RESUMO
More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.
Assuntos
Anti-Hipertensivos , Géis , Hipertensão , Losartan , Losartan/farmacocinética , Losartan/administração & dosagem , Losartan/farmacologia , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Animais , Hipertensão/tratamento farmacológico , Masculino , Ratos , Disponibilidade Biológica , Administração Intranasal , Nanopartículas/química , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Tamanho da Partícula , Angiotensina II/farmacocinética , Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ratos Wistar , Química Farmacêutica/métodosRESUMO
OBJECTIVE: To review and summarize data on angiotensin II (AT-II), approved by the Food and Drug Administration (FDA) in December 2017 to increase blood pressure in adults with septic or other distributive shock. DATA SOURCES: A PubMed/MEDLINE search was conducted using the following terms: (angiotensin ii OR angiotensin 2) AND (shock) from 1966 to February 2018. STUDY SELECTION AND DATA EXTRACTION: A total of 691 citations were reviewed with only relevant clinical data extracted. DATA SYNTHESIS: AT-II is a peptide hormone with a multitude of physiological effects-namely, vasoconstriction of venous and arterial smooth muscle. The priority approval granted by the FDA was secondary to a phase 3 study of patients receiving at least 0.2 µg/kg/min of norepinephrine or equivalent for vasodilatory shock. Compared with placebo, AT-II had a significantly higher rate of response, defined as a mean arterial pressure of 75 mm Hg or an increase of 10 mm Hg. No significant difference was found in death by day 28. CONCLUSIONS: AT-II is a newly available vasoactive agent with a novel mechanism for the treatment of distributive shock. Further research is needed to define its exact role in therapy of shock states, identify patients most likely to benefit, and further study its safety profile in critical illness.
Assuntos
Angiotensina II/administração & dosagem , Choque/tratamento farmacológico , Vasoconstritores/administração & dosagem , Angiotensina II/efeitos adversos , Angiotensina II/farmacocinética , Animais , Humanos , Choque/metabolismo , Resultado do Tratamento , Vasoconstritores/efeitos adversos , Vasoconstritores/farmacocinéticaRESUMO
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .
Assuntos
Cuidados Críticos/métodos , Angiotensina II/farmacocinética , Angiotensina II/uso terapêutico , Angiotensinas/farmacocinética , Angiotensinas/uso terapêutico , Cuidados Críticos/tendências , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/etiologia , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Vasoconstritores/farmacocinética , Vasoconstritores/uso terapêuticoRESUMO
Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target.
Assuntos
Angiotensina II/farmacocinética , Proteínas dos Microfilamentos/metabolismo , Tono Muscular/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Angiotensina II/farmacologia , Animais , Aorta , Autofagia/efeitos dos fármacos , Células Cultivadas , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/genética , Camundongos , Proteínas dos Microfilamentos/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteína Sequestossoma-1 , Sódio na Dieta/farmacologia , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , VasoconstriçãoRESUMO
Intracerebroventricular (i.c.v.) administration of angiotensin IV (Ang IV) or Leu-Val-Val-haemorphin 7 (LVV-H7) improves memory performance in normal rats and reverses memory deficits in rat models for cognitive impairment. These memory effects were believed to be mediated via the putative 'AT4 receptor'. However, this binding site was identified as insulin-regulated aminopeptidase (IRAP). Correspondingly, Ang IV and LVV-H7 were characterised as IRAP inhibitors. This study investigates whether and how IRAP may be involved in the central effects of Ang IV and LVV-H7. We determined the effects of i.c.v. administration of Ang IV or LVV-H7 on hippocampal neurotransmitter levels using microdialysis in rats. We observed that Ang IV modulates hippocampal acetylcholine levels, whereas LVV-H7 does not. This discrepancy was reflected in the observation that Ang IV binds with micromolar affinity to the AT1 receptor whereas no binding affinity was observed for LVV-H7. Correspondingly, we demonstrated that the AT1 receptor is involved in the effects of Ang IV on hippocampal neurotransmitter levels and on spatial working memory in a plus maze spontaneous alternation task. However, the AT1 receptor was not involved in the spatial memory facilitating effect of LVV-H7. Finally, we demonstrated that Ang IV did not diffuse to the hippocampus following i.c.v. injection, suggesting an extrahippocampal site of action. We propose that AT1 receptors are implicated in the neurochemical and cognitive effects of Ang IV, whereas LVV-H7 may mediate its effects via IRAP.
