ABC | Volume 113, Nº5, November 2019

Original Article Sousa et al. Antioxidant effect of rat environmental enrichment Arq Bras Cardiol. 2019; 113(5):905-912 antioxidant effect of enrichment on the ventrolateral medulla and kidneys. The finding that hypertensive rats (2K1C-St) showed higher values of MAP than control animals (Sham-St) is consistent with obtained by other studies. 3,5 The two-kidney, one-clip (2k1c) Goldblatt hypertensive model is characterized by hyperactivity of the renin‑angiotensin system, especially by angiotensin II. Angiotensin II has actions at AT 1 receptors to elevate blood pressure via numerous mechanisms including vasoconstriction, oxidative stress and increases sympathetic neural discharge. In addition to this classical circulating system, components of the renin-angiotensin system are found locally in the brain. Angiotensin II AT 1 receptors are abundant in the autonomic nervous system and regulatory brain regions, to influence neurotransmission and blood pressure. The actions of angiotensin II in the ventrolateral medulla contribute to sympathoexcitation and hypertension in animals, in part by stimulating oxidative stress. 26 The present study showed that the enrichment was effective in making MAP of 2K1C-EE rats similar to that of sham rats. Additionally, the enrichment restored the ROS components in ventrolateral medulla, kidney and left ventricle. Previous studies have showed a hyperactivity of Ang II in both RVLM 27,28 and CVLM 9,29 areas of ventrolateral medulla on 2K1C rats. In addition, Ang II has been correlated with ROS in these brain areas. 30 On the other hand, Ang II is a strong inductor of ROS generation in the ventricle and kidney. 31,32 Antioxidant compounds are essential to protecting against cardiovascular and nervous systems. Here, the ventrolateral medulla of 2K1C-EE rats had higher SOD and catalase activity in relation to 2K1C-St rats. Thus, environmental enrichment appears to protect against oxidative stress through increasing antioxidant defence, thereby reducing MAP in hypertensive rats. Study shows that increase of antioxidants defences in the ventrolateral medulla reduces the MAP of hypertensive rats. 6 Likewise, previous research found that spontaneously hypertensive rats experienced a decrease in RVLM SOD activity, but also decreased MAP and sympathetic nerve activity when SOD was overexpressed. 33 Carbonyl protein concentration was higher in the ventrolateral medulla of 2K1C-EE rats compared with control groups (Sham-St and Sham-EE). This surprising result suggests that environmental enrichment was either detrimental to hypertensive rats, or the ventrolateral medulla is simply less capable of dealing with protein oxidation, even under advantageous conditions. Similarly, a previous study found that environmental enrichment does not reduce protein oxidation in the cortex of male normotensive rats. 16 However, we also demonstrated that enrichment lowered the TBARS concentration in the ventrolateral medulla of 2K1C rats, indicating that endogenous antioxidants were successfully triggered to neutralise lipid peroxidation. These results corroborate previous research in normotensive rats. 16 Oxidative stress in the ventrolateral medulla increases sympathetic nerve activity, suggesting that this brain region is important to modulating ROS-induced elevation. 28 Overall, environmental enrichment appears to exert a neuroprotective effect through ameliorating oxidative stress, the mechanism of neuroprotection has not been established. Oxidative stress is involved in the pathogenesis of acute and chronic neurological diseases. This is because the nervous tissue is uniquely sensitive to oxidative stress, due to the great quantity of sources of ROS. 1 The synthesis of trophic factors has been suggested to play a role in mediating the neuroprotective effects of enrichment. Environmental enrichment has been found to cause increased brain-derived neurotrophic factor (BDNF) in the glial cell, striatum and substantia nigra. 34 Thus, we suggest that environmental enrichment is not only relevant to brain aging, dementia and neurodegenerative diseases, but also to other neurological disorders and cardiovascular diseases. Oxidative stress in the heart is an essential causal agent of hypertension, activating intracellular signalling that induces heart dysfunction through apoptosis or cell overgrowth. 10,35 We found higher left-ventricle TBARS levels and lower catalase activity in 2K1C-St rats than in Sham (St and EE) rats. Consistent with our results, sedentary 2K1C rats had higher TBARS levels in the left ventricle. In general, renovascular hypertension is expected to increase relative heart weights, cardiomyocyte diameter, myocardial inflammatory cell count, and collagen deposition in the left ventricle. 5 Environmental enrichment did not seem to alter MAP, TBARS, and overall antioxidant defence in the left ventricle of hypertensive rats. Environmental enrichment did not seem to alter MAP, TBARS, and overall antioxidant defence in the left ventricle of hypertensive rats. 36,37 We hypothesize that environmental enrichment should include physical activity (e.g. wheel running) for antioxidant effects to be observable in the heart of hypertensive rats. Multiple studies examining hypertension and cardiovascular diseases have illustrated that physical activity confers antioxidant effects in the heart. 5,38,39 We also observed elevated SOD activity in both kidneys of environmentally enriched hypertensive and normotensive rats. Additionally, left-kidney catalase activity decreased in hypertensive rats (2K1C-St and 2K1C-EE) comparedwith control, probably because it is the clipped kidney. These data suggest that oxidative stress increased in the kidneys of hypertensive animals. 5 Activation of the renin-angiotensin-aldosterone system causes ROS to increase in the kidney via multiple pathways, including elevation of NADPH oxidase, mitochondrial dysfunction, decreased NO availability, and decreased antioxidant enzymes. Accordingly, high angiotensin II-related ROS generation is implicated in hypertension development among several animal models, including 2K1C rats. 40,41 Catalase and SOD activity is reduced in clipped and nonclipped renal cortices of 2K1Cpigs. Relatedly, 8-isoprostane PGF 2 and malondialdehyde excretion are elevated in the kidneys of 2K1C rats. 40,42 Increased ROS production, induced by angiotensin II infusion, in kidneys can initiate hypertension. SOD protects the kidney against stress by attenuating renal p22 phox expression, NADPH oxidase activation. 43 Moreover, SOD overexpression of in the kidney mitigates oxidative stress and hypertension. Adenoviral gene transfer of human SOD-3 in spontaneously hypertensive rats increased SOD-3 expression in kidneys and blood vessels, thereby reducing vascular O 2 •- while improving endothelial function and vascular reactivity. 44 909