RESUMO
In aquaculture, many stressors can negatively affect growth in teleosts. It is believed that cortisol performs glucocorticoid and mineralocorticoid functions because teleosts do not synthesize aldosterone. However, recent data suggest that 11-deoxycorticosterone (DOC) released during stress events may be relevant to modulate the compensatory response. To understand how DOC modifies the skeletal muscle molecular response, we carried out a transcriptomic analysis. Rainbow trout (Oncorhynchus mykiss) were intraperitoneally treated with physiological doses of DOC in individuals pretreated with mifepristone (glucocorticoid receptor antagonist) or eplerenone (mineralocorticoid receptor antagonist). RNA was extracted from the skeletal muscles, and cDNA libraries were constructed from vehicle, DOC, mifepristone, mifepristone plus DOC, eplerenone, and eplerenone plus DOC groups. The RNA-seq analysis revealed 131 differentially expressed transcripts (DETs) induced by DOC with respect to the vehicle group, mainly associated with muscle contraction, sarcomere organization, and cell adhesion. In addition, a DOC versus mifepristone plus DOC analysis revealed 122 DETs related to muscle contraction, sarcomere organization, and skeletal muscle cell differentiation. In a DOC versus eplerenone plus DOC analysis, 133 DETs were associated with autophagosome assembly, circadian regulation of gene expression, and regulation of transcription from RNA pol II promoter. These analyses indicate that DOC has a relevant function in the stress response of skeletal muscles, whose action is differentially modulated by GR and MR and is complementary to cortisol.
Assuntos
Oncorhynchus mykiss , Animais , Oncorhynchus mykiss/genética , Transcriptoma , Desoxicorticosterona/metabolismo , Desoxicorticosterona/farmacologia , Mifepristona/metabolismo , Mifepristona/farmacologia , Eplerenona/metabolismo , Eplerenona/farmacologia , Hidrocortisona/metabolismo , Músculo Esquelético/metabolismoRESUMO
O hipoadrenocorticismo primário ou doença de Addison é uma endocrinopatia que envolve a deficiência de glicocorticoides, comumente associada a deficiência mineralocorticoide. O tratamento mais utilizado para reposição hormonal envolve a associação de fludrocortisona e prednisona. O pivalato de desoxicorticosterona (DOCP) tem sido demonstrado na literatura como superior no controle eletrolítico no paciente com hipoadrenocorticismo, e sempre deve ser associado a prednisona/prednisolona. Neste trabalho, relatamos o benefício do DOCP e o protocolo de ajuste de dose desse fármaco em duas etapas em dois casos distintos. Houve uma eficácia superior no controle eletrolítico e redução dos efeitos colaterais com o protocolo de DOCP e prednisolona em relação ao uso de fludrocortisona em ambos os pacientes.(AU)
Primary hypoadrenocorticism or Addison's disease is an endocrinopathy involving glucocorticoid deficiency, commonly associated with mineralocorticoid deficiency. The most commonly used treatment for hormone replacement involves the combination of fludrocortisone and prednisone. Deoxycorticosterone pivalate (DOCP) has been shown in the literature to be superior in electrolyte control in patients with hypoadrenocorticism, and should always be associated with prednisone/prednisolona. In this study, we report the benefit of DOCP and the two-stage dose adjustment protocol for this drug in 2 different cases. There was superior efficacy in electrolyte control and reduction of side effects with the DOCP and prednisolone protocol compared to the use of fludrocortisone in both patients.(AU)
El hipoadrenocorticismo primario o enfermedad de Addison es una endocrinopatía que cursa con deficiencia de glucocorticoides, comúnmente asociada con deficiencia de mineralocorticoides. El tratamiento más utilizado para el reemplazo hormonal consiste en la combinación de fludrocortisona y prednisona. El pivalato de desoxicorticosterona (DOCP) ha demostrado en la literatura ser superior en el control de electrolitos en pacientes con hipoadrenocorticismo, y siempre debe asociarse con prednisona/prednisolona. En este trabajo, reportamos el beneficio de DOCP y el protocolo de ajuste de dosis en dos etapas para este fármaco en 2 casos diferentes. Hubo una eficacia superior en el control de electrolitos y la reducción de los efectos secundarios con el protocolo DOCP y prednisolona en comparación con el uso de fludrocortisona en ambos pacientes.(AU)
