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[PMID]:28461598
[Au] Autor:Mirabito Colafella KM; Danser AHJ
[Ad] Endereço:From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands (K.M.M.C., A.H.J.D.); and Cardiovascular Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Australia (K.M.M.C.).
[Ti] Título:Recent Advances in Angiotensin Research.
[So] Source:Hypertension;69(6):994-999, 2017 06.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Angiotensinas/metabolismo
Encéfalo/metabolismo
Hipertensão/metabolismo
Rim/metabolismo
Receptores de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Masculino
Gravidez
Sistema Renina-Angiotensina/fisiologia
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Angiotensins); 0 (Receptors, Angiotensin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.08931


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[PMID]:29059221
[Au] Autor:Stilhano RS; Samoto VY; Silva LM; Pereira GJ; Erustes AG; Smaili SS; Won Han S
[Ad] Endereço:Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
[Ti] Título:Reduction in skeletal muscle fibrosis of spontaneously hypertensive rats after laceration by microRNA targeting angiotensin II receptor.
[So] Source:PLoS One;12(10):e0186719, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Regeneration of injured skeletal muscles is affected by fibrosis, which can be improved by the administration of angiotensin II (AngII) receptor (ATR) blockers in normotensive animals. However, the role of ATR in skeletal muscle fibrosis in hypertensive organisms has not been investigated yet. The tibialis anterior (TA) muscle of spontaneously hypertensive (SHR) and Wistar rats (WR) were lacerated and a lentivector encoding a microRNA targeting AngII receptor type 1 (At1) (Lv-mirAT1a) or control (Lv-mirCTL) was injected. The TA muscles were collected after 30 days to evaluate fibrosis by histology and gene expression by real-time quantitative PCR (RT-qPCR) and Western blot. SHR's myoblasts were analyzed by RT-qPCR, 48 h after transduction. In the SHR's TA, AT1 protein expression was 23.5-fold higher than in WR without injury, but no difference was observed in the angiotensin II receptor type 2 (AT2) protein expression. TA laceration followed by suture (LS) produced fibrosis in the SHR (23.3±8.5%) and WR (7.9±1.5%). Lv-mirAT1 treatment decreased At1 gene expression in 50% and reduced fibrosis to 7% 30 days after. RT-qPCR showed that reduction in At1 expression is due to downregulation of the At1a but not of the At1b. RT-qPCR of myoblasts from SHR transduced with Lv-mirAT1a showed downregulation of the Tgf-b1, Tgf-b2, Smad3, Col1a1, and Col3a1 genes by mirAT1a. In vivo and in vitro studies indicate that hypertension overproduces skeletal muscle fibrosis, and AngII-AT1a signaling is the main pathway of fibrosis in SHR. Moreover, muscle fibrosis can be treated specifically by in loco injection of Lv-mirAT1a without affecting other organs.
[Mh] Termos MeSH primário: MicroRNAs/genética
Músculo Esquelético/patologia
Receptores de Angiotensina/genética
[Mh] Termos MeSH secundário: Animais
Regulação para Baixo
Fibrose
Perfilação da Expressão Gênica
Ratos
Ratos Endogâmicos SHR
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MicroRNAs); 0 (Receptors, Angiotensin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171024
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186719


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[PMID]:28870804
[Au] Autor:Zha D; Cheng H; Li W; Wu Y; Li X; Zhang L; Feng YH; Wu X
[Ad] Endereço:Division of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China.
[Ti] Título:High glucose instigates tubulointerstitial injury by stimulating hetero-dimerization of adiponectin and angiotensin II receptors.
