RESUMO
OBJECTIVES: The study was pursued to understand and compare the vascular reactivity to angiotensin II (Ang II) and its receptor expression in thoracic and abdominal aorta under insulin resistance. METHODS: Vascular reactivity to Ang II was recorded isometrically, AT1/AT2 receptor gene and protein expression was checked by RT-PCR and western blotting, respectively, and abundance of phospho (serine-10 Ph) H3 on promoter regions of Agtr1/Agtr2 genes was done by chromatin immunoprecipitation assay in aortic rings isolated from high fat diet (HFD)-fed rats. RESULTS: Our functional studies showed an increased (Emax in mg/mm: Con: 319â±â29 and HFD: 1095â±â72, Pâ<â0.001) and unaltered (Emax in mg/mm: Con: 299â±â29 and HFD: 350â±â20, meanâ±âSEM, nâ=â6) Ang II-induced contractile responses in thoracic and abdominal aorta of HFD rats, respectively, as compared to control rats. Interestingly, AT2R-mediated relaxation was increased in abdominal aorta (% relaxation: Con: 25â±â5.3 and HFD: 76.4â±â8.9, Pâ<â0.001) of HFD rats but not in thoracic aorta (% relaxation: Con: 25â±â5.2 and HFD: 32â±â5.2, meanâ±âSEM, nâ=â6). At the molecular level, increased mRNA (â¼14-folds) and protein expression (â¼2.5-folds) of AT2R in abdominal aorta of HFD rats was found as compared to control rats. However, AT1R mRNA and protein expression did not show any change. Chromatin immunoprecipitation with phospho H3 showed increased abundance of ser-10 phosphorylation on Agtr1 and Agtr2 gene promoter regions in thoracic and abdominal segments, respectively. But it got decreased on Agtr2 and Agtr1 genes promoter regions in thoracic and abdominal segments, respectively. CONCLUSION: We provide first evidence that insulin resistance induces segmental difference in thoracic and abdominal aorta and this may provide reason of heterogeneity for incidence of aneurysms.
Assuntos
Aorta Abdominal/metabolismo , Aorta Torácica/metabolismo , Resistência à Insulina , Receptores de Angiotensina/metabolismo , Western Blotting , Imunoprecipitação da Cromatina , Teste de Tolerância a Glucose , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Angiotensina/classificaçãoRESUMO
Among the most conserved osmoregulatory hormone systems in vertebrates are the renin-angiotensin system (RAS) and the natriuretic peptides (NPs). We examined the RAS and NP system in the euryhaline Atlantic stingray, Dasyatis sabina (Lesueur). To determine the relative sensitivity of target organs to these hormonal systems, we isolated cDNA sequences encoding the D. sabina angiotensin receptor (AT) and natriuretic peptide type-B receptor (NPR-B). We then determined the tissue-specific expression of their mRNAs in saltwater D. sabina from local Texas waters and an isolated freshwater population in Lake Monroe, Florida. AT mRNA was most abundant in interrenal tissue from both populations. NPR-B mRNA was most abundant in rectal gland tissue from both populations, and also highly abundant in the kidney of saltwater D. sabina. This study is the first to report the sequence of an elasmobranch angiotensin receptor, and phylogenetic analysis indicates that the D. sabina receptor is more similar to AT(1) vs. AT(2) proteins. This classification is further supported by molecular analysis of AT(1) and AT(2) proteins demonstrating conservation of AT(1)-specific amino acid residues and motifs in D. sabina AT. Molecular classification of the elasmobranch angiotensin receptor as an AT(1)-like protein provides fundamental insight into the evolution of the vertebrate RAS.