Assuntos
Animais , Doença de Addison/prevenção & controle , Doença de Addison/veterinária , Desoxicorticosterona/efeitos adversos , Cães/genéticaRESUMO
Endothelins regulate catecholaminergic activity in the olfactory bulb (OB) in normotensive and hypertensive animals. Administration of an endothelin ETA receptor antagonist decreases blood pressure in deoxycorticosterone acetate-salt (DOCA-salt) rats along with a reduction in tyrosine hydroxylase (TH) activity and expression. In the present work, we sought to establish the role of brain endothelin ETB receptor on blood pressure regulation and its relationship with the catecholaminergic system within the OB of DOCA-Salt rats. Sprague-Dawley male rats were divided into control and DOCA-Salt groups. Blood pressure, heart rate and TH activity as well as neuronal nitric oxide synthase (nNOS) expression were assessed following IRL-1620 (selective endothelin ETB receptor agonist) applied to be brain. IRL-1620 significantly reduced systolic, diastolic, and mean arterial pressure in DOCA-Salt hypertensive rats. It also decreased TH activity, TH total and phosphorylated forms expression as well as its mRNA in the OB of hypertensive animals. The expression of phospho-Ser1417-nNOS, which reflects nNOS activation, was significantly decreased in the of OB of DOCA-salt rats, but it was enhanced by IRL-1620. These findings suggest that DOCA-Salt hypertension depends on endogenous central endothelin ETA receptor activity, rather than on ETB, and that low endothelin ETB stimulation is essential for blood pressure elevation in this animal model. The effect of endothelin ETA receptor antagonism may also result from endothelin ETB receptor overstimulation. The present study shows that endothelin receptors are involved in the regulation of TH in the OB and that such changes are likely implicated in the hemodynamic control and sympathetic outflow.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Bulbo Olfatório/efeitos dos fármacos , Receptor de Endotelina B/agonistas , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Desoxicorticosterona , Endotelinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Óxido Nítrico Sintase Tipo I/biossíntese , Óxido Nítrico Sintase Tipo I/genética , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-DawleyRESUMO
Congenital adrenal hyperplasia (CAH) is a group of rare orphan disorders caused by mutations in seven different enzymes that impair cortisol biosynthesis. The 17α-hydroxylase deficiency (17OHD) is one of the less common forms of CAH, corresponding to approximately 1% of the cases, with an estimated annual incidence of 1 in 50,000 newborns. Cases description - two phenotypically female Ecuadorian sisters, both with primary amenorrhea, absence of secondary sexual characteristics, and osteoporosis. High blood pressure was present in the older sister. Hypergonadotropic hypogonadism profile was observed: decreased cortisol and dehydroepiandrosterone sulfate (DHEAS), increased adrenocorticotropic hormone (ACTH) and normal levels of 17-hydroxyprogesterone, extremely high deoxycorticosterone (DOC) levels, and a tomography showed bilateral adrenal hyperplasia in both sisters. Consanguinity was evident in their ancestors. Furthermore, in the exon 7, the variant c.1216T > C, p.Trp406Arg was detected in homozygosis in the CYP17A1 gene of both sisters. We report a homozygous missense mutation in the CYP17A1 gene causing 17OHD in two sisters from Loja, Ecuador. According to the authors, this is the first time such deficiency and mutation are described in two members of the same family in Ecuador.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Irmãos , Esteroide 17-alfa-Hidroxilase/genética , 17-alfa-Hidroxiprogesterona/metabolismo , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Amenorreia/etiologia , Consanguinidade , Sulfato de Desidroepiandrosterona/metabolismo , Desoxicorticosterona/metabolismo , Erros de Diagnóstico , Equador , Feminino , Homozigoto , Humanos , Hidrocortisona/metabolismo , Hipertensão/etiologia , Hipogonadismo/etiologia , Hipogonadismo/metabolismo , Hipopotassemia/etiologia , Mosaicismo , Osteoporose/etiologia , Síndrome de Turner/diagnóstico , Adulto JovemRESUMO