[So] Source:Biochem Biophys Res Commun;493(1):840-846, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Abnormal expression and dysfunction of adiponectin and the cognate receptors are involved in diabetes and diabetic kidney disease (DKD), whereas angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) alleviate diabetic albuminuria and prevent development of DKD through upregulation of adiponectin expression. Here we report that high glucose stimulates expression of angiotensin II (AngII) receptors (AT1 and AT2) in renal proximal tubular epithelial cells (NRK-52E). These receptors underwent hetero-dimerization with adiponectin receptor AdipoR1 and AdipoR2, respectively. High glucose inhibited the dimerization between AT1 and AT2. Interestingly, these hetero-dimers instigated tubulointerstitial injury by inhibiting the cytoprotective action of the adiponectin receptors. These modes of receptor-receptor hetero-dimerization may contribute to high glucose-induced renal tubulointerstitial injury and could be potential therapeutic targets.
[Mh] Termos MeSH primário: Nefropatias Diabéticas/metabolismo
Glucose/metabolismo
Nefrite Intersticial/metabolismo
Receptores de Adiponectina/metabolismo
Receptores de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Dimerização
Ligação Proteica
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Adiponectin); 0 (Receptors, Angiotensin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28719636
[Au] Autor:Alshahrani S; Rapoport RM; Zahedi K; Jiang M; Nieman M; Barone S; Meredith AL; Lorenz JN; Rubinstein J; Soleimani M
[Ad] Endereço:Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America.
[Ti] Título:The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states.
[So] Source:PLoS One;12(7):e0181376, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides. Thus, a vasodilator action of thiazides is proposed, likely via Ca2+-activated K+ (BK) channels in vascular smooth muscles. This study ascertains the role of volume depletion induced by salt restriction or salt wasting in NCC KO mice on the non-diuretic hypotensive action of HCTZ. HCTZ (20mg/kg s.c.) lowered BP in 1) NCC KO on a salt restricted diet but not with normal diet; 2) in volume depleted but not in volume resuscitated pendrin/NCC dKO mice; the BP reduction occurs without any enhancement in salt excretion or reduction in cardiac output. HCTZ still lowered BP following treatment of NCC KO on salt restricted diet with paxilline (8 mg/kg, i.p.), a BK channel blocker, and in BK KO and BK/NCC dKO mice on salt restricted diet. In aortic rings from NCC KO mice on normal and low salt diet, HCTZ did not alter and minimally decreased maximal phenylephrine contraction, respectively, while contractile sensitivity remained unchanged. These results demonstrate 1) the non-diuretic hypotensive effects of thiazides are augmented with volume depletion and 2) that the BP reduction is likely the result of HCTZ inhibition of vasoconstriction through a pathway dependent on factors present in vivo, is unrelated to BK channel activation, and involves processes associated with intravascular volume depletion.
[Mh] Termos MeSH primário: Anti-Hipertensivos/farmacologia
Hidroclorotiazida/farmacologia
Hipovolemia/fisiopatologia
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Angiotensina/farmacologia
Animais
Pressão Sanguínea/efeitos dos fármacos
Débito Cardíaco/efeitos dos fármacos
Dieta Hipossódica
Hipovolemia/metabolismo
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo
Camundongos
Receptores de Angiotensina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin Receptor Antagonists); 0 (Antihypertensive Agents); 0 (Large-Conductance Calcium-Activated Potassium Channels); 0 (Receptors, Angiotensin); 0J48LPH2TH (Hydrochlorothiazide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181376


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[PMID]:28515172
[Au] Autor:Wang L; Song J; Wang S; Buggs J; Chen R; Zhang J; Wang L; Rong S; Li W; Wei J; Liu R
[Ad] Endereço:Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida; leiwang@health.usf.edu.
[Ti] Título:Cross-sex transplantation alters gene expression and enhances inflammatory response in the transplanted kidneys.
