Efeitos do tratamento com alisquireno e L-arginina sobre a sensibilidade barorreflexa e estresse oxidativo em ratos com hipertensão renovascular

A hipertensão renovascular é caracterizada pelo aumento da angiotensina II, estresse oxidativo e disfunção endotelial. O objetivo deste estudo foi testar se a administração de alisquireno (ALSK) e L-arginina (L-Arg), restauraria a sensibilidade barorreflexa prejudicada e reduziria o estresse oxidativo em ratos em um modelo hipertensão renovascular. A hipertensão foi induzida através da clipagem da artéria renal esquerda, sendo dividido os animais em cinco grupos: SHAM, 2-rim, 1-clipe (2R1C); 2R1C mais ALSK (ALSK); 2R1C mais L-arg (L-arg); e 2R1C mais ALSK + L-ARG (ALSK+L-ARG). A expressão e atividade de SOD-2 e catalase foi medida no ventrículo esquerdo, o ensaio de produtos avançados de oxidação proteica foram medidos no plasma e ventrículo esquerdo. Após 21 dias de tratamento apenas o grupo ALSK+L-ARG foi eficaz na normalização da pressão arterial sistólica quando comparado ao grupo 2R1C (123,91±1,68 vs. 200,50±5,36 mmHg). Os grupos L-ARG e ALSK+L-arg reverteram a hipertrofia do ventrículo esquerdo quando comparado ao grupo 2R1C (2,22±0,15 e 2,47±0,09 vs. 3,32±0,16, respectivamente, P<0,05). Todos os tratamentos foram capazes de restaurar a sensibilidade do barorreflexo mostrando valores muito similares ao grupo SHAM em ambos os componentes, parassimpático e simpático. A administração aguda de TEMPOL restaurou a sensibilidade do barorreflexo deprimido no grupo 2R1C aos valores que se assemelha aqueles apresentadas pelos outros grupos. Os níveis de produtos avançados de oxidação proteica no plasma mostrou-se aumentada no grupo 2R1C e reduzido nos demais grupos SHAM, ALSK, L-ARG e ALSK+L-ARG (5,79 ± 0,67 vs. 3,79 ± 0,41; 3,96 ± 0,35; 4,26 ± 0,47 e 3,91 ± 0,36 umol/Lchloramine-T, respectivamente, P<0,05). Respostas similares foram encontradas no ventrículo esquerdo. A expressão de SOD-2 e expressão e atividade de catalase no tecido cardíaco foi significativamente aumentada em ALSK, L-ARG e ALSK+L-ARG. A gp91phox no tecido cardíaco foi significativamente diminuída nos grupos L-ARG e ALSK+L-Arg quando comparados com os grupos 2K1C e ALSK. Em conclusão, o tratamento associado de alisquireno e L-arginina normaliza pressão arterial e impede hipertrofia ventricular em ratos com hipertensão 2R1C, um efeito que pode ser parcialmente atribuído ao aumento da sensibilidade do barorreflexo e diminuição do estresse oxidativo. Palavras Chave: Hipertensão 2R1C, Alisquireno, L-arginina, sensibilidade barorreflexa, estresse oxidativ

Role of Renal Nerves in the Treatment of Renovascular Hypertensive Rats with L

The purpose was to determine the role of renal nerves in mediating the effects of antihypertensive treatment with L-arginine in a renovascular hypertension model. The 2K1C (two-kidney one-clip model) hypertensive rats were submitted to bilateral surgical-pharmacological renal denervation. The animals were subdivided into six experimental groups: normotensive control rats (SHAM), 2K1C rats, 2K1C rats treated with L-arginine (2K1C + L-arg), denervated normotensive (DN) rats, denervated 2K1C (2K1C + DN) rats, and denervated 2K1C + L-arg (2K1C + DN + L-arg) rats. Arterial blood pressure, water intake, urine volume, and sodium excretion were measured. The 2K1C rats exhibited an increase in the mean arterial pressure (MAP) (from 106 ± 3 to 183 ± 5.8 mmHg, P<0.01), whereas L-arg treatment induced a reduction in the MAP (143 ± 3.4 mmHg) without lowering it to the control level. Renal nerve denervation reduced the MAP to normotensive levels in 2K1C rats with or without chronic L-arg treatment. L-arg and denervation induced increases in water intake and urine volume, and L-arg caused a significant natriuretic effect. Our results suggest that renal sympathetic activity participates in the genesis and the maintenance of the hypertension and also demonstrate that treatment with L-arg alone is incapable of normalizing the MAP and that the effect of such treatment is not additive with the effect of kidney denervation

Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension

Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress

Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats

Estrogen deficiency and hypertension are considered major risk factors for the development of coronary heart disease. On the other hand, exercise training is considered an effective form to prevent and treat cardiovascular diseases. However, the effects of swimming training (SW) on coronary vascular reactivity in female ovariectomized hypertensive rats are not known. We aimed to evaluate the effects of SW on endothelium-dependent coronary vasodilation in ovariectomized hypertensive rats. Three-month old spontaneously hypertensive rats (SHR, n=50) were divided into four groups: sham (SH), sham plus swimming training (SSW), ovariectomized (OVX), and ovariectomized plus swimming training (OSW). The SW protocol (5 times/week, 60 min/day) was conducted for 8 weeks. The vasodilatory response was measured in isolated hearts in the absence and presence of a nitric oxide synthase inhibitor (L-NAME, 100 µM). Cardiac oxidative stress was evaluated in situ by dihydroethidium fluorescence, while the expression of antioxidant enzymes (SOD-2 and catalase) and their activities were assessed by western blotting and spectrophotometry, respectively. Vasodilation in SHR was significantly reduced by OVX, even in the presence of L-NAME, in conjunction with an increased oxidative stress. These effects were prevented by SW, and were associated with a decrease in oxidative stress. Superoxide dismutase 2 (SOD-2) and catalase expression increased only in the OSW group. However, no significant difference was found in the activity of these enzymes. In conclusion, SW prevented the endothelial dysfunction in the coronary bed of ovariectomized SHR associated with an increase in the expression of antioxidant enzymes, and therefore may prevent coronary heart disease in hypertensive postmenopausal women