Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.482
Filtrar
1.
PLoS One ; 12(5): e0176713, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28464037

RESUMO

Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current densities. Second, the hypertrophic program can modify signaling between the angiotensin receptor and target current.


Assuntos
Angiotensina II/metabolismo , Cardiopatias/fisiopatologia , Miócitos Cardíacos/fisiologia , Sistema Renina-Angiotensina/fisiologia , Estresse Fisiológico/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipertrofia/fisiopatologia , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Técnicas de Patch-Clamp , Pressão , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Saralasina/farmacologia , Estresse Fisiológico/efeitos dos fármacos
2.
Peptides ; 81: 1-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27060674

RESUMO

The discovery of a receptor that binds prorenin and renin in human endothelial and mesangial cells highlights the possible effect of renin-independent prorenin in the resumption of meiosis in oocytes that was postulated in the 1980s.This study aimed to identify the (pro)renin receptor in the ovary and to assess the effect of prorenin on meiotic resumption. The (pro)renin receptor protein was detected in bovine cumulus-oocyte complexes, theca cells, granulosa cells, and in the corpus luteum. Abundant (pro)renin receptor messenger ribonucleic acid (mRNA) was detected in the oocytes and cumulus cells, while prorenin mRNA was identified in the cumulus cells only. Prorenin at concentrations of 10(-10), 10(-9), and 10(-8)M incubated with oocytes co-cultured with follicular hemisections for 15h caused the resumption of oocyte meiosis. Aliskiren, which inhibits free renin and receptor-bound renin/prorenin, at concentrations of 10(-7), 10(-5), and 10(-3)M blocked this effect (P<0.05). To determine the involvement of angiotensin II in prorenin-induced meiosis resumption, cumulus-oocyte complexes and follicular hemisections were treated with prorenin and with angiotensin II or saralasin (angiotensin II antagonist). Prorenin induced the resumption of meiosis independently of angiotensin II. Furthermore, cumulus-oocyte complexes cultured with forskolin (200µM) and treated with prorenin and aliskiren did not exhibit a prorenin-induced resumption of meiosis (P<0.05). Only the oocytes' cyclic adenosine monophosphate levels seemed to be regulated by prorenin and/or forskolin treatment after incubation for 6h. To the best of our knowledge, this is the first study to identify the (pro)renin receptor in ovarian cells and to demonstrate the independent role of prorenin in the resumption of oocyte meiosis in cattle.


Assuntos
Corpo Lúteo/transplante , Meiose/fisiologia , Ovário/fisiologia , Receptores de Superfície Celular/metabolismo , Renina/metabolismo , Reprodução/fisiologia , Amidas/farmacologia , Angiotensina II/metabolismo , Animais , Bovinos , Células Cultivadas , Colforsina/farmacologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/fisiologia , Células do Cúmulo/citologia , Células do Cúmulo/efeitos dos fármacos , Células do Cúmulo/fisiologia , Feminino , Fumaratos/farmacologia , Células da Granulosa/citologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/fisiologia , Humanos , Meiose/efeitos dos fármacos , Nucleotídeos Cíclicos/metabolismo , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Ovário/citologia , Ovário/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Renina/antagonistas & inibidores , Renina/genética , Reprodução/efeitos dos fármacos , Saralasina/farmacologia , Células Tecais/citologia , Células Tecais/efeitos dos fármacos , Células Tecais/fisiologia
3.
Bull Exp Biol Med ; 158(1): 115-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25403411

RESUMO

We developed and tested an experimental model to study in vitro the type 1 angiotensin antagonistic activity of compounds on the isolated portal vein of rats. The reliability of this method was confirmed in tests with saralasin (nonselective antagonist of angiotensin receptors) and losartan (selective antagonist of type 1 angiotensin receptors) in concentrations of 10(-9)-10(-5) mol/liter. The half-maximal inhibitory concentrations (IC50) of these substances were calculated.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Losartan/farmacologia , Saralasina/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Veia Porta/efeitos dos fármacos , Veia Porta/fisiologia , Ratos Wistar , Vasoconstrição/efeitos dos fármacos
4.
Neuroscience ; 231: 315-27, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-23219939