[So] Source:Am J Physiol Renal Physiol;313(2):F326-F338, 2017 Aug 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kidney transplantation (KTX) is a life-saving procedure for patients with end-stage renal disease. Expression levels of many genes in the kidney vary between males and females, which may play an essential role in the sex differences in graft function. However, whether these differences are affected after cross-sex-KTX is unknown. In the present study, we assessed postoperative changes in genotype, function, and inflammatory responses of the grafts in same-sex- and cross-sex-KTX. Single kidney transplants were performed between same and different sex C57BL/6 mice paired into four combination groups: female donor/female recipient (F/F); male donor/male recipient (M/M); female donor/male recipient (F/M); and male donor/female recipient (M/F). The remnant native kidney was removed 4 days posttransplant. Expression levels of genes related to the contractility of the afferent arteriole and tubular sodium reabsorption were assessed. Same-sex-KTX did not significantly alter the magnitude or sex difference pattern of gene expression in male or female grafts. Cross-sex-KTX showed an attenuated sex difference in gene expressions. The measurements of endothelin 1, endothelin ET receptor, Na -K -2Cl cotransporter 2 (NKCC2), and epithelial Na channels (ENaC) subunits exhibited decreases in M/F compared with M/M and increases in F/M compared with F/F. There were no significant differences in hemodynamics or sodium excretion in response to acute volume expansion for any sex combinations. Cross-sex-KTX stimulated more robust inflammatory responses than same-sex-KTX. IL-6 and KC mRNA levels elevated 5- to 20-fold in cross-sex-KTX compared with same-sex-KTX. In conclusion, cross-sex-KTX alters gene expression levels and induces inflammatory responses, which might play an important role in long-term graft function.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Transplante de Rim/efeitos adversos
Rim/metabolismo
Rim/cirurgia
Nefrite/genética
[Mh] Termos MeSH secundário: Animais
Endotelina-1/genética
Endotelina-1/metabolismo
Canais Epiteliais de Sódio/genética
Canais Epiteliais de Sódio/metabolismo
Feminino
Interação Gene-Ambiente
Genótipo
Hemodinâmica
Mediadores da Inflamação/metabolismo
Rim/irrigação sanguínea
Rim/patologia
Masculino
Camundongos Endogâmicos C57BL
Modelos Animais
Nefrite/metabolismo
Nefrite/patologia
Nefrite/fisiopatologia
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptores de Angiotensina/genética
Receptores de Angiotensina/metabolismo
Receptores de Endotelina/genética
Receptores de Endotelina/metabolismo
Circulação Renal
Eliminação Renal
Fatores Sexuais
Sódio/metabolismo
Trocador 3 de Sódio-Hidrogênio
Trocadores de Sódio-Hidrogênio/genética
Trocadores de Sódio-Hidrogênio/metabolismo
Membro 1 da Família 12 de Carreador de Soluto/genética
Membro 1 da Família 12 de Carreador de Soluto/metabolismo
Membro 3 da Família 12 de Carreador de Soluto/genética
Membro 3 da Família 12 de Carreador de Soluto/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin-1); 0 (Epithelial Sodium Channels); 0 (Inflammation Mediators); 0 (RNA, Messenger); 0 (Receptors, Angiotensin); 0 (Receptors, Endothelin); 0 (Slc12a1 protein, mouse); 0 (Slc12a3 protein, mouse); 0 (Sodium-Hydrogen Exchanger 3); 0 (Sodium-Hydrogen Exchangers); 0 (Solute Carrier Family 12, Member 1); 0 (Solute Carrier Family 12, Member 3); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00039.2017


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[PMID]:28501115
[Au] Autor:Wang ZF; Wang NP; Harmouche S; Philip T; Pang XF; Bai F; Zhao ZQ
[Ad] Endereço:Department of Otolaryngology, First Affiliated Hospital of Sun Yat-Sen University, Guang Zhou, P. R. China.
[Ti] Título:Postconditioning attenuates coronary perivascular and interstitial fibrosis through modulating angiotensin II receptors and angiotensin-converting enzyme 2 after myocardial infarction.
[So] Source:J Surg Res;211:178-190, 2017 May 01.