Hypertension-induced cardiovascular and renal damage can be mediated by activation of the renin-angiotensin-aldosterone system. There are different factors beyond renin-angiotensin-aldosterone system involved in hypertension and renal damage. Inflammation has emerged as an important mediator of hypertension and cardiovascular and kidney damage. Angiotensin-(1-9), a peptide of the renin-angiotensin system, counter-regulates both the physiological and pathological actions of angiotensin II. Recent data has shown that angiotensin-(1-9) protects the heart and blood vessels from adverse cardiovascular remodeling in experimental models of hypertension and/or heart failure and reduces cardiac fibrosis in stroke-prone, spontaneously hypertensive rats. These effects are mediated by the angiotensin II type 2 receptor (AT2R). However, it remains unknown whether angiotensin-(1-9) also has an anti-inflammatory effect. In the present study, we investigate whether angiotensin-(1-9) reduces inflammation and fibrosis in the heart, arteries, and kidney in a DOCA-salt hypertensive model and explore the mechanisms underlying the amelioration of end-organ damage. DOCA-salt hypertensive rats received: a) vehicle, b) angiotensin-(1-9), c) PD123319 (AT2R blocker), d) angiotensin-(1-9) plus A779 (a Mas receptor blocker) or e) angiotensin-(1-9) plus PD123319, and sham rats were used as a control. Our results showed that angiotensin-(1-9) decreased hypertension and increased vasodilation in DOCA-salt hypertensive rats. These actions were partially inhibited by PD123319. Moreover, angiotensin-(1-9) decreased diuresis, fibrosis, and inflammation. These beneficial effects were not mediated by Mas or AT2R blockers. We concluded that angiotensin-(1-9) protects against volume overload-induced hypertensive cardiovascular and kidney damage by decreasing inflammation in the heart, aortic wall, and kidney, through mechanisms independent of the Mas or AT2R.
Assuntos
Angiotensinas/farmacologia , Hipertensão/induzido quimicamente , Inflamação/induzido quimicamente , Nefropatias/induzido quimicamente , Renina/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/patologia , Desoxicorticosterona/toxicidade , Hipertensão/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Hancornia speciosa Gomes is an herb traditionally used in Brazil for blood pressure control. PURPOSE: The present work investigated the antihypertensive effect of an extract from Hancornia speciosa leaves (SFH) and analyzed its underlying mechanisms of action. METHODS: Hypertension was induced in mice by surgical removal of a kidney and by subcutaneous administration of a pellet with deoxycorticosterone. Vasodilatation was measured in mesenteric arteries with a wire myograph. Nitrites were measured by fluorescence with 2,3-diaminonaphthalene and H2O2 was measured with carbon microsensors. RESULTS: SFH (0.03, 0.1 or 1 mg/kg; po) induced a dose-dependent, long-lasting reduction in the systolic blood pressure in conscious DOCA-salt hypertensive mice (DOCA). Administration of SFH produced a significant increase in the plasmatic level of nitrites. The systemic inhibition of nitric oxide synthase by L-NAME (20 mg/kg) reduced its antihypertensive effect. SFH also induced a concentration-dependent vasodilatation of mesenteric resistance arteries contracted with phenylephrine, which was more potent in arteries from DOCA mice. Removal of the endothelium or pretreatment with L-NAME or catalase reduced the vasodilator response for SFH. The nitrite production induced by SFH was significantly bigger in mesenteric arteries from DOCA than in SHAM mice. However, the production of H2O2 induced by SFH was twice higher in DOCA mice. CONCLUSION: Altogether, our results point to an antihypertensive effect of SFH due to a reduction in peripheral resistance through the production of NO and by a mechanism involving an increased production of H2O2 in the mesenteric arteries from hypertensive mice. These findings are further evidence to support the use of Hancornia speciosa by traditional medicine as an antihypertensive drug.
Assuntos
Anti-Hipertensivos/farmacologia , Apocynaceae/química , Hipertensão/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Brasil , Desoxicorticosterona , Peróxido de Hidrogênio/metabolismo , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/metabolismo , Folhas de Planta/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin-angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8-isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension.
