RESUMO
The Betta fish displays a remarkable variety of phenotypes selected during domestication. However, the genetic basis underlying these traits remains largely unexplored. Here, we report a high-quality genome assembly and resequencing of 727 individuals representing diverse morphotypes of the Betta fish. We show that current breeds have a complex domestication history with extensive introgression with wild species. Using a genome-wide association study, we identify the genetic basis of multiple traits, including coloration patterns, the "Dumbo" phenotype with pectoral fin outgrowth, extraordinary enlargement of body size that we map to a major locus on chromosome 8, the sex determination locus that we map to dmrt1, and the long-fin phenotype that maps to the locus containing kcnj15. We also identify a polygenic signal related to aggression, involving multiple neural system-related genes such as esyt2, apbb2, and pank2. Our study provides a resource for developing the Betta fish as a genetic model for morphological and behavioral research in vertebrates.
Assuntos
Peixes , Estudo de Associação Genômica Ampla , Agressão , Animais , Peixes/genética , Fenótipo , Análise de Sequência de DNARESUMO
Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.
Assuntos
Acetilcolina/fisiologia , Estrogênios/fisiologia , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Cromossomo X/fisiologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Feminino , Genes sry/genética , Genótipo , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fenótipo , Fatores Sexuais , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.
Assuntos
Aldosterona/fisiologia , Anti-Hipertensivos/uso terapêutico , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Resistência a Medicamentos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Hormônios Esteroides Gonadais/fisiologia , Humanos , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/genética , Hiperaldosteronismo/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/genética , Canais Iônicos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Terapia de Alvo Molecular , Medicina de Precisão , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Caracteres Sexuais , Cromossomos Sexuais , Equivalência Terapêutica , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ≈30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anlodipino/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Indóis/toxicidade , Pirimidinas/uso terapêutico , Pirróis/toxicidade , Sulfonamidas/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/fisiopatologia , Inibidores da Angiogênese/toxicidade , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Antagonistas do Receptor de Endotelina A/uso terapêutico , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Ratos , Ratos Endogâmicos WKY , Sunitinibe , Resultado do TratamentoRESUMO
Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.
Assuntos
Amidas/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Fumaratos/farmacologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Oligopeptídeos/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Renina/genética , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Feminino , Masculino , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores de Superfície Celular/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Estreptozocina/efeitos adversos , Receptor de Pró-ReninaRESUMO
SIGNIFICANCE: Angiogenesis inhibition with humanized antibodies targeting vascular endothelial growth factor (VEGF) or orally active small tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment modality for various forms of cancer. A common side effect of angiogenesis inhibition is the development of sometimes severe hypertension, which simultaneously appears to be predictive for a favorable antitumor response. RECENT ADVANCES: Since VEGF increases the expression and activity of endothelial nitric oxide synthase, it has been assumed that the mean blood pressure (MAP) rise during angiogenesis inhibition is caused by a decrease in nitric oxide bioavailability. Yet, the results from experimental and clinical studies exploring this possibility are conflicting. Recent studies provided evidence that the MAP rise during angiogenesis inhibition rather is mediated by activation of the endothelin-1 (ET-1) axis, which, among others, induces oxidative stress. Nevertheless, conclusive evidence for the involvement of reactive oxygen species in the MAP rise could not be obtained so far. CRITICAL ISSUES: The mechanism underlying activation of the ET-1 axis during angiogenesis inhibition is unclear, and this activation was not anticipated in view of studies showing that VEGF stimulates both the expression and production of ET-1 by endothelial cells. FUTURE DIRECTIONS: In fact, this activation of the ET-1 axis may support the use of ET receptor antagonists for the treatment of angiogenesis inhibition-induced hypertension, especially because ET receptor stimulation in vascular smooth muscle cells results in VEGF production and mitogenesis in a mitogen-activated protein kinase pathway-dependent manner.