RESUMO

Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5-8) has generally been considered to be inactive, we show here that Ang (5-8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5-8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. The non-selective Ang-receptor (Ang-R) antagonist saralasin blocked Ang (5-8) antinociception, but selective antagonists of Ang-R types I, II, IV, and Mas did not, suggesting that Ang (5-8) may act via an unknown receptor. Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5-8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5-8)-induced antinociception. In conclusion, Ang (5-8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO-sGC and endogenous opioid in the vlPAG.


Assuntos
Angiotensina I/farmacologia , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Nociceptividade/efeitos dos fármacos , Peptídeos Opioides/metabolismo , Fragmentos de Peptídeos/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Aorta/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/fisiologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Peptídeos Opioides/antagonistas & inibidores , Ratos , Ratos Wistar , Saralasina/farmacologia , Guanilil Ciclase Solúvel , Teprotida/farmacologia
5.
Am J Physiol Renal Physiol ; 303(1): F11-20, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22535800

RESUMO

While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10(-7) M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10(-7) M alone similarly and significantly induced transforming growth factor-ß(1), plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-ß(1) via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.


Assuntos
Angiotensina I/metabolismo , Células Mesangiais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Renina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Células Cultivadas , Fibronectinas/genética , Fibronectinas/metabolismo , Masculino , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Ratos , Ratos Sprague-Dawley , Saralasina/farmacologia , Fator de Crescimento Transformador beta1/genética
6.
Cell Physiol Biochem ; 28(3): 513-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22116365

RESUMO

Intercalated cells in the collecting duct system express V-type H(+)-ATPases which participate in acid extrusion, bicarbonate secretion, and chloride absorption depending on the specific subtype. The activity of H(+)-ATPases is regulated by acid-base status and several hormones, including angiotensin II and aldosterone. Angiotensin II stimulates chloride absorption mediated by pendrin in type B intercalated cells and this process is energized by the activity of H(+)-ATPases. Moreover, angiotensin II stimulates bicarbonate secretion by the connecting tubule (CNT) and early cortical collecting duct (CCD). In the present study we examined the effect of angiotensin II (10 nM) on H(+)-ATPase activity and localization in isolated mouse connecting tubules and cortical collecting ducts. Angiotensin II stimulated Na(+)-independent intracellular pH recovery about 2-3 fold, and this was abolished by the specific H(+)-ATPase inhibitor concanamycin. The effect of angiotensin II was mediated through type 1 angiotensin II receptors (AT(1)-receptors) because it could be blocked by saralasin. Stimulation of H(+)-ATPase activity required an intact microtubular network--it was completely inhibited by colchicine. Immunocytochemistry of isolated CNT/CCDs incubated in vitro with angiotensin II suggests enhanced membrane associated staining of H(+)-ATPases in pendrin expressing intercalated cells. In summary, angiotensin II stimulates H(+)-ATPases in CNT/CCD intercalated cells, and may contribute to the regulation of chloride absorption and bicarbonate secretion in this nephron segment.


Assuntos
Angiotensina II/farmacologia , Córtex Renal/enzimologia , Túbulos Renais Coletores/enzimologia , ATPases Vacuolares Próton-Translocadoras/metabolismo , Animais , Proteínas de Transporte de Ânions/metabolismo , Bicarbonatos/metabolismo , Membrana Celular/metabolismo , Cloretos/metabolismo , Colchicina/farmacologia , Concentração de Íons de Hidrogênio , Imuno-Histoquímica , Córtex Renal/citologia , Córtex Renal/patologia , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/patologia , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Angiotensina/química , Receptores de Angiotensina/metabolismo , Saralasina/farmacologia , Sódio/metabolismo , Transportadores de Sulfato , ATPases Vacuolares Próton-Translocadoras/análise , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores
7.
Endocrinology ; 152(12): 4957-65, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22009728