Assuntos
Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Hipertensão/tratamento farmacológico , Nitrito de Sódio/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona/toxicidade , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/patologia , Peróxidos Lipídicos/sangue , Masculino , NADPH Oxidases/metabolismo , Nitritos/sangue , Óxidos de Nitrogênio/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Nitrito de Sódio/farmacologia , Xantina Oxidase/metabolismoRESUMO
INTRODUCTION: Aldosterone can induce changes in the expression or activity of Na(+)/H(+) exchanger isoform 1 (NHE-1) in vascular smooth muscle cells. We aimed to clarify whether chronic mineralocorticoid receptor activation exerts an effect on the activity of NHE-1 in the aorta of mineralocorticoid-induced hypertensive rats. METHODS: Uninephrectomized male Sprague-Dawley rats received subcutaneously 10 mg/week of desoxycorticosterone (DOCA) with or without 20 mg/kg of spironolactone, or vehicle alone (n = 20). After four weeks of treatment, the animals were sacrificed; the aorta was excised for subsequent studies, including histological analysis, RT-PCR, Western blot, measurement of NHE-1 activity and vascular contractility in the presence or absence of the selective NHE-1 inhibitor ethyl-isopropyl amiloride (EIPA). RESULTS: Chronic DOCA treatment increased the NHE-1 activity, systolic and diastolic blood pressure, and aortic wall thickness. All these effects were prevented by co-treatment with Spironolactone (p < 0.05). Phenylephrine-induced vascular contractility was significantly reduced in the DOCA group when EIPA was added in the media (p < 0.05). No significant differences in NHE-1 mRNA or protein levels were detected between groups. CONCLUSIONS: Chronic DOCA administration induced functional and morphological alterations in the rat aorta that are partially explained by enhanced NHE-1 activity and prevented by spironolactone. However, we did not observe changes in the NHE-1 transcript or protein levels, suggesting that the effect may be due to post-transcriptional modifications induced by mineralocorticoid receptor activation.
Assuntos
Aorta/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Espironolactona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona/farmacologia , Hipertensão/fisiopatologia , Masculino , Mineralocorticoides , Fenilefrina/farmacologia , Ratos Sprague-Dawley , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Coloração e Rotulagem , Vasoconstrição/efeitos dos fármacosRESUMO
This study investigated the cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) in deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Furthermore, in vitro experiments using isolated thoracic aortic rings were performed to assess the vascular effects of the EOCZ. In conscious hypertensive rats, intravenous (i.v.) injections of EOCZ (1-20 mg/kg) induced rapid (2-4 s) and dose-dependent hypotension and bradycardia (phase 1). The hypotension was followed by a significant pressor effect that was more evident at the higher doses (10 and 20 mg/kg) of EOCZ. Hypotension and bradycardia of EOCZ (phase 1) were abolished and respectively reversed into pressor and tachycardiac effects by methylatropine (1 mg/kg, i.v.) pretreatment. In isolated endothelium-intact aortic preparations, increasing concentrations (1-1000 microg/mL) of EOCZ relaxed the potassium-induced contraction in a concentration-dependent manner with an IC50 (geometric mean [95% confidence interval]) value of 202.0 [92.0-443.7] microg/mL. This vasorelaxant effect remained unaffected by either mechanical removal of functional vascular endothelium (IC50 = 189.0 [159.4-224.7] microg/mL) or the addition of atropine (1 microM) (IC50 = 158.6 [79.8-316.2] microg/mL) in the perfusion medium. These data show that i.v. administration of EOCZ in DOCA-salt hypertensive rats induces a vago-vagal reflex decreases in heart rate and blood pressure (phase 1). EOCZ may induce a second and delayed hypotension due to its direct endothelium-independent vasorelaxant effects, but it seems to be buffered by the pressor component (subsequent to phase 1) of EOCZ. This pattern of blood pressure and heart rate responses to EOCZ seems unaltered by DOCA-salt hypertension, as was similar to that previously reported in conscious normotensive rats.