Assuntos
Endotelina-1/metabolismo , Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Humanos , Hipertensão/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: Elevated prorenin levels associate with microvascular complications in patients with diabetes mellitus, possibly because prorenin affects vascular function in diabetes mellitus, for example by generating angiotensins following its binding to the (pro)renin receptor [(P)RR]. Here we evaluated whether the renin inhibitor aliskiren, with or without the putative (P)RR antagonist handle region peptide (HRP) improved the disturbed vascular function in diabetic TGR(mREN2)27 rats, a high-prorenin, high-(P)RR hypertensive model. METHODS: Telemetry transmitters were implanted to monitor blood pressure. After 3 weeks of treatment, rats were sacrificed, and iliac and mesenteric arteries were removed to evaluate vascular reactivity. RESULTS: Diabetes mellitus enhanced the contractile response to nitric oxide synthase (NOS) blockade, potentiated the response to phenylephrine, diminished the effectiveness of endothelin type A (ETA) receptor blockade and allowed acetylcholine to display constrictor, cyclo-oxygenase-2 mediated, endothelium-dependent responses in the presence of NOS inhibition and blockers of endothelium-derived hyperpolarizing factors. Aliskiren normalized blood pressure, suppressed renin activity, and reversed the above vascular effects, with the exception of the altered effectiveness of ETA receptor blockade. Remarkably, when adding HRP on top of aliskiren, its beneficial vascular effects either disappeared or were greatly diminished, although HRP did not alter the effect of aliskiren on blood pressure and renin activity. CONCLUSIONS: Renin inhibition improves vascular dysfunction in diabetic hypertensive rats, and HRP counteracts this effect independently of blood pressure and angiotensin. (P)RR blockade therefore is unlikely to be a new tool to further suppress the renin-angiotensin system (RAS) on top of existing RAS blockers.
Assuntos
Amidas/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Endotélio Vascular/fisiopatologia , Fumaratos/farmacologia , Peptídeos/fisiologia , Receptores de Superfície Celular/antagonistas & inibidores , Regulação para Cima/fisiologia , Animais , Sequência de Bases , Primers do DNA , Diabetes Mellitus Experimental/metabolismo , Endotélio Vascular/metabolismo , Contração Muscular , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptor de Pró-ReninaRESUMO
Angiogenesis inhibition by blocking vascular endothelial growth factor (VEGF)-mediated signalling with monoclonal antibodies or tyrosine kinase inhibitors has become an established treatment of various forms of cancer. This treatment is frequently associated with the development of hypertension and proteinuria. As VEGF increases the expression and the activity of nitric oxide synthase in endothelial cells, a decrease in the bioavailability of nitric oxide has been proposed as a key mechanism leading to hypertension during angiogenesis inhibition. However, results of clinical and experimental studies exploring this possibility are conflicting. Rarefaction, that is a structural decrease of microcirculatory vessels, has been reported during antiangiogenic treatment, but evidence that it plays a role in development of hypertension is lacking. Elevated circulating and urinary levels of endothelin-1 have been observed in clinical and experimental studies with angiogenesis inhibitors. Furthermore, the observation that endothelin receptor blockers can prevent or revert the rise in blood pressure during angiogenesis inhibition and attenuate proteinuria provides strong evidence that an activated endothelin-signalling pathway is a final common mediator of angiogenesis inhibition-induced rise in blood pressure and renal toxicity.
Assuntos
Inibidores da Angiogênese/farmacologia , Endotelina-1/fisiologia , Hipertensão/fisiopatologia , Proteinúria/fisiopatologia , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Angiotensin II type 2 (AT(2)) receptor stimulation has been linked to vasodilation. Yet, AT(2) receptor-independent hypertension and hypotension (or no effect on blood pressure) have been observed in vivo after application of the AT(2) receptor agonist compound 21 (C21). We, therefore, studied its effects in vitro, using preparations known to display AT(2) receptor-mediated responses. Hearts of Wistar rats, spontaneously hypertensive rats (SHRs), C57Bl/6 mice, and AT(2) receptor knockout mice were perfused according to Langendorff. Mesenteric and iliac arteries of these animals, as well as coronary microarteries from human donor hearts, were mounted in Mulvany myographs. In the coronary vascular bed of Wistar rats, C57Bl/6 mice, and AT(2) receptor knockout mice, C21 induced constriction followed by dilation. SHR hearts displayed enhanced constriction and no dilation. Irbesartan (angiotensin II type 1 receptor blocker) abolished the constriction and enhanced or (in SHRs) reintroduced dilation, and PD123319 (AT(2) receptor blocker) did not block the latter. C21 relaxed preconstricted vessels of all species, and this did not depend on angiotensin II receptors, the endothelium, or the NO-guanylyl cyclase-cGMP pathway. C21 constricted SHR iliac arteries but none of the other vessels, and irbesartan prevented this. C21 shifted the concentration-response curves to U46619 (thromboxane A(2) analog) and phenylephrine (α-adrenoceptor agonist) but not ionomycine (calcium ionophore) to the right. In conclusion, C21 did not cause AT(2) receptor-mediated vasodilation. Yet, it did induce vasodilation by blocking calcium transport into the cell and constriction via angiotensin II type 1 receptor stimulation. The latter effect is enhanced in SHRs. These data may explain the varying effects of C21 on blood pressure in vivo.