[Is] ISSN:1095-8673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Postconditioning (Postcon) is known to reduce infarct size. This study tested the hypothesis that Postcon attenuates the perivascular and interstitial fibrosis after myocardial infarction through modulating angiotensin II-activated fibrotic cascade. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to 45-min coronary occlusion followed by 1 and 6 wk of reperfusion. Postcon was applied at the onset of reperfusion with four cycles of 10/10-s reperfusion-ischemia at the onset of reperfusion. Preconditioning (Precon) with two cycles of 5/5-min ischemia-reperfusion was applied before coronary occlusion. RESULTS: Postcon reduced angiotensin-converting enzyme protein and expression in the perivascular area and intermyocardium, coincident with the less-expressed angiotensin II receptor, type 1, enhanced angiotensin II receptor, type 2, and angiotensin converting enzyme 2. Postcon lowered the monocyte chemoattractant protein-1 and inhibited the populations of interstitial macrophages (60 ± 12 versus 84 ± 9.5 number per high-powered field [HPF] in control, P < 0.05). Along with these modulations, Postcon also downregulated transforming growth factor ß1 protein and inhibited proliferation of α-smooth muscle actin expressing myofibroblasts (41 ± 11 versus 79 ± 8.2 number per HPF in control, P < 0.05), consistent with downregulated phospho-Smad2 and phospho-Smad3. Furthermore, the synthesis of collagen I and III was attenuated, and the perivascular-interstitial fibrosis was inhibited by Postcon as demonstrated by reduced perivascular fibrosis ratio (0.6 ± 0.6 versus 1.6 ± 0.5 per HPF in control, P < 0.05) and smaller collagen-rich area (16 ± 4.7 versus 34 ± 9.2% per HPF in control, P < 0.05). Precon conferred a comparable level of protection as Postcon did in all parameters measured, suggesting protection trigged by this endogenous stimulation can be achieved when it was applied either before ischemia or after reperfusion. CONCLUSIONS: These results suggest that Postcon could be selected as an adjunctive intervention with other existing therapeutic drugs to treat the fibrosis-derived heart failure patients after myocardial infarction.
[Mh] Termos MeSH primário: Pós-Condicionamento Isquêmico/métodos
Infarto do Miocárdio/terapia
Traumatismo por Reperfusão Miocárdica/prevenção & controle
Miocárdio/patologia
Peptidil Dipeptidase A/metabolismo
Receptores de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Fibrose/etiologia
Fibrose/metabolismo
Fibrose/prevenção & controle
Masculino
Infarto do Miocárdio/metabolismo
Infarto do Miocárdio/patologia
Traumatismo por Reperfusão Miocárdica/metabolismo
Traumatismo por Reperfusão Miocárdica/patologia
Miocárdio/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor Tipo 1 de Angiotensina/metabolismo
Receptor Tipo 2 de Angiotensina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Receptor, Angiotensin, Type 1); 0 (Receptor, Angiotensin, Type 2); 0 (Receptors, Angiotensin); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170515
[St] Status:MEDLINE


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[PMID]:28476949
[Au] Autor:Royea J; Zhang L; Tong XK; Hamel E
[Ad] Endereço:Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada H3A 2B4.
[Ti] Título:Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer's Disease.