Assuntos
Aorta Torácica/efeitos dos fármacos , Bradicardia/induzido quimicamente , Fármacos Cardiovasculares/análise , Croton/química , Óleos Voláteis/farmacologia , Animais , Desoxicorticosterona , Técnicas In Vitro , Masculino , Óleos Voláteis/química , Ratos , Ratos WistarRESUMO
Cysticerci and tapeworms from Taenia crassiceps WFU, ORF and Taenia solium synthesize sex-steroid hormones in vitro. Corticosteroids increase the 17ß-estradiol synthesis by T. crassiceps cysticerci. T. crassiceps WFU cysticerci synthesize corticosteroids, mainly 11-deoxycorticosterone (DOC). The aim of this work was to investigate whether classical steroidogenic inhibitors modify the capacity of T. crassiceps WFU cysticerci to synthesize corticosteroids and sex steroid hormones. For this purpose, T. crassiceps WFU cysticerci were obtained from the abdominal cavity of mice, pre-cultured for 24h in DMEM+antibiotics/antimycotics and cultured in the presence of tritiated progesterone ((3)H-P4), androstendione ((3)H-A4), or dehydroepiandrosterone ((3)H-DHEA) plus different doses of the corresponding inhibitors, for different periods. Blanks with the culture media adding the tritiated precursors were simultaneously incubated. At the end of the incubation period, parasites were separated and media extracted with ether. The resulting steroids were separated by thin layer chromatography (TLC). Data were expressed as percent transformation of the tritiated precursors. Results showed that after 2h of exposure of the cysticerci to 100 µM formestane, the (3)H-17ß-estradiol synthesis from tritiated androstenedione was significantly inhibited. The incubation of cysticerci in the presence of (3)H-DHEA and danazol (100 nM) resulted in (3)H-androstenediol accumulation and a significant reduction of the 17ß-estradiol synthesis. The cysticerci (3)H-DOC synthesis was significantly inhibited when the parasites were cultured in the presence of different ketoconazole dosis. The drug treatments did not affect parasite's viability. The results of this study showed that corticosteroid and sex steroid synthesis in T. crassiceps WFU cysticerci can be modified by steroidogenic enzyme inhibitors. As was shown previously by our laboratory and others, parasite survival and development depends on sex steroids, therefore the inhibition of their synthesis is a good starting point exploited in situations where the inhibition of steroidogenesis could help to control the infection for the development of new treatments, or replacement of the usual therapy in resistant parasite infections. We raise the possibility that these drug actions may be beneficially.
Assuntos
Inibidores Enzimáticos/farmacologia , Esteroides/metabolismo , Taenia/efeitos dos fármacos , Taenia/metabolismo , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Cromatografia em Camada Fina , Danazol/farmacologia , Desoxicorticosterona/farmacologia , Estradiol/metabolismo , Cetoconazol/farmacologiaRESUMO
FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Assuntos
Animais , Masculino , Ratos , Benzamidas/farmacologia , Fibrose Endomiocárdica/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Western Blotting , Benzamidas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona , Modelos Animais de Doenças , Fibrose Endomiocárdica/patologia , Fibronectinas/análise , Fibronectinas/metabolismo , Fibrose/tratamento farmacológico , Fibrose/patologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Nefrectomia/métodos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Resultado do Tratamento , Tenascina/análise , Tenascina/metabolismoRESUMO
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRß) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were significantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Assuntos
Benzamidas/farmacologia , Fibrose Endomiocárdica/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Benzamidas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Desoxicorticosterona , Modelos Animais de Doenças , Fibrose Endomiocárdica/patologia , Fibronectinas/análise , Fibronectinas/metabolismo , Fibrose/tratamento farmacológico , Fibrose/patologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Mesilato de Imatinib , Masculino , Nefrectomia/métodos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Tenascina/análise , Tenascina/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVES: Tension cost, the ratio of myosin ATPase activity to tension, reflects the economy of tension development in the myocardium. To evaluate the mechanical advantage represented by the tension cost, we studied papillary muscle contractility and the activity of myosin ATPase in the left ventricles in normal and pathophysiological conditions. METHODS: Experimental protocols were performed using rat left ventricles from: (1) streptozotocin-induced diabetic and control Wistar rats; (2) N-nitro-L-arginine methyl ester (L-NAME) hypertensive and untreated Wistar rats; (3) deoxycorticosterone acetate (DOCA) salt-treated, nephrectomized and salt- and DOCA-treated rats; (4) spontaneous hypertensive rats (SHR) and Wistar Kyoto (WKY) rats; (5) rats with myocardial infarction and shamoperated rats. The isometric force, tetanic