Assuntos
Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/fisiologia , Artéria Ilíaca/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Adulto , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Cálcio/metabolismo , Ionóforos de Cálcio/farmacologia , Vasos Coronários/fisiologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Artéria Ilíaca/fisiologia , Imidazóis/farmacologia , Técnicas In Vitro , Irbesartana , Masculino , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Animais , Fenilefrina/farmacologia , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Receptor Tipo 2 de Angiotensina/genética , Sulfonamidas/farmacologia , Tetrazóis/farmacologia , Tiofenos/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/fisiologiaRESUMO
INTRODUCTION: Angiotensin II, the active endproduct of the renin-angiotensin system (RAS), exerts its effects via angiotensin II type 1 and type 2 (AT(1), AT(2)) receptors. AT(1) receptors mediate all well-known effects of angiotensin II, ranging from vasoconstriction to tissue remodeling. Thus, to treat cardiovascular disease, RAS blockade aims at preventing angiotensin II-AT(1) receptor interaction. Yet RAS blockade is often accompanied by rises in angiotensin II, which may exert beneficial effects via AT(2) receptors. AREAS COVERED: This review summarizes our current knowledge on AT(2) receptors, describing their location, function(s), endogenous agonist(s) and intracellular signaling cascades. It discusses the beneficial effects obtained with C21, a recently developed AT(2) receptor agonist. Important questions that are addressed are do these receptors truly antagonize AT(1) receptor-mediated effects? What about their role in the diseased state and their heterodimerization with other receptors? EXPERT OPINION: The general view that AT(2) receptors exclusively exert beneficial effects has been challenged, and in pathological models, their function sometimes mimics that of AT(1) receptors, for example, inducing vasoconstriction and cardiac hypertrophy. Yet given its upregulation in various pathological conditions, the AT(2) receptor remains a promising target for treatment, allowing effects beyond blood pressure-lowering, for example, in stroke, aneurysm formation, inflammation and myocardial fibrosis.
Assuntos
Angiotensina II/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Receptor Tipo 2 de Angiotensina/metabolismoRESUMO
CONTEXT: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. OBJECTIVE: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. DESIGN: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). SETTING: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. INTERVENTION: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. MAIN OUTCOME MEASURES: TSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed. RESULTS: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. CONCLUSION: Sunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression.
Assuntos
Antineoplásicos/efeitos adversos , Hipotireoidismo/induzido quimicamente , Indóis/efeitos adversos , Iodeto Peroxidase/biossíntese , Pirróis/efeitos adversos , Glândula Tireoide/metabolismo , Idoso , Animais , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Capilares/efeitos dos fármacos , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Hipotireoidismo/enzimologia , Indóis/uso terapêutico , Neoplasias Renais/complicações , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/uso terapêutico , Ratos , Ratos Endogâmicos WKY , Fluxo Sanguíneo Regional , Análise de Regressão , Estudos Retrospectivos , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Sunitinibe , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/enzimologia , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT(1)) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R)) and 4-fold (homozygous Fibulin-4(R/R)) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-ß signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-ß. Tissue levels of Ang II, a regulator of TGF-ß signaling, were increased. Prenatal treatment with the AT(1) receptor antagonist losartan, which blunts TGF-ß signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R) mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1) receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.
Assuntos
Aorta Torácica/fisiopatologia , Aneurisma Aórtico/fisiopatologia , Proteínas da Matriz Extracelular/deficiência , Vasoconstrição/fisiologia , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/prevenção & controle , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Losartan/farmacologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Fenilefrina/farmacologia , Gravidez , Receptor Tipo 1 de Angiotensina/fisiologia , Proteína Smad2/genética , Proteína Smad2/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/genética , Vasoconstritores/farmacologiaRESUMO
Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.