Assuntos
Proteínas de Peixes/genética , Receptores de Angiotensina/genética , Receptores do Fator Natriurético Atrial/genética , Rajidae/genética , Sequência de Aminoácidos , Animais , DNA Complementar/química , Proteínas de Peixes/classificação , Proteínas de Peixes/metabolismo , Água Doce , Dados de Sequência Molecular , Filogenia , RNA Mensageiro/metabolismo , Receptores de Angiotensina/classificação , Receptores de Angiotensina/metabolismo , Receptores do Fator Natriurético Atrial/classificação , Receptores do Fator Natriurético Atrial/metabolismo , Salinidade , Alinhamento de Sequência , Rajidae/metabolismoRESUMO
We have recently described, in the mouse aorta, the vasodilator effect of angiotensin-(1-7) (Ang-(1-7)) was mediated by activation of the Mas Ang-(1-7) receptor and that A-779 and D-Pro7-Ang-(1-7) act as Mas receptor antagonists. In this work we show pharmacological evidence for the existence of a different Ang-(1-7) receptor subtype mediating the vasodilator effect of Ang-(1-7) in the aorta from Sprague-Dawley (SD) rats. Ang-(1-7) induced an endothelium-dependent vasodilator effect in aortic rings from SD rats which was inhibited by removal of the endothelium and by L-NAME (100 microM) but not by indomethacin (10 microM). The Ang-(1-7) receptor antagonist D-Pro7-Ang-(1-7) (0.1 microM) abolished the vasodilator effect of the peptide. However, the other specific Ang-(1-7) receptor antagonist, A-779 in concentrations up to 10 microM, did not affect vasodilation induced by Ang-(1-7). The Ang II AT1 and AT2 receptors antagonists CV11974 (0.01 microM) and PD123319 (1 microM), respectively, the bradykinin B2 receptor antagonist HOE 140 (1 microM) and the inhibitor of ACE captopril (10 microM) did not change the effect of Ang-(1-7). Our results show that in the aorta of SD rats, the vasodilator effect of Ang-(1-7) is dependent on endothelium-derived nitric oxide. This effect is mediated by the activation of Ang-(1-7) receptors sensitive to D-Pro7-Ang-(1-7), but not to A-779, which suggests the existence of a different Ang-(1-7) receptor subtype.
Assuntos
Angiotensina I/metabolismo , Aorta Torácica/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de Angiotensina/classificação , Receptores de Angiotensina/metabolismo , Angiotensina I/antagonistas & inibidores , Angiotensina I/farmacologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Técnicas In Vitro , Indometacina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Insulin-resistant states are often associated with hypertension, and the accumulated data indicate that ARB decrease new-onset of diabetes with vasoprotective effects. Recent evidence suggests that activation of Ang II receptor subtypes could regulate insulin sensitivity at multiple sites of insulin signaling in various diabetic animal models and regulate vascular remodeling in concert with insulin in potentially distinct fashions. Moreover, the roles of Ang II receptor subtypes have been highlighted in insulin resistance in obesity, which is one of the major risk factors for the development of hypertension. More detailed analysis of the crosstalk of Ang II and insulin-mediated signaling in various tissues would provide further information to understand the clinical relevance of the effect of ARB on insulin resistance, thereby preventing cardiovascular events associated with insulin resistance.
Assuntos
Resistência à Insulina/fisiologia , Insulina/fisiologia , Receptor Cross-Talk/fisiologia , Receptores de Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Angiotensina II/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Camundongos , Modelos Animais , Ratos , Receptores de Angiotensina/classificação , Receptores de Angiotensina/efeitos dos fármacos , Fatores de RiscoRESUMO
Renin-angiotensin (Ang) system (RAS) peptides injected into the periaqueductal gray matter (PAG) elicit antinociception. Saralasin blocks Ang II-elicited antinociception. Thus, it is possible that endogenous RAS peptides could participate on the modulation of nociception in the PAG. This possibility was tested here injecting, in the PAG, the specific Ang type 1 and type 2 receptor (AT1 receptor and AT(2 receptor) antagonists losartan and CGP42,112A, respectively, either alone or before Ang II. The effects of Ang II, losartan and CGP42,112A on nociception were measured using the tail flick test and the model of incision allodynia. Ang II increased tail-flick latency, an effect inhibited by both losartan and CGP42,112A. Ang II reduced incisional allodynia. Either losartan or CGP42,112A alone increased incision allodynia, suggesting that endogenous Ang II and/or an Ang-peptide participates in the control of allodynia by the PAG. AT1 and AT2 receptors were immunolocalized in neuronal cell bodies and processes in the ventrolateral PAG. Taken together, the antinociceptive effect of Ang II injection into the ventrolateral PAG, the increase of allodynia elicited by injecting either losartan or CGP42,112A alone in the PAG, and the presence of AT1 and AT2 receptors in neurons and neuronal processes in the same region, represent the first evidence that part of the tonic nociceptive control mediated by the PAG is carried out locally by endogenous Ang II and/or an Ang-peptide acting on AT1 and AT2 receptors.
