Efeitos cardiovasculares e renais induzidos pela infusão central de alamandina em animais hipertensos
Background and aim. The treatment of hypertension advanced a lot in the last decades, nevertheless around 20% of the subjects with hypertension have a condition named resistant hypertension and do not respond well to the currently available therapy. Among the mechanisms involved in the genesis and m...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | Brasil |
| Institución: | Universidade Federal de Minas Gerais (UFMG) |
| Repositorio: | Repositório Institucional da UFMG |
| Idioma: | portugués |
| OAI Identifier: | oai:repositorio.ufmg.br:1843/65771 |
| Acceso en línea: | http://hdl.handle.net/1843/65771 |
| Access Level: | acceso abierto |
| Palabra clave: | Hipertensão arterial Sistema renina-angiotensina Sistema nervoso central Alamandina Lesões em órgãos-alvo Coração Rim Fisiologia Hipertensão Sistema Renina-Angiotensina Sistema Nervoso Central |
| Sumario: | Background and aim. The treatment of hypertension advanced a lot in the last decades, nevertheless around 20% of the subjects with hypertension have a condition named resistant hypertension and do not respond well to the currently available therapy. Among the mechanisms involved in the genesis and maintenance of hypertension we highlight the overactivity of angiotensin (Ang) II-AT1 receptor axis of the circulating and tissue reninangiotensin system (RAS), including the brain RAS, which is associated to an imbalance of the autonomic nervous system activity. Recently, a new axis of the RAS composed by alamandine and MrgD receptor was described. The studies done heretofore show that alamandine has similar biological effects to those demonstrated to Ang-(1-7), suggesting that this axis could be an additional contraregulatory mechanism of the RAS. The aim of this study was to investigate the effects of the increased levels of alamandine in the central nervous system on cardiovascular parameters, the heart, the kidney, and the brain of hypertensive animals. Methods. To perform this study, Sprague-Dawley (SD) rats and two experimental models of hypertension were used: transgenic hypertensive rats, TGR(mREN2)27 (TG), and DOCA-Salt hypertensive rats (DOCA). Part of the animals received treatment with short-term intracerebroventricular (ICV) infusion of alamandine (90 minutes), and another part of the animals received treatment with long-term ICV infusion of alamandine (14 or 28 days, with osmotic minipumps). The assessment of cardiovascular parameters (arterial pressure, heart rate, and baroreflex sensitivity) was carried out through one of the following methods: arterial pressure acquisition system (AP, BIOPAC), telemetry, or by tail-cuff pletismography. Damage in the heart and kidney was evaluated by the following parameters: 1) cardiac hypertrophy by the heart weight and cardiomyocytes diameter by histology and gene expression (mRNA) of two hypertrophy markers: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); 2) assessment of extracellular matrix deposition by histology and gene expression (mRNA) of extracellular matrix proteins in the left ventricle of the heart (LV) and in the kidney; 3) cardiac function by echocardiogram; 4) measurement of inflammatory mediators in the LV and kidney (ELISA); 5) evaluation of inflammatory infiltrate and tubulointerstitial injury in the kidney by histology; 6) renal function assessment. The possible brain mediators involved on alamandine effects were evaluated by: 1) RNASeq; 2) gene expression of components of the nitrergic (nNOS), glutamatergic (glutaminase, excitatory aminoacid transporter, and NR1 subunit of the NMDA receptor) systems, and of the RAS [angiotensinogen, angiotensin converting enzyme (ACE), ACE2, MrgD and Mas receptors]; and 3) measurement of inflammatory mediators (ELISA). Results. The short-term (hours) increased levels of alamandine in the CNS decreased the APof hypertensive animals and improved the baroreflex sensitivity in both normotensive and hypertensive rats. The long-term (4 weeks) ICV infusion of alamandine decreased the arterial pressure (SAP, DAP, and MAP) and heart rate of 12 weeks old TG rats. The ICV infusion of alamandine (2 weeks) improved the baroreflex sensitivity of DOCA rats, without changing the AP of these rats. The long-term ICV infusion of alamandine did not change cardiac hypertrophy in both experimental models of hypertension but attenuated the increased extracellular matrix deposition observed in the LV of TG hypertensive rats. The cardiac function and levels of inflammatory cytokines were not changed. Regarding the kidney, the treatment with alamandine decreased the inflammatory infiltrate, the tubulointerstitial injury, the levels of TNF-α, IL-6, and IL-1β, and reverted collagen deposition in TG rats. Concerning central mechanisms of alamandine, TG rats presented increased levels of proinflammatory cytokines in hypothalamus and medulla oblongata. The treatment with alamandine attenuated these changes. There was no change between groups regarding the expression of the RAS components, with exception of the MrgD receptor, which expression is increased in hypertensive rats and is not influenced by the increased levels of alamandine. About the expression of the glutamatergic and nitrergic systems components, we did not find important differences between groups. The expression of a great number of genes is changed in the brain of hypertensive animals and hypertensive animals treated with alamandine. Some of these genes are common to these two groups, nonetheless the changes observed in the expression of these genes is not uniform. Thus, the expression of some genes is increased or decreased in the two groups while other genes present opposite changes in hypertensive animals in comparison to the treated hypertensive animals. Conclusion. Together, the results of this study support the importance of the brain RAS in the pathophysiology of hypertension and indicate alamandine as an alternative and contraregulatory pathway of the RAS. |
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