[So] Source:J Neurosci;37(22):5562-5573, 2017 May 31.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The use of angiotensin receptor blockers (ARBs) correlates with reduced onset and progression of Alzheimer's disease (AD). The mechanism depicting how ARBs such as losartan restore cerebrovascular and cognitive deficits in AD is unknown. Here, we propose a mechanism underlying losartan's benefits by selectively blocking the effects of angiotensin IV (AngIV) at its receptor (AT4R) with divalinal in mice overexpressing the AD-related Swedish and Indiana mutations of the human amyloid precursor protein (APP mice) and WT mice. Young (3-month-old) mice were treated with losartan (∼10 mg/kg/d, 4 months), followed by intracerebroventricular administration of vehicle or divalinal in the final month of treatment. Spatial learning and memory were assessed using Morris water mazes at 3 and 4 months of losartan treatment. Cerebrovascular reactivity and whisker-evoked neurovascular coupling responses were measured at end point (∼7 months of age), together with biomarkers related to neuronal and vascular oxidative stress (superoxide dismutase-2), neuroinflammation (astroglial and microglial activation), neurogenesis (BrdU-labeled newborn cells), and amyloidosis [soluble amyloid-ß (Aß) species and Aß plaque load]. Divalinal countered losartan's capacity to rescue spatial learning and memory and blocked losartan's benefits on dilatory function and baseline nitric oxide bioavailability. Divalinal reverted losartan's anti-inflammatory effects, but failed to modify losartan-mediated reductions in oxidative stress. Neither losartan nor divalinal affected arterial blood pressure or significantly altered the amyloid pathology in APP mice. Our findings identify activation of the AngIV/AT4R cascade as the underlying mechanism in losartan's benefits and a target that could restore Aß-related cognitive and cerebrovascular deficits in AD. Antihypertensive medications that target the renin angiotensin system, such as angiotensin receptor blockers (ARBs), have been associated with lower incidence and progression of Alzheimer's disease (AD) in cohort studies. However, the manner by which ARBs mediate their beneficial effects is unknown. Here, the angiotensin IV receptor (AT4R) was identified as mediating the cognitive and cerebrovascular rescue of losartan, a commonly prescribed ARB, in a mouse model of AD. The AT4R was further implicated in mediating anti-inflammatory benefits. AT4R-mediated effects were independent from changes in blood pressure, amyloidosis, and oxidative stress. Overall, our results implicate the angiotensin IV/AT4R cascade as a promising candidate for AD intervention.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/fisiopatologia
Circulação Cerebrovascular/efeitos dos fármacos
Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/fisiopatologia
Losartan/administração & dosagem
Receptores de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem
Animais
Cognição/efeitos dos fármacos
Relação Dose-Resposta a Droga
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Aprendizagem Espacial/efeitos dos fármacos
Memória Espacial/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AT4 receptor); 0 (Angiotensin II Type 1 Receptor Blockers); 0 (Receptors, Angiotensin); JMS50MPO89 (Losartan)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0329-17.2017


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[PMID]:28233239
[Au] Autor:Reyes S; Varagic J; Ahmad S; VonCannon J; Kon ND; Wang H; Groban L; Cheng CP; Dell'Italia LJ; Ferrario CM
[Ad] Endereço:Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
[Ti] Título:Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease.
[So] Source:Curr Hypertens Rep;19(2):16, 2017 Feb.
[Is] ISSN:1534-3111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF THE REVIEW: Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). RECENT FINDINGS: Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Angiotensina/uso terapêutico
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
Angiotensinogênio/metabolismo
Quimases/metabolismo
Insuficiência Cardíaca/tratamento farmacológico
Hipertensão/tratamento farmacológico
Fragmentos de Peptídeos/metabolismo
Sistema Renina-Angiotensina/fisiologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Receptores de Angiotensina/fisiologia
Sistema Renina-Angiotensina/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Angiotensin Receptor Antagonists); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Peptide Fragments); 0 (Receptors, Angiotensin); 0 (angiotensin-(1-12), human); 11002-13-4 (Angiotensinogen); EC 3.4.21.39 (Chymases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1007/s11906-017-0708-3


  9 / 6443 MEDLINE  
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[PMID]:28027487
[Au] Autor:Schrage R; Kostenis E
[Ad] Endereço:Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany. Electronic address: rschrage@uni-bonn.de.
[Ti] Título:Functional selectivity and dualsteric/bitopic GPCR targeting.
[So] Source:Curr Opin Pharmacol;32:85-90, 2017 Feb.