Assuntos
Nociceptores/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de Angiotensina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Anestésicos Locais/farmacologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Relação Dose-Resposta a Droga , Imuno-Histoquímica/métodos , Lidocaína/farmacologia , Losartan/farmacologia , Masculino , Nociceptores/efeitos dos fármacos , Oligopeptídeos/farmacologia , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores de Angiotensina/classificação , Receptores de Angiotensina/efeitos dos fármacos , Fatores de TempoRESUMO
The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin II type 1 and 2 (AT(1) and AT(2)) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT(1) receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT(1) receptor antagonism prevented the stress-induced increase in adrenomedullary AT(2) receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT(1) receptor or with PD 123319, an AT(2) receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT(1) receptor antagonism decreased the levels of Fra-2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT(2) antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT(1) and AT(2) receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT(1) and AT(2) receptor types.
Assuntos
Medula Suprarrenal/metabolismo , Angiotensina II/metabolismo , Catecolaminas/biossíntese , Regulação Enzimológica da Expressão Gênica , Receptores de Angiotensina/metabolismo , Estresse Fisiológico/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Angiotensina II/fisiologia , Animais , Masculino , Fosforilação , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores de Angiotensina/classificação , Estresse Fisiológico/fisiopatologiaRESUMO
The renin-angiotensin-aldosterone system regulates renal vasomotor activity, maintains optimal salt and water homeostasis, and controls tissue growth in the kidney. However, pathologic consequences can result from overactivity of this cascade, involving it in the pathophysiology of kidney disease. An activated renin-angiotensin-aldosterone system promotes both systemic and glomerular capillary hypertension, which can induce hemodynamic injury to the vascular endothelium and glomerulus. In addition, direct profibrotic and proinflammatory actions of angiotensin II and aldosterone may also promote kidney damage. The majority of the untoward effects associated with angiotensin II appear to be mediated through its binding to the angiotensin II type 1 receptor. Aldosterone can also induce renal injury by binding to its receptor in the kidney. An understanding of this system is important to appreciate that inhibitors of this cascade can reduce the progression of chronic kidney disease in proteinuric disease states. Pharmacologic agents that can interfere with this cascade include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists. This paper will provide an overview of the renin-angiotensin system, review its role in kidney disease, examine the renal effects of inhibition of this cascade in experimental animal models, and review clinical studies utilizing renin-angiotensin-aldosterone inhibitors in patients with diabetic and nondiabetic nephropathies.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Nefropatias/fisiopatologia , Rim/fisiologia , Receptores de Angiotensina , Sistema Renina-Angiotensina/fisiologia , Animais , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Antagonistas de Receptores de Mineralocorticoides , Receptores de Angiotensina/classificação , Receptores de Angiotensina/fisiologia , Renina/biossíntese , Renina/fisiologiaRESUMO