Assuntos
Angiotensina II/análogos & derivados , Hemoglobinas/administração & dosagem , Hipocampo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Neurotransmissores/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Receptor Tipo 1 de Angiotensina/fisiologia , Angiotensina II/administração & dosagem , Angiotensina II/farmacocinética , Animais , Relação Dose-Resposta a Droga , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Injeções Intraventriculares/métodos , Isótopos de Iodo/farmacocinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microdiálise/métodos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Percepção Espacial/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
We set out to confirm the long-held, but untested, assumption that dietary salt affects proximal reabsorption through reciprocal effects on the renin-angiotensin system in a way that facilitates salt homeostasis. Wistar rats were fed standard or high-salt diets for 7 days and then subjected to renal micropuncture for determination of single-nephron GFR (SNGFR) and proximal reabsorption. The tubuloglomerular feedback (TGF) system was used as a tool to manipulate SNGFR in order to distinguish primary changes in net proximal reabsorption (Jprox) from changes due to glomerulotubular balance. The influence of Ang II over Jprox was determined by the sensitivity of Jprox to the AT1 receptor antagonist, losartan. Plasma, whole kidneys, and fluid from midproximal tubules were assayed for Ang II content by radioimmunoassay. In rats on the standard diet, losartan reduced Jprox by 25% and reduced the maximum range of the TGF response by 50%. The high-salt diet suppressed plasma and whole-kidney Ang II levels. But the high-salt diet failed to reduce the impact of losartan on Jprox or the TGF response and actually caused tubular fluid Ang II content to increase. The persistent effect of Ang II on Jprox prevented a major rise in late proximal flow rate in response to the high-salt diet. These observations challenge the traditional model and indicate that the role of proximal tubular Ang II in salt-replete rats is to stabilize nephron function rather than to contribute to salt homeostasis.
Assuntos
Angiotensina II/metabolismo , Túbulos Renais Proximais/fisiologia , Sódio na Dieta/metabolismo , Absorção/fisiologia , Angiotensina II/sangue , Angiotensina II/farmacocinética , Animais , Homeostase , Túbulos Renais Proximais/metabolismo , Masculino , Néfrons/fisiologia , Ratos , Ratos Wistar , Sódio na Dieta/administração & dosagemRESUMO
Accumulation of specific deposits and extracellular molecules under the retinal pigment epithelium (RPE) has been previously observed in eyes with age-related macular degeneration (AMD) and may play a role in the pathogenesis of AMD. Even though age is the major determinant for developing AMD, clinical studies have revealed hypertension (HTN) as another systemic risk factor. Angiotensin II (Ang II) is considered the most important hormone associated with HTN. To evaluate the relationship of Ang II to AMD, we studied whether mouse RPE expresses functional Ang II receptor subtypes and whether HTN-induced Ang II regulates expression of these receptors as well as critical ECM molecules (MMP-2 and type IV collagen) involved in ECM turnover in RPE. We used 9-month-old C57BL/6 male mice infused with Ang II alone or Ang II in combination with the AT1 receptor antagonist candesartan or the AT2 receptor antagonist PD123319 for 4 weeks to determine whether HTN-associated Ang II was important for ECM regulation in RPE. We found that mouse RPE expressed both Ang II receptor subtypes at the mRNA and protein levels. Infusion with Ang II induced HTN and elevated plasma and ocular Ang II levels. Ang II also regulated AT1a and AT1b receptor mRNA expression, the intracellular concentration of calcium [Ca(2+)](i), MMP-2 activity, and type IV collagen accumulation. Concurrent administration of Ang II with the AT1 receptor blocker prevented the increase in blood pressure and rise in ocular Ang II levels, as well as the calcium and MMP-2 responses. In contrast, the type IV collagen response to Ang II was prevented by blockade of AT2 receptors, but not AT1 receptors. Plasma Ang II levels were not modified by the AT1 or AT2 receptor blockade. Since the effects of Ang II on MMP-2 and type IV collagen require inhibition of both Ang II receptor subtypes, these receptors may play a role as a potential therapeutic targets to prevent ECM turnover dysregulation in the RPE basement membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD.