RESUMO

It is generally understood that angiotensin II (AngII) promotes follicle atresia in rats, although recent data suggested that this may not be true in cattle. In this study, we aimed to determine in vivo whether AngII alters follicle development in cattle, using intrafollicular injection of AngII or antagonist into the growing dominant follicle or the second largest subordinate follicle. Injection of saralasin, an AngII antagonist, into the growing dominant follicle inhibited follicular growth, and this inhibitory effect was overcome by systemic FSH supplementation. Injection of AngII into the dominant follicle did not affect follicular growth, whereas injection of AngII into the second largest follicle prevented the expected atresia of this subordinate follicle, and the treated follicle grew at the same rate as the dominant follicle for the next 24 h. Inhibition of AngII action in the dominant follicle decreased estradiol concentrations in follicular fluid and the abundance of mRNA encoding aromatase, 3ß-hydroxysteroid dehydrogenase, LH receptor, and cyclinD2 in granulosa cells, with minimal effects on theca cells. The effect of AngII on aromatase mRNA levels was confirmed using an in vitro granulosa cell culture system. In conclusion, these data suggest that AngII signaling promotes follicle growth in cattle and does so by regulating genes involved in estradiol secretion and granulosa cell proliferation and differentiation.


Assuntos
Angiotensina II/farmacologia , Folículo Ovariano/crescimento & desenvolvimento , Transdução de Sinais , Angiotensina II/administração & dosagem , Angiotensina II/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Aromatase , Bovinos , Diferenciação Celular , Proliferação de Células , Estradiol , Feminino , Regulação da Expressão Gênica , Células da Granulosa/citologia , Células da Granulosa/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Saralasina/administração & dosagem , Saralasina/farmacologia , Transdução de Sinais/efeitos dos fármacos
8.
Am J Physiol Cell Physiol ; 301(3): C559-65, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21613610

RESUMO

Angiotensin II is a modulator of myometrial activity; both AT(1) and AT(2) receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in myometrial cells in a dose-dependent manner. The effect was abolished by the AT(1) receptor antagonist losartan but not by the AT(2) receptor antagonist PD-123319. Disruption of the endo-lysosomal system, but not that of Golgi apparatus, prevented the angiotensin II-induced increase in [Ca(2+)](i). Blockade of AT(1) receptor internalization had no effect, whereas blockade of microautophagy abolished the increase in [Ca(2+)](i) produced by intracellular injection of angiotensin II; this indicates that microautophagy is a critical step in transporting the peptide into the endo-lysosomes lumenum. The response to angiotensin II was slightly reduced in Ca(2+)-free saline, indicating a major involvement of Ca(2+) release from internal stores. Blockade of inositol 1,4,5-trisphosphate (IP(3)) receptors with heparin and xestospongin C or inhibition of phospholipase C (PLC) with U-73122 abolished the response to angiotensin II, supporting the involvement of PLC-IP(3) pathway. Angiotensin II-induced increase in [Ca(2+)](i) was slightly reduced by antagonism of ryanodine receptors. Taken together, our results indicate for the first time that in myometrial cells, intracellular angiotensin II activates AT(1)-like receptors on lysosomes and activates PLC-IP(3)-dependent Ca(2+) release from endoplasmic reticulum; the response is further augmented by a Ca(2+)-induced Ca(2+) release mechanism via ryanodine receptors activation.


Assuntos
Angiotensina II/metabolismo , Sinalização do Cálcio/fisiologia , Miométrio/metabolismo , Transdução de Sinais/fisiologia , Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Arsenicais/farmacologia , Autofagia/efeitos dos fármacos , Brefeldina A/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Carbolinas/farmacologia , Células Cultivadas , Ácido Egtázico/farmacologia , Endocitose/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Feminino , Heparina/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Losartan/administração & dosagem , Losartan/farmacologia , Lisossomos/metabolismo , Compostos Macrocíclicos/farmacologia , Macrolídeos/farmacologia , Modelos Biológicos , Miométrio/citologia , Miométrio/efeitos dos fármacos , NADP/análogos & derivados , NADP/metabolismo , Oxazóis/farmacologia , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Rianodina/farmacologia , Saralasina/administração & dosagem , Saralasina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
9.
Neurobiol Learn Mem ; 94(4): 509-20, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20828629