The 'Schild regression' method is based on the principle of assessing the rightward shift of agonist dose-effect curves in the presence of different doses/concentrations of the respective receptor antagonist and presenting their relationship in a double log plot (i.e. the 'Schild plot'). The original method was developed to quantitatively characterize antagonistic drugs in experimental pharmacology. The method was adopted for evaluation of various AT1 antagonists in humans utilizing (human) angiotensin II as the agonist. Angiotensin II (Ang II) in continuous intravenous dose-incremental administration resulted in a clearly dose-dependent increase in blood pressure. All AT1 antagonists tested after oral administration yielded concentration-dependent rightward shifts of those Ang II dose-effect curves that were quantified as dose ratio (DR). DR minus 1 (DR-1) enabled the assessment of antagonist time kinetics in humans and a quantitatively precise determination of the half-life of antagonism in vivo. Schild plots allowed for assessment of apparent Ki doses indicative of a twofold rightward shift of the Ang II effect, thus providing the means for a rational comparison of the pharmacological potency of many of these compounds, where the Ki doses obtained at 24 h after administration were in the range of 'therapeutic' doses. Schild plots of a variety of substances showed linear relations independent of whether the blockade was deemed surmountable or not. It is therefore assumed that this property does not play a role at clinical doses/concentrations. Slopes slightly below 1 in the Schild plots of all tested antagonists point to a second 'counterregulatory' vasodilatory mechanism of action of Ang II which becomes apparent with AT1 blockade in conditions of high doses/concentrations of Ang II. Concentration vs. effect relationships indicate that if assessed at the same degree of direct vascular antagonism, other effects, such as increase in plasma renin activity, may be present to a varying degree with different antagonists. Thus for irbesartan, the potency to stimulate renin release was found to be at least twice that of candesartan. These observations should stimulate further research into the relevance of these dynamic differences between the various compounds. Thus, methodologies relying on fundamental principles of experimental pharmacology can provide the clinical pharmacologist with powerful tools to measure accurately degree of antagonism and time kinetics and to investigate the nature of receptor antagonism in humans.
Assuntos
Angiotensina II/administração & dosagem , Antagonistas de Receptores de Angiotensina , Angiotensina I/antagonistas & inibidores , Angiotensina I/farmacologia , Angiotensina II/agonistas , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Receptores de Angiotensina/classificação , Análise de RegressãoRESUMO
ANG II controls the vascular tone of pre- and postglomerular arterioles, and thereby glomerular filtration, through binding to either AT1A, AT1B, or AT2 receptors. AT1 receptors, which are coupled to intracellular Ca2+ signaling, have vasoconstricting effects, whereas AT2 receptors, whose signaling mechanism is unknown, induce vasodilatation. The angiotensin receptors have been characterized in afferent arterioles, which express the three types of receptors, but not in efferent arterioles. Two subpopulations of juxtamedullary efferent arterioles, muscular ones which terminate as vasa rectae and thin ones which terminate as peritubular capillaries, have been described. They display functional heterogeneity with regard to the ANG II response. To evaluate whether these differences are associated with differential expression of ANG II receptors, we examined the expression pattern of AT1A, AT1B, and AT2 receptor mRNAs by RT-PCR in these arterioles and studied the effect of valsartan, a specific AT1-receptor antagonist. Results indicate that muscular arterioles express AT1A, AT1B, and AT2 receptors, whereas thin arterioles only express the AT1A and AT2 types, and at a much lower level. Valsartan fully inhibited ANG II-induced increases in intracellular Ca2+ in both arteriolar types, but with different kinetics. In muscular arterioles, inhibition was monoexponential, whereas it displayed a marked positive cooperativity in thin arterioles. Finally, the apparent affinity for valsartan was higher in muscular than in thin arterioles. In conclusion, this study further documents the differences between muscular and thin efferent arterioles with regard to ANG II signalization in the rat kidney.