Assuntos
Angiotensina II/farmacologia , Matriz Extracelular/efeitos dos fármacos , Hipertensão/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Angiotensina II/farmacocinética , Animais , Pressão Sanguínea/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Colágeno Tipo IV/metabolismo , Matriz Extracelular/metabolismo , Olho/metabolismo , Proteínas do Olho/biossíntese , Proteínas do Olho/genética , Proteínas do Olho/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração Macular/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Receptor Tipo 2 de Angiotensina/biossíntese , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/fisiologia , Epitélio Pigmentado da Retina/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismoRESUMO
A transient reduction in the barrier nature of the skin can be a pre-requisite for successful (trans)dermal delivery of some drugs. The aim of this present study was to investigate and effect of a dermal abrading "rotating brush" device on percutaneous absorption and skin integrity. In vitro experiments were conducted using excised human epidermal membrane. The effect of device parameters (bristle type, treatment duration and applied pressure) on skin permeability of model solutes (methyl paraben, butyl paraben, caffeine, acyclovir and angiotensin II) with varying physicochemical properties was examined and compared to established methods of skin penetration enhancement (positive controls). The device parameter which was found to have the most marked effect on permeability of the compounds was bristle type. Profound changes (2- to 100-fold increase) were observed in the epidermal permeability of the hydrophilic penetrants (caffeine, acyclovir and angiotensin II), when the brush device was employed compared to positive controls (ethanol enhancement, delipidisation, iontophoresis and tape-stripping). Findings from this present study support the effectiveness of a rotating brush applied to the skin in enhancing epidermal permeability. Further optimization of operational parameters is required to exploit this simple and effective delivery device.
Assuntos
Pele/metabolismo , Aciclovir/química , Aciclovir/farmacocinética , Angiotensina II/química , Angiotensina II/farmacocinética , Cafeína/química , Cafeína/farmacocinética , Humanos , Parabenos/química , Parabenos/farmacocinética , Permeabilidade , Rotação , Tecnologia FarmacêuticaRESUMO
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, ß-site APP cleaving enzyme (BACE1) expression and production of amyloid ß (Aß)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aß generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by senescence. Loss of sAPPα in senescent cells treated with Ang II exacerbates detrimental effects of senescence on APP processing. Notably, inhibition of BACE1 has beneficial effects on senescence induced endothelial dysfunction. Reported findings may help to explain contributions of senescent cerebral microvascular endothelium to development of cerebral amyloid angiopathy and Alzheimer's disease (AD) pathology.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Angiotensina II/farmacocinética , Ácido Aspártico Endopeptidases/metabolismo , Células Endoteliais/efeitos dos fármacos , Vasoconstritores/farmacologia , Envelhecimento , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Western Blotting , Encéfalo , Angiopatia Amiloide Cerebral , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica , HumanosRESUMO
Endothelium-derived steroidogenic factor (EDSF) is an endothelial peptide that stimulates aldosterone release from bovine adrenal zona glomerulosa (ZG) cells. The regulation of aldosterone release by combinations of EDSF and angiotensin II (AII) or EDSF and ACTH was investigated. Endothelial cells (ECs) and EC-conditioned media (ECCM) increased aldosterone release from ZG cells, an activity attributed to EDSF. AII (10(-12) to 10(-8) M) and ACTH (10(-12) to 10(-9) M) also stimulated the release of aldosterone from ZG cells. The stimulation by AII, but not ACTH, was greatly enhanced when ZG cells were coincubated with ECs. AII was metabolized by ECs to peptides identified by mass spectrometry as angiotensin (1-7) and angiotensin IV. There was very little metabolism of AII by ZG cells. Neither of these two AII metabolites altered aldosterone release from ZG cells, so they could not account for the enhanced response with ECs. AII-induced aldosterone release from ZG cells was enhanced by ECCM but not cell-free conditioned medium. This enhanced response was not due to increased EDSF release from ECs by AII. The synergistic effect of EDSF and AII was apparent when AII was added during or after the generation of ECCM and not observed when the AII component of the enhancement was blocked by the AII antagonist, losartan. These studies indicate that EDSF enhances the steroidogenic effect of AII. In the adrenal gland, ECs are in close anatomical relationship with ZG cells and may sensitize ZG cells to the steroidogenic action of AII by releasing EDSF.