tension, and the activity of myosin ATPase were measured. RESULTS: The results obtained from infarcted, diabetic, and deoxycorticosterone acetate-salt-treated rats showed reductions in twitch and tetanic tension compared to the control and sham-operated groups. Twitch and tetanic tension increased in the N-nitro-L-arginine methyl ester-treated rats compared with the Wistar rats. Myosin ATPase activity was depressed in the infarcted, diabetic, and deoxycorticosterone acetate salt-treated rats compared with control and sham-operated rats and was increased in N-nitro-L-arginine methyl ester-treated rats. These parameters did not differ between SHR and WKY rats. In the studied conditions (e.g., post-myocardial infarction, deoxycorticosterone acetate salt-induced hypertension, chronic N-nitro-L-arginine methyl ester treatment, and streptozotocin-induced diabetes), a positive correlation between force or plateau tetanic tension and myosin ATPase activity was observed. CONCLUSION: Our results suggest that the myocardium adapts to force generation by increasing or reducing the tension cost to maintain myocardial contractility with a better mechanical advantage.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Hipertensão/fisiopatologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/fisiopatologia , Músculos Papilares/fisiopatologia , Função Ventricular Esquerda , Miosinas Ventriculares/metabolismo , Animais , Desoxicorticosterona/análogos & derivados , Diabetes Mellitus Experimental/induzido quimicamente , Inibidores Enzimáticos , Hipertensão/induzido quimicamente , Masculino , Contração Miocárdica/efeitos dos fármacos , NG-Nitroarginina Metil Éster , Nefrectomia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Angiotensin-(ANG)-(1-7) is known by its central and peripheral actions, which mainly oppose the deleterious effects induced by accumulation of ANG II during pathophysiological conditions. In the present study we evaluated whether a chronic increase in ANG-(1-7) levels in the brain would modify the progression of hypertension. After DOCA-salt hypertension was induced for seven days, Sprague-Dawley rats were subjected to 14 days of intracerebroventricular (ICV) infusion of ANG-(1-7) (200 ng/h, DOCA-A7) or 0.9% sterile saline. As expected, on the 21st day, DOCA rats presented increased mean arterial pressure (MAP) (≈40%), and impaired baroreflex control of heart rate (HR) and baroreflex renal sympathetic nerve activity (RSNA) in comparison with that in normotensive control rats (CTL). These changes were followed by an overactivity of the cardiac sympathetic tone and reduction of the cardiac parasympathetic tone, and exaggerated mRNA expression of collagen type I (≈9-fold) in the left ventricle. In contrast, DOCA rats treated with ANG-(1-7) ICV had an improvement of baroreflex control of HR, which was even higher than that in CTL, and a restoration of the baroreflex control of RSNA, the balance of cardiac autonomic tone, and normalized mRNA expression of collagen type I in the left ventricle. Furthermore, DOCA-A7 had MAP lowered significantly. These effects were not accompanied by significant circulating or cardiac changes in angiotensin levels. Taken together, our data show that chronic increase in ANG-(1-7) in the brain attenuates the development of DOCA-salt hypertension, highlighting the importance of this peptide in the brain for the treatment of cardiovascular diseases.
Assuntos
Angiotensina I/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Desoxicorticosterona , Hipertensão/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Hipertensivos/sangue , Barorreflexo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Infusões Intraventriculares , Rim/inervação , Ventrículos Laterais , Masculino , Fragmentos de Peptídeos/sangue , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Fatores de TempoRESUMO
The Mas protooncogene encodes a G protein-coupled receptor that has been described as a functional receptor for the cardioprotective fragment of the renin-angiotensin system (RAS), Angiotensin (Ang)-(1-7). The aim of this current study was to evaluate the responsiveness of Mas expression in hearts during different physiological and pathological conditions in rats. Physical training was considered a physiological condition, while isoproterenol-induced hypertrophy, myocardial infarction and DOCA-salt model of hypertension were used as pathological models of heart injury. The expression of Mas was analyzed by western blotting. Although swim-trained rats presented significant cardiac hypertrophy, our physical training protocol was unable to induce changes in the expression of Mas. On the other hand, cardiac hypertrophy and damage elicited by isoproterenol treatment led to a reduction in Mas expression. Myocardial infarction also significantly decreased the expression of Mas after 21 days of myocardial ischemia. Additionally, Mas expression levels were increased in hearts of DOCA-salt rats. Our present data indicate that Mas expression is responsive to different pathological stimuli, thereby suggesting that Mas receptor is involved in the homeostasis of the heart, as well as in the establishment and progression of cardiac diseases.