RESUMO

Memory reconsolidation is a dynamic process in which a previously consolidated memory becomes labile following reactivation by a reminder. In a previous study in the crab Chasmagnathus memory model, we showed that a water-shortage episode, via angiotensin modulation during reconsolidation, could reveal a memory that otherwise remains unexpressed: weakly trained animals cannot reveal long-term memory (LTM) except when an episode of noticeable ethological meaning, water deprivation, is contingent upon reconsolidation. However, these results are at variance with two of our previous interpretations: weak training protocols do not build LTM and angiotensin II modulates the strength of the information storing process. A parsimonious hypothesis is that in Chasmagnathus angiotensins regulate LTM expression, but not LTM storage. Here, we tested three predictions of this hypothesis. First, the well-known retrograde amnesic effect of the angiotensin II antagonist saralasin is not due to interference on memory storage, but to modulation of memory expression. Second, the recovery of the LTM memory expression of the apparently amnesic retrograde effect produced by saralasin, through the water-shortage episode contingent upon reconsolidation, must be reconsolidation specific. Consequently, summation-like effects and retrieval deficits cannot explain these results because of the parametric conditions of reconsolidation. Third, weak training protocols build an unexpressed LTM that requires mRNA transcription and translation, a diagnostic characteristic of LTM. Results show that angiotensin modulates LTM expression but not LTM memory storage in the crab Chasmagnathus. The results lead us to suggest that, in Chasmagnathus, LTM expression - the process of gaining appreciable control over behavior of the reactivated trace in the retrieval session - may be considered a distinct attribute of its long-term storage. This strategy, a positive modulation during reconsolidation, is proposed to distinguish between memories that can be reactivated, labilized and are not expressed, and memories that are not stored long term, obliterated or altered in other retrieval mechanisms.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/fisiologia , Braquiúros/fisiologia , Memória de Longo Prazo/fisiologia , Saralasina/farmacologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Meio Ambiente , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Privação de Água/fisiologia
10.
Drug Chem Toxicol ; 33(3): 302-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20429803

RESUMO

In order to elucidate the involvement of the brain renin-angiotensin system (RAS) in cadmium intracerebroventricular (ICV) hypertension, we evaluated the effects of a pretreatment with different drugs: clonidine, an alpha(2) adrenergic agonist, enalapril and captopril, both ACE inhibitors, and saralasin, a competitive nonselective AT(1) and AT(2) receptor antagonist. We used a rat strain with low levels of kallikrein (LKR) that was more sensitive to ICV cadmium hypertension, compared with normal kallikrein rats (NKRs), the control strain. The interplay between the kallikrein-kinin system and the RAS in the LKR strain caused various hemodynamic alterations, which we believe were the result of elevated RAS activity in these animals. Moreover, we suggest that the defective kallikrein-kinin system in LKR may also cause an alteration in the activation of brain RAS in these animals. The LKR displayed elevated concentrations of plasma AII, hypertrophy of the myocardium, and initial alterations in the renal glomerulotubular system. With the exception of clonidine, all of the other drugs showed greater antihypertensive effects of differing statistical significance in LKR, compared with NKR. Both ACE inhibitors were able to significantly reduce pressor response to cadmium ICV in LKR throughout the experiment, whereas in NKR, they were only able to reduce the hypertensive peak of cadmium. A significant protective effect was also observed in LKR pretreated with saralasin, while no effect was observed in NKR. These findings confirm the presence of brain RAS activation in LKR and its contribution to the central control of pressor response to cadmium ICV.