Assuntos
Arteríolas/metabolismo , Sistema Justaglomerular/irrigação sanguínea , Receptores de Angiotensina/classificação , Receptores de Angiotensina/genética , Valina/análogos & derivados , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Animais , Arteríolas/efeitos dos fármacos , Cálcio/metabolismo , Regulação da Expressão Gênica , Sistema Justaglomerular/efeitos dos fármacos , Masculino , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/metabolismo , Tetrazóis/farmacologia , Valina/farmacologia , ValsartanaRESUMO
Mesenteric arteries from male Sprague-Dawley rats were mounted in a pressurized myograph system. Ang-(1-7) concentration-dependent responses were determined in arteries preconstricted with endothelin-1 (10(-7)M). The receptor(s) mediating the Ang-(1-7) evoked dilation were investigated by pretreating the mesenteric arteries with specific antagonists of Ang-(1-7), AT(1) or AT(2) receptors. The effects of Ang-(3-8) and Ang-(3-7) were also determined. Ang-(1-7) caused a concentration-dependent dilation (EC(50): 0.95 nM) that was blocked by the selective Ang-(1-7) receptor antagonist D-[Ala(7)]-Ang-(1-7). Administration of a specific antagonist to the AT(2) receptor (PD123319) had no effect. On the other hand, losartan and CV-11974 attenuated the Ang-(1-7) effect. These results demonstrate that Ang-(1-7) elicits potent dilation of mesenteric resistance vessels mediated by a D-[Ala(7)]-Ang-(1-7) sensitive site that is also sensitive to losartan and CV-11974.
Assuntos
Artérias Mesentéricas/metabolismo , Receptores de Angiotensina/classificação , Receptores de Angiotensina/metabolismo , Angiotensina I/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Endotelina-1/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacosRESUMO
Previous experiments demonstrated that periarterial electrical nerve stimulation induced a double-peaked vasoconstriction consisting of an initial transient, predominantly P2X-purinoceptor-mediated, constriction followed by a prolonged, mainly alpha1-adrenoceptor-mediated, response in the canine splenic artery. Angiotensin II at a concentration of 0.1 nM did not affect the basal vascular tone and vasoconstrictions to exogenously administered noradrenaline (0.03-3 nmol) and adenosine 5'-triphosphate (0.01-1 micromol), but it markedly potentiated the double-peaked responses to nerve stimulation. The potentiating effect of angiotensin II was inhibited by KRH-594 (10 nM), a selective angiotensin II type 1 receptor antagonist, but was not influenced by PD123319 (0.01-0.1 microM), a selective angiotensin II type 2 receptor antagonist. The results indicate that angiotensin II potentiates sympathetic purinergic and adrenergic vasoconstrictions through the prejunctional angiotensin II type 1 receptor subtype in the canine splenic artery.
Assuntos
Angiotensina II/farmacologia , Receptores de Angiotensina/fisiologia , Artéria Esplênica/fisiologia , Vasoconstrição/fisiologia , Animais , Cães , Estimulação Elétrica/métodos , Feminino , Técnicas In Vitro , Masculino , Perfusão , Agonistas Purinérgicos , Receptor Tipo 1 de Angiotensina , Receptores Adrenérgicos/fisiologia , Receptores de Angiotensina/agonistas , Receptores de Angiotensina/classificação , Receptores Purinérgicos/fisiologia , Artéria Esplênica/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
A role for neuropeptide receptors in glial tumorigenesis has recently been proposed. Although angiotensin receptors are known to mediate proliferative effects in many cell types, including brain astrocytes, the possible participation of these receptors in glial tumorigenesis remains unknown. In the present study, we have examined the expression of the molecularly defined angiotensin receptor subtypes AT(1a), AT(1b), and AT(2) in normal perinatal rat astrocytes and in a panel of tumor adult astrocytoma cells, using the reverse transcriptase-polymerase chain reaction (RT-PCR). Subsequently, we compared the mitogenic effect of the angiotensins A(1-8), A(2-8), A(3-8) and the heptapeptide "metabolite" A(1-7), on both normal and tumor astrocytes, measured in terms of the incorporation of tritiated thymidine. Our results indicate that AT(1a), AT(1b), and