Assuntos
Aldosterona/metabolismo , Angiotensina II/farmacocinética , Peptídeos/metabolismo , Vasoconstritores/farmacocinética , Zona Glomerulosa/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Animais , Bovinos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Endotélio/metabolismo , Radioisótopos do Iodo , Fragmentos de Peptídeos/metabolismo , Zona Glomerulosa/citologia , Zona Glomerulosa/efeitos dos fármacosRESUMO
BACKGROUND: The response of proximal convoluted tubules (PCTs) to angiotensin II is mediated by specific type 1 receptors found on both apical and basolateral surface membrane cells. After ligand association with type 1 receptors, different signaling pathways are triggered and determine changes in fluid absorption (Jv). The presence of AT1 and actin cytoskeleton, which are directly related to Jv, can undergo changes in distribution based on the actions of AngII and losartan. METHODS: Using a microperfusion technique and immunohistochemistry analysis, we investigated the basolateral action in PCTs, of AngII and/or losartan on Jv in rabbits, with regard to AT1 and actin cytoskeleton. RESULTS: AngII increased Jv, while in contrast, losartan and combined AngII + losartan led to its decrease. AngII did not change fluorescence intensity of AT1 receptors on tubular membranes, while losartan and AngII + losartan demonstrated a slight increase after treatment. On the other hand, AngII increased the fluorescence intensity of actin cytoskeleton, while losartan induced a decrease. AngII + losartan led actin cytoskeleton having a higher fluorescence intensity than in the control group. CONCLUSIONS: In the present study, we demonstrated that treatment of the basolateral side of PCT cells with AngII and losartan could lead to changes in absorptive tubular function. Important alterations were detected in AT1 receptor fluorescence on the luminal and basolateral membranes, and changes in F-actin cytoskeleton were verified by fluorescence following these protocols.
Assuntos
Actinas/metabolismo , Angiotensina II/farmacologia , Citoesqueleto/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Absorção/fisiologia , Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Losartan/farmacocinética , Losartan/farmacologia , Masculino , CoelhosAssuntos
Angiotensina II/farmacocinética , Aneurisma da Aorta Abdominal/fisiopatologia , Aterosclerose/fisiopatologia , Angiotensina II/administração & dosagem , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aterosclerose/metabolismo , Modelos Animais de Doenças , Infusões Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacocinéticaRESUMO
Low efficacy of cationic polymer-based formulations (polyplexes) for systemic gene delivery to tumors remains the crucial concern for their clinical translation. Here we show that modulating the physiological state of a tumor using clinically approved pharmaceuticals can improve delivery of intravenously injected polyplexes to murine melanoma tumors with different characteristics. Direct comparison of drugs with different mechanisms of action has shown that application of nitroglycerin or losartan improved extravasation and tumor uptake of polyplex nanoparticles, whereas angiotensin II had almost no effect on polyplex accumulation and microdistribution in the tumor tissue. Application of nitroglycerin and losartan caused from 2- to 6-fold enhanced efficacy of polyplex-mediated gene delivery depending on the tumor model. The results obtained on polyplex behavior in tumor tissues depending on physiological state of the tumor can be relevant to optimize delivery of polyplexes and other nanomedicines with similar physicochemical properties.
Assuntos
Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Melanoma Experimental/terapia , Administração Intravenosa , Angiotensina II/administração & dosagem , Angiotensina II/farmacocinética , Angiotensina II/farmacologia , Animais , Linhagem Celular Tumoral , Colágeno Tipo I/metabolismo , DNA/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Losartan/administração & dosagem , Losartan/farmacocinética , Losartan/farmacologia , Luciferases de Vaga-Lume/genética , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nanopartículas/administração & dosagem , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacocinética , Nitroglicerina/farmacologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polietilenoimina/administração & dosagem , Polietilenoimina/análogos & derivados , Polietilenoimina/farmacocinética , Polietilenoimina/farmacologia , Receptor Tipo 1 de Melanocortina/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacocinética , Vasoconstritores/farmacologia , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologiaRESUMO
Selective competitive angiotensin AT(1) receptor antagonists exhibit diverse patterns of antagonism of angiotensin-II-mediated responses in functional assays. These range from the classical parallel rightward shift of agonist concentration-response curves with no depression of the maximum response to an apparently straightforward insurmountable antagonism with complete depression of the maximum response and no rightward shift. This article reviews some earlier equilibrium-based models that have been used to explain the insurmountable antagonism, and suggests that a kinetic model might provide a more satisfactory account of the observations. Such a model might provide deeper insights into the pharmacology of G-protein-coupled receptors than the more popular equilibrium models.