Assuntos
Cardiomegalia/metabolismo , Hipertensão/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Angiotensina I/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Desoxicorticosterona , Isoproterenol , Masculino , Atividade Motora , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/biossíntese , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Acoplados a Proteínas G/biossínteseRESUMO
Taenia solium and Taenia crassiceps WFU cysticerci and tapeworms have the ability to synthesize sex steroid hormones and have a functional 3ß-hydroxisteroid dehydrogenase. Corticosteroids (CS) like corticosterone and dexamethasone have been shown to stimulate in vitro estrogen production by Taenia crassiceps WFU cysticerci. The aim of this work was to study the ability of T. crassiceps WFU cysticerci to synthesize corticosteroids, and the effect of the inhibitor metyrapone on the CS synthesis. For this purpose T. crassiceps WFU cysticerci were obtained from the abdominal cavity of mice, thoroughly washed and pre-incubated in multiwells for 24 h in DMEM plus antibiotics/antimycotics. The tritiated CS precursor progesterone ((3)H-P4) was added to the culture media and parasites cultured for different periods. Blanks containing the culture media plus the (3)H-P4 were simultaneously incubated. Blanks and parasite culture media were ether extracted and analyzed by thin layer chromatography (TLC) in two different solvent systems. Corticosterone production was measured in the culture media by RIA. In some experiments metyrapone (0.1-0.5 mM) was added for 24, 48 or 72 h. Results showed that cysticerci mainly synthesized tritiated 11-deoxy corticosterone (DOC) and small amounts of corticosterone that was also detected by RIA. Small amounts of (3)H-11-deoxy cortisol were also found. Corticosteroid synthesis was time dependent. The addition of metyrapone significantly inhibited tritiated DOC, deoxycortisol and corticosterone synthesis. These results show for the first time that parasites have the capacity to synthesize CS that is modulated by metyrapone. Data suggest that DOC is the main corticosteroid in the parasites.
Assuntos
Antimetabólitos/farmacologia , Desoxicorticosterona/metabolismo , Metirapona/farmacologia , Progesterona/metabolismo , Taenia/metabolismo , Animais , Cromatografia em Camada Fina , Desoxicorticosterona/análise , RadioimunoensaioRESUMO
OBJECTIVES: Tension cost, the ratio of myosin ATPase activity to tension, reflects the economy of tension development in the myocardium. To evaluate the mechanical advantage represented by the tension cost, we studied papillary muscle contractility and the activity of myosin ATPase in the left ventricles in normal and pathophysiological conditions. METHODS: Experimental protocols were performed using rat left ventricles from: (1) streptozotocin-induced diabetic and control Wistar rats; (2) N-nitro-L-arginine methyl ester (L-NAME) hypertensive and untreated Wistar rats; (3) deoxycorticosterone acetate (DOCA) salt-treated, nephrectomized and salt- and DOCA-treated rats; (4) spontaneous hypertensive rats (SHR) and Wistar Kyoto (WKY) rats; (5) rats with myocardial infarction and shamoperated rats. The isometric force, tetanic tension, and the activity of myosin ATPase were measured. RESULTS: The results obtained from infarcted, diabetic, and deoxycorticosterone acetate-salt-treated rats showed reductions in twitch and tetanic tension compared to the control and sham-operated groups. Twitch and tetanic tension increased in the N-nitro-L-arginine methyl ester-treated rats compared with the Wistar rats. Myosin ATPase activity was depressed in the infarcted, diabetic, and deoxycorticosterone acetate salt-treated rats compared with control and sham-operated rats and was increased in N-nitro-L-arginine methyl ester-treated rats. These parameters did not differ between SHR and WKY rats. In the studied conditions (e.g., post-myocardial infarction, deoxycorticosterone acetate salt-induced hypertension, chronic N-nitro-L-arginine methyl ester treatment, and streptozotocin-induced diabetes), a positive correlation between force or plateau tetanic tension and myosin ATPase activity was observed. CONCLUSION: Our results suggest that the myocardium adapts to force generation by increasing or reducing the tension cost to maintain myocardial contractility with a better mechanical advantage.