Assuntos
Encéfalo/fisiologia , Cádmio/toxicidade , Hipertensão/induzido quimicamente , Sistema Calicreína-Cinina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Angiotensina II/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/farmacologia , Clonidina/farmacologia , Enalapril/farmacologia , Coração/fisiopatologia , Histocitoquímica , Hipertensão/fisiopatologia , Sistema Calicreína-Cinina/fisiologia , Calicreínas/urina , Rim/fisiopatologia , Masculino , Ratos , Ratos Wistar , Saralasina/farmacologia
11.
Toxicol In Vitro ; 24(3): 803-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20035857

RESUMO

Survivors of paraquat poisoning are left with pulmonary fibrosis which results in a restrictive type of long-term pulmonary dysfunction. Connective tissue growth factor (CTGF) is a key growth factor that initiates tissue repair and underlies the development of lung fibrosis. Angiotensin (ANG) II may induce CTGF expression in the heart and kidney and plays an important role in the pathogenesis of lung fibrosis. The biological effects of ANG II are mediated by ANG II type 1 receptor (AT1R) and AT2R. The aims of this study were to investigate the effects of paraquat on ANG II, ANG II receptors, CTGF, and collagen expressions and to assess the role of ANG II receptors in paraquat-induced collagen synthesis in human lung fibroblasts (MRC-5). MRC-5 cells were incubated with various concentrations of paraquat with or without the ANG II receptor antagonist, saralasin. Paraquat increased ANG II production and AT1R mRNA and protein expression and decreased AT2R mRNA expression. Furthermore, paraquat treatment increased CTGF and collagen mRNA and protein expression in a dose-dependent manner and saralasin inhibited these effects. These results indicate that paraquat increases CTGF and collagen expression by activating angiotensin signaling pathway in human lung fibroblasts.


Assuntos
Angiotensina II/fisiologia , Colágeno/biossíntese , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/efeitos dos fármacos , Herbicidas/toxicidade , Paraquat/toxicidade , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Western Blotting , Colágeno Tipo I/biossíntese , Colágeno Tipo II/biossíntese , Relação Dose-Resposta a Droga , Imunofluorescência , Herbicidas/antagonistas & inibidores , Humanos , Paraquat/antagonistas & inibidores , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor Tipo 2 de Angiotensina/biossíntese , Receptor Tipo 2 de Angiotensina/genética , Receptores de Angiotensina/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saralasina/farmacologia , Transdução de Sinais/efeitos dos fármacos
12.
Minerva Cardioangiol ; 57(6): 773-85, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19942847

RESUMO

Chronic activation of the renin-angiotensin system (RAS) plays a crucial role in the development of various cardiovascular diseases (CVD). Thus, effective RAS inhibition has been a major achievement to improve the treatment of patients at risk for CVDs, such as myocardial infarction, heart failure and stroke. Three substance classes that block RAS-activation are currently available, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockade (ARB) and renin inhibitors. Although the overall goal of these drugs remains the blockade of RAS activation, their individual targets in this system vary and may substantially influence the clinical benefit derived from the long term use of these substances. Here, we summarize the evidence available for the use of ARBs in different cardiovascular pathologies and the impact of this evidence on current treatment guidelines for patients at risk for CVD. Today, ARBs represent a good alternative in case of ACE-inhibitor intolerance due to their outstanding tolerability. ARBs in comparison to ACE-inhibitors have been proven to exert similar effective in the treatment of systolic heart failure, primary prevention of stroke, new onset of diabetes mellitus (DM) type 2 and DM type 2 dependent macroalbuminuria. ARBs should be considered as alternatives to ACE-inhibitors in subjects post-myocardial infarction. Overall however, there is no profound proof for a specific cardiovascular protection by blockade of the angiotensin II Type 1 (AT1) receptor that exceeds the impact of ACE-inhibition or synergises with ACE-blockade. In fact, combination of ARBs and ACE-inhibitor result in an increased rate of adverse effects and, therefore, this combination should not be encouraged. To summarize, the initial hope for a more specific impact on cardiovascular diseases by inhibition of the AT1-receptor in comparison to ACE-inhibition has not come true. However, ARBs have been proven to be equally effective as ACE-blockade in a large variety of clinical settings.