Assuntos
Angiotensina II/farmacocinética , Antagonistas de Receptores de Angiotensina , Modelos Químicos , Animais , Células CHO , Cricetinae , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/metabolismoRESUMO
BACKGROUND: The aim of the present study was to compare glomerular permeability alterations associated with experimental hypertension models known to have different effects on the circulating renin-angiotensin system (RAS). METHODS: Five groups, 10 animals each, were studied. One group served as a nonhypertensive control. The other four groups of hypertensive animals were composed of spontaneously hypertensive rats, deoxycorticosterone acetate hypertensive rats, Goldblatt two-kidney, one-clip rats, and a group of Wistar rats infused with angiotensin II (200 ng/kg/min). Tail-cuff sphygmomanometric systolic blood pressure (BP), albumin permeability determined in isolated glomeruli exposed to oncotic gradients (P(alb)), glomerular filtration rate (GFR, iopamidol method), plasma renin activity (PRA), and albuminuria were evaluated. RESULTS: Alterations in P(alb) and albumin excretion rate were more evident in the experimental models with an activation of the RAS despite similar levels of systolic BP and GFR. A positive correlation was found between P(alb) and albuminuria (r = 0.51; P < .001) and between systolic BP and albuminuria (r = 0.37; P < .01). No relation was found between systolic BP and P(alb). CONCLUSIONS: The present study indicates that the activation of the RAS plays a significant role in the development of glomerular albumin permeability defects in hypertensive models and may contribute to the mechanisms that lead to target organ damage in hypertension.
Assuntos
Hipertensão/metabolismo , Glomérulos Renais/metabolismo , Sistema Renina-Angiotensina/fisiologia , Albuminas/metabolismo , Angiotensina II/farmacocinética , Animais , Pressão Sanguínea/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/toxicidade , Modelos Animais de Doenças , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Radioimunoensaio , Ratos , Ratos Endogâmicos Dahl , Ratos Endogâmicos SHR , Ratos Wistar , Renina/sangue , Vasoconstritores/farmacocinéticaRESUMO
Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.
Assuntos
Angiotensina II/farmacologia , Rim/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Angiotensina II/farmacocinética , Angiotensinogênio/análise , Animais , Compostos de Bifenilo/farmacologia , Hipertensão/induzido quimicamente , Imidazóis/farmacologia , Losartan , Masculino , Ratos , Ratos Sprague-Dawley , Renina/sangue , Tetrazóis/farmacologiaRESUMO
Angiotensin (Ang) type 1a (AT1a) receptors are critical in the control of blood pressure and water balance. Experiments were performed to determine the influence of dehydration on brain Ang receptors and plasma vasopressin (VP) in mice lacking this receptor. Control or AT1a knockout (AT1aKO) male mice were give water ad libitum or deprived of water for 48 hours. Animals were anesthetized with halothane, blood samples were collected by heart puncture, and brains were processed for Ang-receptor autoradiography with 125I-sarthran (0.4 nmol/L). Dehydration produced an increase in AT1 receptors in the paraventricular nucleus (PVN) and anterior pituitary (AP) in control mice (PVN: 70+/-16 versus 146+/-10 fmol/mg protein; AP: 41+/-7 versus 86+/-15 fmol/mg protein). No changes were noted in the median preoptic nucleus. The majority of the brain receptors were of the AT1 subtype. There was little or no specific Ang binding in AT1aKO mice and no effect of dehydration. Plasma VP levels were elevated in the halothane-anesthetized animals (>200 pg/mL) with no significant effect of dehydration. A separate experiment was performed with decapitated mice anesthetized with pentobarbital. Dehydration increased plasma VP in control mice, from 3.3+/-0.6 to 13.3+/-4.7 pg/mL, whereas no change was noted in the AT1aKO mice, 5.1+/-0.3 versus 6.1+/-0.7 pg/mL (water versus dehydration). These results demonstrate a differential response to dehydration in mice lacking AT1a receptors. There was no evidence for AT1 receptors of any subtype in the brain regions examined and no effect of dehydration on VP secretion or brain Ang receptors.