Assuntos
Animais , Masculino , Ratos , Diabetes Mellitus Experimental/fisiopatologia , Hipertensão/fisiopatologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/fisiopatologia , Músculos Papilares/fisiopatologia , Função Ventricular Esquerda , Miosinas Ventriculares/metabolismo , Desoxicorticosterona/análogos & derivados , Diabetes Mellitus Experimental/induzido quimicamente , Inibidores Enzimáticos , Hipertensão/induzido quimicamente , Contração Miocárdica/efeitos dos fármacos , Nefrectomia , NG-Nitroarginina Metil Éster , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17ß-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E(2) was simultaneously determined by counting the number of doublecortin-immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)-positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E(2) pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA-salt-treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA-salt hypertensive rats and (ii) E(2) was able to normalise these biologically important functions in the hippocampus of hypertensive animals.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipertensão/fisiopatologia , Neurogênese/fisiologia , Fármacos Neuroprotetores/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Desoxicorticosterona/metabolismo , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Hipocampo/citologia , Hipocampo/patologia , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mineralocorticoides/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-DawleyRESUMO
We evaluated the development of arterial hypertension, cardiac function, and collagen deposition, as well as the level of components of the renin-angiotensin system in the heart of transgenic rats that overexpress an angiotensin (Ang)-(1-7)-producing fusion protein, TGR(A1-7)3292 (TG), which induces a lifetime increase in circulating levels of this peptide. After 30 days of the induction of the deoxycorticosterone acetate (DOCA)-salt hypertension model, DOCA-TG rats were hypertensive but presented a lower systolic arterial pressure in comparison with DOCA-Sprague-Dawley (SD) rats. In contrast to DOCA-SD rats that presented left ventricle (LV) hypertrophy and diastolic dysfunction, DOCA-TG rats did not develop cardiac hypertrophy or changes in ventricular function. In addition, DOCA-TG rats showed attenuation in mRNA expression for collagen type I and III compared with the increased levels of DOCA-SD rats. Ang II plasma and LV levels were reduced in SD and TG hypertensive rats in comparison with normotensive animals. DOCA-TG rats presented a reduction in plasma Ang-(1-7) levels; however, there was a great increase in Ang-(1-7) ( approximately 3-fold) accompanied by a decrease in mRNA expression of both angiotensin-converting enzyme and angiotensin-converting enzyme 2 in the LV. The mRNA expression of Mas and Ang II type 1 receptors in the LV was not significantly changed in DOCA-SD or DOCA-TG rats. This study showed that TG rats with increased circulating levels of Ang-(1-7) are protected against cardiac dysfunction and fibrosis and also present an attenuated increase in blood pressure after DOCA-salt hypertension. In addition, DOCA-TG rats showed an important local increase in Ang-(1-7) levels in the LV, which might have contributed to the attenuation of cardiac dysfunction and prefibrotic lesions.
Assuntos
Angiotensina I/genética , Desoxicorticosterona/farmacologia , Hipertensão/genética , Fragmentos de Peptídeos/genética , Sistema Renina-Angiotensina/genética , Remodelação Ventricular/genética , Análise de Variância , Angiotensina I/sangue , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Testes de Função Cardíaca , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Imuno-Histoquímica , Fragmentos de Peptídeos/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Hemodynamic parameters and natriuretic peptide levels were evaluated in cardiac hypertrophy produced by sequentially applied renovascular (RV) and deoxycorticosterone acetate-salt (DS) models of hypertension. We studied hypertensive rats by RV or DS treatment at 2 and 4 wk, as well as by the combination of 2 wk of each treatment in an inverse sequence: RV 2 wk/DS 2 wk (RV2/DS2) and DS 2 wk/RV 2 wk (DS2/RV2). The in vivo cardiac function, interstitial fibrosis, and synthesis and secretion of types A (ANP) and B (BNP) natriuretic peptides were monitored in hypertensive models compared with their corresponding sham (Sh2, Sh4). There were no differences in relaxation parameters among RV or DS groups and combined treatments. Left ventricular +dP/dt(max) increased only in RV4 (P < 0.01 vs. Sh4), and this increase was abolished in RV2/DS2. Interstitial collagen concentration increased after 4 wk in both RV4 and RV2/DS2 groups. Although there were no changes in collagen concentration in either DS2 or DS4 groups, clipping after 2 wk of DS (DS2/RV2) remarkably stimulated interstitial fibrosis (P < 0.01 vs. DS2). Plasma BNP increased in RV treatment at 4 wk (P < 0.001 vs. Sh4), but not in DS. Interestingly, RV applied after the 2 wk of DS treatment induced a marked increase in BNP levels (P < 0.001 vs. Sh4). In this regard, plasma BNP appears to be a reliable indicator of pressure overload. Our results suggest that the second stimulus of mechanical overload in combined models of hypertension determines the evolution of hypertrophy and synthesis and secretion of ANP and BNP.