AT(2) angiotensin receptor mRNA is commonly expressed by many of these cells. Of notable exception is the astrocytoma U373 which was not found to express AT(1) or AT(2) mRNA. Chronic (24-h) incubation of cells with A(1-8) and A(1-7) lead to the induction of mitogenesis, even in the AT(1) and AT(2) mRNA negative astrocytoma cell line U373. Moreover, pharmacological analysis indicated that the observed mitogenic effects are not mediated by the AT(1) or AT(2) type receptors, but rather by a novel, specific A((1-7)) angiotensin receptor, since mitogenesis was shown to be partially blocked by the A(1-7) analogue D-Ala(7)A(1-7) and by the protease inhibitor orthophenanthroline (100 microM). Using Fura-2 spectrophotometry, we found that activation of this receptor does not alter intracellular calcium levels; however, preincubation with the protein kinase kinase inhibitor U0126 (10 microM) was found to inhibit these mitogenic effects partially. Overall, these results which demonstrate that normal and tumor astrocytes express a greater variety of angiotensin receptor subtypes than previously thought, support the idea that A(1-7) and its receptor signaling system may play an important role in shaping the astrocyte population during development. Moreover, the untimely expression of this A((1-7)) receptor may represent an important etiological component in the development of brain astrocytomas.
Assuntos
Astrócitos/metabolismo , Astrocitoma/metabolismo , Receptores de Angiotensina/biossíntese , Receptores de Angiotensina/classificação , Angiotensinas/farmacologia , Angiotensinas/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/citologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , RNA Mensageiro/biossíntese , Ratos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Células Tumorais CultivadasRESUMO
Angiotensin II (Ang II), the physiologically active component of the renin-angiotensin system (RAS), plays an important role in the regulation of the renal function. Based on their different pharmacologic and biochemical properties, 2 distinct subtypes of Ang II receptor have been defined and designated as type 1 (AT(1)) and type 2 (AT(2)) receptors. Most of the well-characterized actions of Ang II are now generally considered to result from stimulation of AT(1) receptors, whereas AT(2) receptors may exert opposite effects against AT(1) receptors. In the kidney, activation of the AT(2) receptor has been reported to regulate pressure-natriuresis and to stimulate the production of nitric oxide, bradykinin, or epoxyeicosatrienoic acids, which may cause vasodilation and modulate the vasoconstrictor action mediated by AT(1) receptors. In addition, recent studies have reported that Ang II exerts important effects on the normal renal development through both AT(1) and AT(2) receptors. Finally, other Ang fragments such as Ang-(1-7) are also involved in the actions of RAS in the kidney. In this review article, we will summarize results obtained from recent studies on the AT(1) and AT(2) receptor-mediated action of Ang II in the kidney. Renal actions of Ang-(1-7), which often oppose against those of Ang II, are also discussed.
Assuntos
Angiotensina II/fisiologia , Angiotensina I/fisiologia , Rim/metabolismo , Fragmentos de Peptídeos/fisiologia , Receptores de Angiotensina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Humanos , Receptores de Angiotensina/classificaçãoRESUMO
Roles of angiotensin II (Ang II) in the regulation of cardiovascular system under normal and pathological condition have been well documented. Although two major subtypes of Ang II receptors, AT(1) and AT(2), are found in various proportions, the role and signaling mechanisms of AT(2) in the control of hypertrophic responses of cardiac ventricle and vasculature are not clear. Although earlier reports indicated that AT(2)'s functions are essentially growth suppression, an increasing number of recent reports indicate that AT(2) in cardiovascular tissues are often growth promoting. In some tissues AT(1) and AT(2) seem to share a common signaling pathways, at least in part. This review focuses on the accumulating evidence for the AT(2) function in the cardiovascular system.