Assuntos
Encéfalo/metabolismo , Desidratação/fisiopatologia , Receptores de Angiotensina/fisiologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacocinética , Animais , Autorradiografia , Desidratação/genética , Radioisótopos do Iodo , Losartan/farmacologia , Masculino , Camundongos , Camundongos Knockout , Núcleo Hipotalâmico Paraventricular/metabolismo , Adeno-Hipófise/metabolismo , Área Pré-Óptica/metabolismo , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/deficiência , Receptores de Angiotensina/genética , Valores de Referência , Vasopressinas/sangue , Privação de ÁguaRESUMO
Since it was previously reported that atrial natriuretic factor (ANF) may exert an inhibitory effect on renin release, the existence of an Angiotensin II (Ang II)-ANF feedback mechanism was investigated. Male rats were infused intraperitoneally for 7 days with either saline, a nonpressor dose of Ang II (200 ng/kg/min), or a pressor dose (800 ng/kg/min) of Ang II. Systolic blood pressure, plasma ANF, 24-hour urinary sodium excretion, urine volume, and water intake were measured. A significant increase in plasma ANF was observed in the group with a pressor response (blood pressure rose from 89.0 +/- 3.9 to 136.7 +/- 11.4 mm Hg; ANF rose from 36.8 +/- 4.9 to 92.7 +/- 17.7 pg/ml). There was no significant time effect on 24-hour sodium excretion, urine volume, and water intake in both Ang II-infused groups. In a second set of experiments, male rats were infused intravenously for 60 minutes with either saline, a nonpressor dose of Ang II (16 ng/kg/min), or a pressor dose (800 ng/kg/min) of Ang II. Left ventricular end-diastolic pressure, right atrial pressure, and mean arterial pressure were monitored. There was a significant increase in plasma ANF and left ventricular end-diastolic pressure only with the pressor dose (blood pressure rose from 85.0 +/- 6.1 to 140.0 +/- 5.5 mm Hg; ANF rose from 22.6 +/- 6.0 to 108.3 +/- 47.7 pg/ml; left ventricular end-diastolic pressure rose from 5.3 +/- 5.7 to 20.8 +/- 7.9 mm Hg). No significant modification of right atrial pressure was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Angiotensina II/farmacocinética , Fator Natriurético Atrial/metabolismo , Aldosterona/sangue , Análise de Variância , Angiotensina II/administração & dosagem , Animais , Fator Natriurético Atrial/sangue , Pressão Sanguínea/efeitos dos fármacos , Estado de Consciência , Átrios do Coração/análise , Átrios do Coração/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Técnicas In Vitro , Bombas de Infusão , Infusões Intravenosas , Infusões Parenterais , Masculino , Ratos , Ratos Endogâmicos , Renina/sangue , Fatores de TempoRESUMO
We determined the mechanism accounting for the removal and metabolism of angiotensin-(1-7) [Ang-(1-7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36 mRen-2 transgenic (TG+) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1-7) was infused for a period of 15 minutes at a rate of 278 nmol . kg-1 . min-1. After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1-7) levels by radioimmunoassay. Infusion of Ang-(1-7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG+ rats. In lisinopril-treated rats, Ang-(1-7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1-7) in all 3 strains. In vehicle-treated SD, SHR and TG+ the half-life (t1/2) of Ang-(1-7) averaged 10+/-1, 10+/-1, and 9+/-1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1-7) in all 3 strains of rats. Plasma clearance of Ang-(1-7) was significantly greater in the untreated SD rats compared with either the SHR or TG+ rat. Lisinopril treatment was associated with reduced clearance of Ang-(1-7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of 125I-Ang-(1-7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1-7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system.
Assuntos
Angiotensina II/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fragmentos de Peptídeos/farmacocinética , Administração Oral , Angiotensina I , Angiotensina II/sangue , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Animais Geneticamente Modificados , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cromatografia Líquida de Alta Pressão , Combinação de Medicamentos , Meia-Vida , Lisinopril/metabolismo , Lisinopril/farmacologia , Losartan/farmacologia , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Radioimunoensaio , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
We conducted studies in conscious chronically catheterized, trained young (3-5 months) and old (18-20 months) rats to assess the impact of aging on baseline renin activity (PRA) and metabolic clearance rate (MCR) of angiotensin II (ANG II). We observed that under unstressed conditions the baseline values of PRA and plasma ANG II were no different in young versus old rats (1.8 +/- 0.2 versus 1.5 +/- 0.2 ng Al/ml/h and 18 +/- 3 versus 15 +/- 2 fmol/ml, respectively). Values of PRA in the present study were similar to those reported by others for old rats, but our young rat values were lower than usually reported. This probably reflects our use of an unstressed preparation. We also observed a blunted increase in PRA in old rats in response to acute converting enzyme inhibition. Overall, our observations suggest that old rats may lose their ability to increase PRA in response to acute stimuli, including perhaps, the stress of blood drawing in emotionally or surgically stressed preparations. We also observed that the MCR of ANG II increased with age, despite similar baseline plasma ANG II concentrations in young and old. This suggests that with aging, an increase occurs in the rate of synthesis of ANG II. These results emphasize the importance of establishing true baseline values for indices of the renin-ANG II system in aging.