Assuntos
Doenças Cardiovasculares/epidemiologia , Hipertensão/tratamento farmacológico , Anlodipino/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Consenso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização , Humanos , Hipertensão/mortalidade , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prevenção Primária , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Saralasina/administração & dosagem , Saralasina/uso terapêutico , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Tetrazóis/administração & dosagem , Tetrazóis/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Valina/administração & dosagem , Valina/análogos & derivados , Valina/uso terapêutico , Valsartana
13.
Vascul Pharmacol ; 51(5-6): 314-22, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19643203

RESUMO

Diverse intracoronary agonists cause cardiac effects while acting on coronary endothelial luminal membrane (CELM) receptor. Our data show: a) the presence of AT(1)R in isolated CELM and in all cardiac cell types and b) sustained intracoronary infusions of Ang II-POL, a large sized molecule (approximately 15,000 kDa) confined to the vessel lumen that can only act on CELM's AT(1)R or Ang II (approximately 1 kDa); both exert the same maximum positive inotropic (PIE) and coronary constriction (CPP). The effects of these two agonists are blocked by Losartan and by Sar-POL; a large size antagonist (approximately 15,000 kDa) that acts only on CELM. Ang II effects are transient due to desensitization and cause tachyphylaxis to Ang II and toward Ang II-POL suggesting that both Ang II and Ang II-POL act on the same receptor group. In contrast, Ang II-POL effects are sustained and do not cause tachyphylaxis. The results show that intravascular Ang II and Ang II-POL act differentially by an unknown mechanism on CELM's AT(1)R and suggest that intravascular Ang II and Ang II-POL cause PIE and CCP by activation limited to CELM's AT(1)R through an unknown mechanism that is space-confined to the CELM's AT(1)R.


Assuntos
Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/agonistas , Angiotensina II/farmacologia , Animais , Vasos Coronários/fisiologia , Endotélio Vascular/fisiologia , Losartan/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Saralasina/farmacologia , Vasoconstrição/efeitos dos fármacos
14.
Reproduction ; 136(6): 733-40, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18768665

RESUMO

Angiotensin II (AngII) prevents the inhibitory effect of follicular cells on oocyte maturation, but its involvement in LH-induced meiotic resumption remains unknown. The aim of this study was to assess the involvement of AngII in LH-induced meiotic resumption and of prostaglandins (PGs) in the action of AngII. In the experiment I, seven cows were superovulated, intrafollicularly injected with 10 muM saralasin (a competitive AngII antagonist) or saline when the follicles reached a diameter larger than 12 mm, and challenged with a GnRH agonist to induce an LH surge. Fifteen hours after GnRH, the animals were ovariectomized and the oocytes were recovered to determine the stage of meiosis. The oocytes from follicles that received saline were in germinal vesicle (GV) breakdown (30.8%) or metaphase I (MI; 69.2%) stage while those that received saralasin were in the GV stage (100%; P<0.001) 15 h after GnRH agonist. In another experiment, oocytes were co-cultured with follicular hemisections for 15 h to determine whether PGs mediate the effect of AngII on meiotic resumption. Indomethacin (10 microM) inhibited AngII-induced meiotic resumption (13.4 vs 77.5% MI without indomethacin; P<0.001). Furthermore, the GV oocytes progressed to MI at a similar rate when PGE(2), PGF(2alpha) or AngII was present in the co-culture system with follicular cells (PGE(2) 77.4%, PGF(2alpha) 70.0%, and AngII 75.0% MI). In conclusion, our results provide strong evidence that AngII mediates the resumption of meiosis induced by an LH surge in bovine oocytes and that this event is dependent on PGE(2) or PGF(2alpha) produced by follicular cells.