[Is] ISSN:1471-4973
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Functional selectivity provides a new avenue to selectively engage particular pathways of the pleiotropic signaling repertoire of a G protein-coupled receptor. First examples for signaling biased compounds at the angiotensin II receptor and the µ opioid receptor have progressed to clinical trials and are promising in regard to selective activation of signaling pathways that can be linked to beneficial clinical outcomes. Dualsteric/bitopic hybrid compounds which consist of at least two pharmacophores combined in one single ligand are more recent examples for functionally selective ligands. Their binding topography makes them ideally suited to disrupt receptor flexibility and rationally induce signaling bias. Therefore, the dualsteric/bitopic design principle is most promising to facilitate generation of structurally diverse biased agonists at G protein-coupled receptors.
[Mh] Termos MeSH primário: Desenho de Drogas
Receptores Acoplados a Proteínas-G/agonistas
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Ligantes
Terapia de Alvo Molecular
Ligação Proteica
Receptores de Angiotensina/agonistas
Receptores de Angiotensina/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Receptores Opioides mu/agonistas
Receptores Opioides mu/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Angiotensin); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Opioid, mu)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170804
[Lr] Data última revisão:
170804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161228
[St] Status:MEDLINE


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[PMID]:28000857
[Au] Autor:Wang TJ; Lian GL; Lin X; Zhong HB; Xu CS; Wang HJ; Xie LD
[Ad] Endereço:Fujian Hypertension Research Institute, The First Clinical College of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China.
[Ti] Título:Hypomethylation of Agtrap is associated with long-term inhibition of left ventricular hypertrophy in prehypertensive losartan-treated spontaneously hypertensive rats.
[So] Source:Mol Med Rep;15(2):839-846, 2017 Feb.
[Is] ISSN:1791-3004
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Prehypertensive losartan treatment may lead to long­term inhibition of the development of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the expression of angiotensin type 1 receptor-associated protein (ATRAP/Agtrap) and methylation of the Agtrap gene in the myocardium following the withdrawal of treatment. Four­week­old SHRs were randomly divided into three groups, and were treated with saline, amlodipine or losartan, respectively, for 6 weeks. Wistar Kyoto rats (WKYs) were used as a control. All rats were followed up regularly until they reached the age of 32 weeks. Systolic blood pressure (SBP), left ventricular mass/body weight (LVM/BW), and cardiac fibrosis and structure were measured. The mRNA and protein expression of ATRAP in the myocardium were determined using reverse transcription­quantitative polymerase chain reaction and western blot analysis. Methylation of the Agtrap promoter was detected by bisulfite pyrosequencing. Reduced levels of SBP, LVM/BW, cardiac fibrosis and interventricular septum thickness were determined to be maintained only in prehypertensive losartan­treated SHRs. Whereas, an increased expression of ATRAP mRNA and protein, and hypomethylation of the Agtrap promoter in the myocardium, were demonstrated only in the losartan­treated SHRs. In conclusion, the results of the present study suggested that the hypomethylation of Agtrap accompanying upregulation of ATRAP expression in the myocardium is associated with the long­term inhibition of LVH in SHRs with prehypertensive losartan treatment.
[Mh] Termos MeSH primário: Anti-Hipertensivos/uso terapêutico
Metilação de DNA
Hipertensão/tratamento farmacológico
Hipertrofia Ventricular Esquerda/tratamento farmacológico
Losartan/uso terapêutico
Receptores de Angiotensina/genética
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea/efeitos dos fármacos
Fibrose
Hipertensão/complicações
Hipertensão/genética
Hipertensão/fisiopatologia
Hipertrofia Ventricular Esquerda/complicações
Hipertrofia Ventricular Esquerda/genética
Hipertrofia Ventricular Esquerda/fisiopatologia
Masculino
Miocárdio/patologia
Regiões Promotoras Genéticas
Ratos Endogâmicos SHR
Ratos Endogâmicos WKY
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agtrap protein, rat); 0 (Antihypertensive Agents); 0 (Receptors, Angiotensin); JMS50MPO89 (Losartan)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.3892/mmr.2016.6040



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