Assuntos
Inibidores da Angiogênese/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotelina-1/metabolismo , Hipertensão/induzido quimicamente , Indóis/farmacologia , Rim/efeitos dos fármacos , Pirróis/farmacologia , Animais , Relação Dose-Resposta a Droga , Hipertensão/metabolismo , Hipertensão/patologia , Rim/metabolismo , Rim/patologia , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sunitinibe , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Thoracic aortic aneurysms (TAAs) are a potential life-threatening disease with limited pharmacological treatment options. Current treatment options are aimed at lowering aortic hemodynamic stress, predominantly with ß-adrenoceptor blockers. Increasing evidence supports a role for the renin-angiotensin system (RAS) in aneurysm development. RAS blockade would not only lower blood pressure, but might also target the molecular pathways involved in aneurysm formation, in particular the transforming growth factor-ß and extracellular signal-regulated kinase 1/2 pathways. Indeed, the angiotensin II type 1 (AT1) receptor blocker losartan was effective in lowering aortic root growth in mice and patients with Marfan's syndrome. RAS inhibition (currently possible at 3 levels, i.e. renin, ACE and the AT1 receptor) is always accompanied by a rise in renin due to interference with the negative feedback loop between renin and angiotensin II. Only during AT1 receptor blockade will this result in stimulation of the non-blocked angiotensin II type 2 (AT2) receptor. This review summarizes the clinical aspects of TAAs, provides an overview of the current mouse models for TAAs, and focuses on the RAS as a new target for TAA treatment, discussing in particular the possibility that AT2 receptor stimulation might be crucial in this regard. If true, this would imply that AT1 receptor blockers (and not ACE inhibitors or renin inhibitors) should be the preferred treatment option for TAAs.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aneurisma da Aorta Torácica/tratamento farmacológico , Aneurisma da Aorta Torácica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Ensaios Clínicos como Assunto , HumanosRESUMO
To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner.
Assuntos
Amidas/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fumaratos/farmacologia , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Renina/antagonistas & inibidores , Amidas/uso terapêutico , Análise de Variância , Animais , Anti-Hipertensivos/uso terapêutico , Bradicinina/farmacologia , Interações Medicamentosas , Endotélio Vascular/efeitos dos fármacos , Fumaratos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Bombas de Infusão Implantáveis , Masculino , Ratos , Ratos Endogâmicos SHR , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TelemetriaAssuntos
Angiotensina II/urina , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/sangue , Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Rim/metabolismo , Ratos , Suínos , Tetrazóis/farmacologiaRESUMO
Angiogenesis inhibition with sunitinib, a multitarget tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, is associated with hypertension and cardiac toxicity, of which the underlying pathophysiological mechanism is unknown. We investigated the effects of sunitinib on blood pressure (BP), its circadian rhythm, and potential mechanisms involved, including the endothelin-1 system, in 15 patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors. In addition, we investigated in rats the effect of sunitinib on BP, serum endothelin-1 levels, coronary microvascular function, cardiac structure, and cardiac mitochondrial function. In patients, BP increased by ≈15 mm Hg, whereas heart rate decreased after 4 weeks of treatment. Furthermore, the nocturnal dipping of BP diminished. Plasma endothelin-1 concentration increased 2-fold (P<0.05) and plasma renin decreased (P<0.05), whereas plasma catecholamines and renal function remained unchanged. In rats, 8 days of sunitinib administration induced an ≈30-mm Hg rise in BP, an attenuation of the circadian BP rhythm, and a 3-fold rise in serum endothelin-1 and creatinine, of which all but the rise in creatinine reversed after sunitinib withdrawal. Coronary microvascular function studies after 8 days of sunitinib administration showed decreased responses to bradykinin, angiotensin II, and sodium nitroprusside, all normalizing after sunitinib withdrawal. Cardiac structure and cardiac mitochondrial function did not change. In conclusion, sunitinib induces a reversible rise in BP in patients and in rats associated with activation of the endothelin-1 system, suppression of the renin-angiotensin system, and generalized microvascular dysfunction.