Assuntos
Dinoprosta/metabolismo , Dinoprostona/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Angiotensina II/antagonistas & inibidores , Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bovinos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Técnicas de Cocultura , Inibidores de Ciclo-Oxigenase/farmacologia , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Indometacina/farmacologia , Hormônio Luteinizante/metabolismo , Meiose/efeitos dos fármacos , Saralasina/farmacologia
15.
Am J Physiol Endocrinol Metab ; 295(4): E810-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18664599

RESUMO

Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10(-7) M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.


Assuntos
Miócitos de Músculo Liso/metabolismo , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Receptores de Superfície Celular/fisiologia , Renina/metabolismo , Angiotensina II/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta Torácica/química , Aorta Torácica/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Ativação Enzimática/fisiologia , Imuno-Histoquímica , Masculino , Miócitos de Músculo Liso/enzimologia , Nefrectomia , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saralasina/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-18571395

RESUMO

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.


Assuntos
Ácido Araquidônico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Ácido Araquidônico/administração & dosagem , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Epinefrina/sangue , Antagonistas de Hormônios/farmacologia , Injeções Intraventriculares , Masculino , Norepinefrina/sangue , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Renina/sangue , Saralasina/farmacologia , Vasopressinas/sangue
17.
Cardiovasc Res ; 79(4): 642-51, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18503051

RESUMO

AIMS: Stretch is an important regulator of atrial function. The functional effects of stretch on human atrium, however, are poorly understood. Thus, we characterized the stretch-induced force response in human atrium and evaluated the underlying cellular mechanisms. METHODS AND RESULTS: Isometric twitch force of human atrial trabeculae (n = 252) was recorded (37 degrees C, 1 Hz stimulation) following stretch from 88 (L88) to 98% (L98) of optimal length. [Na(+)](i) and pH(i) were measured using SBFI and BCECF epifluorescence, respectively. Stretch induced a biphasic force increase: an immediate increase [first-phase, Frank-Starling mechanism (FSM)] to approximately 190% of force at L88 followed by an additional slower increase [5-10 min; slow force response (SFR)] to approximately 120% of the FSM. FSM and SFR were unaffected by gender, age, ejection fraction, and pre-medication with major cardiovascular drugs. There was a positive correlation between the amplitude of the FSM and the SFR. [Na(+)](i) rose by approximately 1 mmol/L and pH(i) remained unchanged during the SFR. Inhibition of Na(+)/H(+)-exchange (3 microM HOE642), Na(+)/Ca(2+)-exchange (5 microM KB-R7943), or stretch-activated channels (0.5 microM GsMtx-4 and 80 microM streptomycin) did not reduce the SFR. Inhibition of angiotensin-II (AngII) receptors (5 microM saralasin and 0.5 microM PD123319) or pre-application of 0.5 microM AngII, however, reduced the SFR by approximately 40-60%. Moreover, stretch increased phosphorylation of myosin light chain 2 (MLC2a) and inhibition of MLC kinase (10 microM ML-7 and 5 microM wortmannin) decreased the SFR by approximately 40-85%. CONCLUSION: Stretch elicits a SFR in human atrium. The atrial SFR is mediated by stretch-induced release and autocrine/paracrine actions of AngII and increased myofilament Ca(2+) responsiveness via phosphorylation of MLC2a by MLC kinase.


Assuntos
Angiotensina II/metabolismo , Miosinas Cardíacas/metabolismo , Mecanotransdução Celular , Força Muscular , Contração Miocárdica , Miocárdio/metabolismo , Cadeias Leves de Miosina/metabolismo , Apêndice Atrial/metabolismo , Tamanho Celular , Humanos , Concentração de Íons de Hidrogênio , Canais Iônicos/metabolismo , Contração Isométrica , Cinética , Mecanotransdução Celular/efeitos dos fármacos , Modelos Biológicos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Reflexo de Estiramento , Reprodutibilidade dos Testes , Saralasina/farmacologia , Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo
18.
Bull Exp Biol Med ; 146(2): 172-5, 2008 Aug.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-19145309

RESUMO

We compared activity of synthetic complexes of angiotensin II and functionally different proteins (transport protein, serum albumin and neurospecific Ca2+-binding protein S100b) as analogues of endogenous protein-peptide complexes. Physiological activity of angiotensin II was specifically modified by these proteins. It was hypothesized that the complex of angiotensin II and S100b is primarily involved in the regulation of hemodynamics, whereas the complex of angiotensin II and bovine serum albumin plays a role in the formation and realization of drinking behavior.


