Alterações de componentes do sistema reninaangiotensina em áreas cerebrais de animais hipertensos submetidos a exercício físico

Abstract

High blood pressure (HBP) is the most important risk factor to the cardiovascular diseases, which in turn are the most important cause of morbi-mortality worldwide. HBP is characterized by an increase in sympathetic drive (SNA) to the periphery. Studies showed that an increase in the activity of the angiotensin (Ang) II/ AT1 receptor axis in the brain may contribute to the increased SNA in hypertension. Otherwise, it has been shown that physical exercise (EF) reduces arterial pressure, improves baroreflex function and the autonomic function in hypertensive animals. Currently it is well known that the renin-angiotensin system (RAS) actions are performed mainly by the balance of two axes: angiotensin converting enzyme (ACE)/ Ang II/ AT1, the vasoconstritor and proliferative, and the ACE2/ Ang-(1-7)/ MAS, the hypotensive and anti-proliferative. The objective of the present study was to evaluate the changes in the RAS components in areas related to the control of the sympathetic activity, the rostroventrolateral area of the medulla (RVLM) and hypothalamus, in hypertensive rats subjected to EF. In addition, we evaluate on of the the possible mechanisms involved in these alterations. Sprague-Dawley rats, 9-10 weeks old, weighting 170 a 230 g, were anesthetized and a silver clip (0.20 mm) was placed around the renal artery to induce Goldblatt 2 kidneys-1clip (2K1C) renovascular hypertension. Other animals were subjected to sham surgery (SHAM) and used as control. One week after, animals started the sessions of EF, which consisted of 1 h of swimming in warm water (300C). The animals performed 20 swimming sessions (5 days/ week). The systolic arterial pressure (SAP) was measured by tail cuff, once a week. BP (mean arterial pressure-MAP and heart rate-HR) was also evaluated by telemetry. At the end of exercise sessions, rats were killed by decapitation and the brain areas, hypothalamus, RVLM and cortex, were quickly dissected and frozen on dry ice. Ang II and Ang-(1-7) were measured in the plasma by RIA and the mRNA expression of components of RAS was determined by qRT-PCR. 2K1C rats subjected to EF presented a lower SAP (141 ± 3 mmHg, n=17 vs 163 ± 4 mmHg, n=11, in 2K1C) and lower MAP (157 ± 3 mmHg, n= 5 vs 122 ± 6 mmHg, n=4, 2K1C). Attenuated hypertension was accompanied by lower baseline HR (349 ± 5 beats/min; n=5 vs 361 ± 5 beats/min; n=4, 2K1C). BP values were higher in 2K1C-EF rats than SHAM rats (124 ± 2 mmHg, n=12). The attenuation in BP did not affect the cardiac hypertrophy evaluated by the ratio between left ventricle weight and body weight. 2K1C presented overactivity of the circulating, as evaluated by the increase plasma renin (7 ± 1,7 ng/ml/h, n=7 vs 2,3 ± 0,6 ng/ml/h, n=6, SHAM ), increase in plasma Ang II (218 ± 35 pg/ml, n=7 vs 130 ± 18 pg/ml, n=6, SHAM) and Ang-(1-7) (68 ± 11 pg/ml, n=7 vs 28 ± 4 pg/ml, n=8, SHAM) levels. In addition, 2K1C presented increased Ang II (2 ± 0,2 pg/mg de proteina, n=6 vs 1,1 ± 0,05 pg/mg de proteina, n=7, SHAM) and Ang-(1-7) (2,3 ± 0,2 pg/mg de proteina, n=6 vs 1,1 ± 0,3 pg/mg de proteina, n=4, SHAM) in the left ventricle. EF completely prevented these alterations in plasma and reduced Ang-II levels in the left ventricle. Ang-(1-7) levels in the heart were kept elevated in 2K1C-EF (1,8 ± 0,2 pg/mg de proteina, n=4 vs 2,3 ± 0,2 pg/mg de proteina, n=6, 2R1C). Regarding the evaluation of RAS components in brain areas, 2K1C presented increased mRNA expression of angiotensinogen (4,5 ± 0,7 u.a., n=4 vs 1,0 ± 0,1 u.a.,n=4, SHAM) and decreased expression of ACE2 (0,4 ± 0,1 u.a., n=4 vs 1,1 ± 0,3 u.a.,n=4, SHAM), without change in mRNA expression AT1 and MAS at the RVLM. 2K1C rats subjected to EF presented reduction in AT1 expression (0,5 ± 0,1 u.a., n=4) and increase in ACE2 (2,3 ± 0,5 u.a., n=4) and in MAS receptor (3,3 ± 0,6 u.a., n=4). In the hypothalamus, 2K1C rats presented increased mRNA expression of AT1 (2,9 ± 0,5 u.a., n=3 vs 1,0 ± 0,1 u.a., n=4, SHAM), without significant change in the other components. EF increased mRNA expression of ACE (2,4 ± 0,3 u.a., n=5), ACE2 (3,7 ± 0,4 u.a., n=4) and MAS receptor (3,2 ± 0,4 u.a., n=4) and attenuated AT1 (2,1 ± 0,1 u.a., n=3). These changes resulted in na increase in the ratio between ACE2/ ACE and MAS/ AT1, in the hypothalamus. In addition, EF normalized Ang-(1-7) (136,4 ± 6,5 pg/mg protein, n=8 vs 97,66 ± 6,9 pg/mg de protein, n=6, in 2K1C) and Ang II (5,7 ± 0,4 pg/mg protein, n=8 vs 7,2 ± 1,2 pg/mg protein, n=5 in 2K1C). In order to investigate one mechanism involved in these changes 2K1C rats were subjected to denervation of the baro/ chemoreceptor (SAD). The effects of EF were partially abolished 2K1C-SAD-EF rats. 2R1C-SAD-EF rats presented elevated levels of BP (190 ± 20 mmHg, n=4 ) similar to 2R1C rats (177 ± 13 mmHg, n= 4), and similar mRNA expression of RAS components in the RVLM and hypothalamus in comparison 2K1C. In summary, the results of the present study showed that physical exercise modulates the activity of components of RAS in brain areas related to cardiovascular control. Further, these effect are mediated through baro/chemorreceptor afferents. Future studies are needed to demonstrate in which proportion the changes in the RAS axis to the ACE2/ Ang-(1-7)/ MAS in the RVLM and hypothalamus are related to the fall in sympathetic drive and BP that is induced by physical exercise in hypertensive animals.