Assuntos
Endotelina-1/sangue , Hipertensão/induzido quimicamente , Indóis/efeitos adversos , Pirróis/efeitos adversos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Idoso , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Células Cultivadas , Circulação Coronária/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotelina-1/metabolismo , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Técnicas In Vitro , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pirróis/farmacologia , Pirróis/uso terapêutico , Ratos , Ratos Endogâmicos WKY , Renina/sangue , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: The blood pressure-lowering effect of the renin inhibitor aliskiren equals that of angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II type 1 (AT1) receptor blockers. Whether aliskiren offers end-organ protection remains to be investigated. Here, we compared the cardiac effects of aliskiren, the AT1 receptor blocker irbesartan and the ACE inhibitor captopril in spontaneously hypertensive rats (SHR) at equi-hypotensive doses. METHODS AND RESULTS: SHR were treated for 1-3 weeks with vehicle, aliskiren, captopril or irbesartan (100, 3 and 15 mg/kg per day, respectively) using an osmotic minipump, and compared to vehicle-treated Wistar-Kyoto (WKY) controls. All drugs lowered (but not normalized) mean arterial pressure in SHR equi-effectively, as monitored by radiotelemetry, without altering heart rate. All drugs also reduced the increased cardiomyocyte area in SHR, and tended to normalize the elevated brain natriuretic peptide plasma levels. In the Langendorff set-up, all drugs normalized the diminished endothelium-dependent vasodilator response to bradykinin in SHR. Moreover, aliskiren and irbesartan, but not captopril, decreased the enhanced coronary Ang II response in SHR. Aliskiren reduced plasma renin activity and the plasma and tissue angiotensin levels at 1 week of treatment; yet, after 3 weeks of aliskiren treatment only the cardiac angiotensin levels remained suppressed, whereas no tissue angiotensin reductions were seen with captopril or irbesartan. CONCLUSION: For a given decrease in blood pressure, aliskiren improves coronary endothelial function and decreases cardiac hypertrophy in SHR to at least the same degree as ACE inhibition and AT1 receptor blockade. In addition, aliskiren diminishes the enhanced Ang II response in the coronary circulation of SHR and offers superior long-term cardiac angiotensin suppression.
Assuntos
Amidas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fumaratos/farmacologia , Coração/efeitos dos fármacos , Hipertensão/fisiopatologia , Renina/antagonistas & inibidores , Amidas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas/sangue , Animais , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/fisiologia , Captopril/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fumaratos/uso terapêutico , Coração/fisiopatologia , Ventrículos do Coração/patologia , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertrofia/tratamento farmacológico , Irbesartana , Masculino , Peptídeo Natriurético Encefálico/sangue , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Renina/sangue , Tetrazóis/farmacologiaRESUMO
AIMS: Our aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT(1a), AT(1b), AT(2)) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors. METHODS AND RESULTS: Hearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT(1a), independently of AT(1b) and AT(2). The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT(1) subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT(1a) deletion alone, independently of the presence or absence of AT(1b) and/or AT(2), reduced renal Ang II by 50% despite a five-fold rise of plasma Ang II. AT(1b) deletion, on top of AT(1a) deletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly. CONCLUSION: The lack of both AT(1) subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT(1a). The lack of AT(1a) or AT(1b) does not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT(1) binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.
Assuntos
Angiotensina II/metabolismo , Miocárdio/metabolismo , Receptor Tipo 1 de Angiotensina/deficiência , Receptor Tipo 2 de Angiotensina/deficiência , Angiotensina II/administração & dosagem , Angiotensina II/sangue , Animais , Atrofia , Circulação Coronária , Fibrose , Genótipo , Rim/metabolismo , Masculino , Camundongos , Camundongos Knockout , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Perfusão , Fenótipo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Função Ventricular Esquerda , Pressão Ventricular , Remodelação VentricularRESUMO
Because angiotensin (Ang) metabolites mediate functions independent of Ang II, we investigated their effects on coronary flow in spontaneously hypertensive rats (SHRs). Results were compared with those in the iliac artery and abdominal aorta and the coronary circulation of the Wistar rat. Ang II, III, and IV decreased coronary flow in SHRs and Wistar rats, with Ang III and IV being approximately 10 and approximately 1000 times less potent than Ang II. Ang-(1-7) decreased coronary flow at concentrations >1 micromol/L in SHRs. The Ang II type 1 receptor antagonist irbesartan blocked the effects of Ang II, III, and IV, whereas the Ang II type 2 receptor antagonist PD123319 blocked the effects of Ang-(1-7). The maximal Ang II- and III-induced decreases in coronary flow in SHRs were twice as large as those in Wistar rats. PD123319 enhanced the constrictor effects of Ang II and III in Wistar rats so that, in the presence of this drug, their effects were comparable to those in SHRs. In contrast, PD123319 did not alter the Ang II- and III-induced responses in SHRs and blocked the constrictor effect of Ang II in iliac arteries. Ang II type 2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of Ang metabolites in these vessels were identical in Wistar rats and SHRs. In conclusion, coronary constriction induced by Ang II, Ang III, and Ang-(1-7) is enhanced in SHRs as compared with Wistar rats. This is attributable to the absence of counterregulatory Ang II type 2 receptor-mediated relaxation and/or a change of the Ang II type 2 receptor phenotype from relaxant to constrictor.