Assuntos
Angiotensina II/fisiologia , Cardiomegalia/fisiopatologia , Receptores de Angiotensina/fisiologia , Animais , Cardiomegalia/etiologia , Previsões , Humanos , Camundongos , Receptores de Angiotensina/classificação , Sistema Renina-Angiotensina/fisiologia , Remodelação Ventricular/fisiologiaAssuntos
Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/farmacologia , Valina/análogos & derivados , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Benzimidazóis/farmacologia , Ligação Competitiva , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Desenho de Fármacos , Humanos , Irbesartana , Losartan/farmacologia , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/classificação , Receptores de Angiotensina/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Saralasina/farmacologia , Tetrazóis/farmacologia , Valina/farmacologia , ValsartanaRESUMO
The structure of the angiotensin molecule has been well preserved throughout the vertebrate scale with some amino acid variations. Specific angiotensin receptors (AT receptors) that mediate important physiological functions have been noted in a variety of tissues and species. Physiological and pharmacological characterization of AT receptors and, more recently, molecular cloning studies have elucidated the presence of AT receptor subtypes. Comparative studies suggest that an AT receptor subtype homologous to the mammalian type 1 receptor subtype (AT(1)), though pharmacologically distinct, is present in amphibians and birds, whereas AT receptors cloned from teleosts show low homology to both AT(1) and AT(2) receptor subtypes. Furthermore, receptors differing from both the AT(1)-homologue receptor and AT(2) receptor exist in some non-mammalian species. This may suggest that the prototype AT receptor evolved in primitive vertebrates and diverged to more than one type of AT receptor subtype during phylogeny. Furthermore, phenotypic modulation of AT receptors appears to occur during individual development/maturation.
Assuntos
Evolução Biológica , Receptores de Angiotensina/genética , Receptores de Angiotensina/fisiologia , Animais , Expressão Gênica , Humanos , Filogenia , Receptores de Angiotensina/classificação , Sistema Renina-Angiotensina , Transdução de Sinais , VertebradosRESUMO
Despite advances characterizing mammalian angiotensin receptors, the phylogeny of fish angiotensin receptors remains unclear. Three aspects of receptor function: (1) the nature of the ligand; (2) the second messenger system activated by it; and (3) the pharmacological profile of specific antagonists, are examined to provide insight into the fish receptor. (1) The octapeptide sequences of fish and mammalian angiotensin II (ANG II) are nearly homologous, differing only at the first and fifth residues. Both peptides are almost equally efficacious and equipotent in heterologous systems and both contain key agonist switches Tyr(4) and Phe(8) necessary to activate mammalian AT(1)-type receptors. (2) ANG II increases inositol trisphosphate production, and elevates intracellular calcium in fish tissues consistent with activation of the AT(1) receptor. (3) However, the specific mammalian sartan-type AT(1) antagonists, e.g. losartan, produce inconsistent results in fish often acting as partial agonists, or inhibiting only at elevated concentrations. Because sartans and ANG II act at distinct sites on the AT(1) receptor, we propose that the teleost receptor is an AT(1)-type receptor that is fairly well conserved with respect to both the ANG binding site and coupling to the second messenger system, whereas the sartan binding site has been poorly conserved. The evidence for non-AT(1) type ANG II receptors in teleosts is limited. Mammalian AT(2) receptor antagonists are generally ineffective but may block at elevated, non-specific doses. Truncated ANG II fragments, ANG III and ANG IV, are often less potent than ANG II, however, their receptors have not been examined. Preliminary studies in trout indicate that angiotensin 1-7 may have a mild vasodilatory effect; additional work is needed to determine if non-AT(1)-type receptors are involved.