Assuntos
Angiotensina II/metabolismo , Proteínas de Transporte/metabolismo , Comportamento de Ingestão de Líquido/fisiologia , Hemodinâmica/fisiologia , Fatores de Crescimento Neural/metabolismo , Proteínas S100/metabolismo , Soroalbumina Bovina/metabolismo , Angiotensina II/administração & dosagem , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Captopril/farmacologia , Proteínas de Transporte/administração & dosagem , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hemodinâmica/efeitos dos fármacos , Masculino , Fatores de Crescimento Neural/administração & dosagem , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/administração & dosagem , Saralasina/farmacologia , Soroalbumina Bovina/administração & dosagem
19.
Chin Med J (Engl) ; 120(21): 1886-9, 2007 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-18067760

RESUMO

BACKGROUND: The decreased degradation of extra-cellular matrix proteins plays an important role in the onset of diabetic nephropathy. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are members of the matrix metalloproteinase family, are associated with this process. Angiotensin II (AII) plays an important role in the development of diabetic nephropathy also. This research aimed to investigate the effect of angiotensin II receptor blocker on glucose-induced mRNA expressions of MMP-9 and TIMP-1 in rat mesangial cells. METHODS: Rat mesangial cells were cultured and divided into 5 groups: normal glucose (group NG), high glucose (group HG), group NG + AII, NG + AII + saralasin (group NG + AII + S, saralasin is the AII receptor blocker) and HG + saralasin (group HG + S). After the cells were incubated for 24 hours, AII concentrations in the supernatant were measured by radioimmunoassay and the expression of MMP-9 and TIMP-1 mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: AII concentrations were higher in group HG ((56.90 +/- 13.54) pg/ml) and group HG + S ((51.30 +/- 5.96) pg/ml) than in group NG ((37.89 +/- 8.62) pg/ml, P < 0.05), whereas there was no significant difference between group HG and group HG + S. The expression of MMP-9 mRNA and MMP-9/TIMP-1 mRNA ratio in group NG + AII (MMP-9, 0.33 +/- 0.04; MMP-9/TIMP-1, 0.40 +/- 0.06) and group HG (MMP-9, 0.36 +/- 0.02; MMP-9/TIMP-1, 0.45 +/- 0.03) were decreased more significantly than those in group NG (MMP-9, 0.72 +/- 0.02; MMP-9/TIMP-1, 1.21 +/- 0.07). These values in group NG + AII + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.18 +/- 0.05) were higher than those in group NG + AII, and the values in group HG + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.16 +/- 0.05) were higher than those in group HG (all were P < 0.05). TIMP-1 mRNA expression was increased more significantly in group NG + AII (0.81 +/- 0.03) and group HG (0.80 +/- 0.03) than in group NG (0.59 +/- 0.02), but it was lower in group NG + AII + S (0.60 +/- 0.01) than in group NG + AII and also lower in group HG + S (0.61 +/- 0.01) than in group HG (all were P < 0.05). CONCLUSIONS: High glucose stimulates AII production. Both high glucose and AII induce a decrease in MMP-9 mRNA expression and MMP-9/TIMP-1 mRNA ratio as well as an increase in TIMP-1 mRNA expression, which can be reversed by saralasin, suggesting that high glucose can aggravate impaired matrix degradation by altering gene expression of MMP-9 and TIMP-1 and that the effect of high glucose may be mediated by AII.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Glucose/farmacologia , Metaloproteinase 9 da Matriz/genética , Células Mesangiais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/genética , Antagonistas de Receptores de Angiotensina , Animais , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Células Mesangiais/citologia , Células Mesangiais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saralasina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA