interventions are available that specifically target the pathogenesis of fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. The renin-angiotensin system (RAS) plays a central physiological role in the control of blood pressure and fluid homeostasis. Emerging evidence has revealed that activation of RAS was consistently found in fibrotic tissue. At the same time, as more components of the RAS are described, other pot Potential therapeutic targets emerge, so it seems sensible to revisit the contribution of RAS in anti-fibrotic therapy. So far, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are the main commercial available drugs for intervening RAS. However, RAS inhibitors had lots of limitations in long-term application owing to occurring AngII and aldosterone escape. Over the past decades, natural products have aroused growing attention as potential RAS inhibitors due to their high efficacy and low risk of side effects. In this review, we revisit the contribution of RAS and its new members to anti-fibrotic therapy. Ultimately, we summarize and evaluate the use of natural products including isolated compounds, crude extracts and traditional Chinese herbal formulas to regulate RAS. These natural products can retard tissue fibrosis by targeting different RAS components, which provide us new therapeutic strategies to discover anti-fibrotic drugs.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Productos Biológicos/farmacología , Fibrosis/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Productos Biológicos/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad
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