Assuntos
Angiotensinas/fisiologia , Peixes/fisiologia , Receptores de Angiotensina/fisiologia , Sequência de Aminoácidos , Angiotensinas/genética , Animais , Fenômenos Fisiológicos Cardiovasculares , Sistema Nervoso Central/fisiologia , Ingestão de Líquidos/fisiologia , Peixes/genética , Brânquias/fisiologia , Humanos , Intestinos/fisiologia , Rim/fisiologia , Fígado/fisiologia , Mamíferos , Receptores de Angiotensina/classificação , Receptores de Angiotensina/genética , Homologia de Sequência , Transdução de SinaisRESUMO
Angiotensin II mediates is biological actions via different subtypes of G protein-coupled receptors, termed AT(1) and AT(2) receptors. In rodents, two AT(1) receptors have been identified, AT(1A) and AT(1B), whereas in humans a single AT(1) receptor exists. Recently, a number of transgenic animal models have been generated which overexpress or lack functional angiotensin II receptor subtypes. This review focuses on the physiological significance of angiotensin II receptor subtype diversity in the cardiovascular system. In the mouse, AT(1A) receptors are the major regulators of cardiovascular homeostasis by determining vascular tone and natriuresis. In addition, AT(1A) receptors mediate growth-stimulating signals in vascular and cardiac myocytes. AT(1B) receptors participate in blood pressure regulation, and their functions become apparent when the AT(1A) receptor gene is deleted. Deletion of the mouse gene for the AT(2) receptor subtype led to hypersensitivity to pressor and antinatriuretic effects of angiotensin II in vivo, suggesting that the AT(2) receptor subtype counteracts some of the biological effects of AT(1) receptor signalling.
Assuntos
Sistema Cardiovascular/metabolismo , Camundongos Transgênicos/metabolismo , Receptores de Angiotensina/metabolismo , Angiotensina II/fisiologia , Animais , Pressão Sanguínea , Cardiomegalia/fisiopatologia , Rim/fisiologia , Camundongos , Receptores de Angiotensina/classificação , Receptores de Angiotensina/deficiência , Receptores de Angiotensina/genética , Transdução de SinaisRESUMO
Sixty years after its initial discovery, the octapeptide hormone angiotensin II (AngII) has proved to play numerous physiological roles that reach far beyond its initial description as a hypertensive factor. In spite of the host of target tissues that have been identified, only two major receptor subtypes, AT1 and AT2, are currently fully identified. The specificity of the effects of AngII relies upon numerous and complex intracellular signaling pathways that often mobilize calcium ions from intracellular stores or from the extracellular medium. Various types of calcium channels (store- or voltage-operated channels) endowed with distinct functional properties play a crucial role in these processes. The activity of these channels can be modulated by AngII in a positive and/or negative fashion, depending on the cell type under observation. This chapter reviews the main characteristics of AngII receptor subtypes and of the various calcium channels as well as the involvement of the multiple signal transduction mechanisms triggered by the hormone in the cell-specific modulation of the activity of these channels.
Assuntos
Angiotensina II/fisiologia , Canais de Cálcio/metabolismo , Receptores de Angiotensina/classificação , Canais de Cálcio/fisiologia , Eletrofisiologia , Humanos , Ativação do Canal Iônico/fisiologia , Receptores de Angiotensina/fisiologia , Transdução de Sinais/fisiologiaRESUMO
All components of the renin-angiotensin system (RAS) are present in the kidneys and constitute a functioning renal RAS. Angiotensin II (Ang II) receptor subtypes AT(1) and AT(2) have been identified in the afferent and efferent arterioles, glomeruli, mesangial cells, and proximal tubules. AT(1) receptors regulate vasoconstriction and sodium and water reabsorption, as well as promote cell growth, proliferation, and collagen matrix deposition. Recent animal studies are elucidating the role of the less well understood AT(2) receptors. The AT(2) receptors appear to counterbalance the AT(1) receptors by increasing the production of bradykinin, nitric oxide, and cyclic guanosine monophosphate-mediating vasodilation and by promoting cell differentiation, antiproliferation, and apoptosis. Ang II subtype 1 receptor blockers prevent Ang II activation of the AT(1) receptor while leaving the AT(2) receptor open to Ang II stimulation.