Efeitos da associação de L-arginina e alisquireno sobre a reatividade vascular mesentérica na hipertensão renovascular

Abstract

Angiotensin II has an important role in the pathogenesis of renovascular hypertension and is associated with endothelial dysfunction, increased inflammation and oxidative stress. The interaction between angiotensin II and the COX pathway has been pointed out in the pathogenesis of vascular injuries, relating to an increase in the production of ROS and a reduction in the production / bioavailability of NO. The aim of this study was to investigate the effects of aliskiren and L-arginine administered alone or in association with vascular changes in rats with renovascular hypertension. Renovascular hypertension was induced in male Wistar rats using a silver clip surgically implanted in the left renal artery and the animals were divided into the following experimental groups: SHAM, 2-kidneys, 1-clip (hypertension 2K1C), 2K1C treated with aliskiren (50 mg.kg-1.day-1; ALSK), 2K1C treated with L arginine (10 mg.kg-1.day-1 ; L-ARG) and 2K1C treated with a combination of aliskiren + L-arginine (ALSK + L-ARG), the treatments were started 7 days after clipping the renal artery for 21 days. Blood pressure was monitored throughout the treatment and at the end of the fourth week after clipping, dose-response curves were performed for norepinephrine (NE) and acetylcholine (ACh) in mesenteric vascular beds (LVM) isolated in the absence and presence of blockers for evaluation. vascular reactivity. After 21 days of treatment, only the ALSK + L-ARG group was effective in normalizing systolic blood pressure when compared to the 2K1C group (123.91 ± 1.68 vs. 200.50 ± 5.36 mmHg). Our findings also show that the treatments were effective in improving the endothelial function in the LVM of rats with renovascular hypertension. Alterations in the nitric oxide (NO) pathway seem to be the main mechanism responsible for the impairment in vascular reactivity, as observed in the dose-response curves to ACh and NE in the presence of L-NAME, although the prostanoid pathway also seems to be associated. The antioxidant effect of aliskiren and its ability to reduce oxidative stress in the superior mesenteric artery may be an important mechanism for the improvement in vascular remodeling found in our studies. In contrast, the increase in the bioavailability of NO and the reduction of oxidative stress provided by L-arginine, associated with the reduction of COX-2 and TNF-alpha may be the main mechanism by which this therapy, in addition to improving vascular function, also reduces blood pressure levels. And that when associated, all the evaluated parameters are enhanced and improved, showing values very similar to our normotensive group. Therefore, our work demonstrates for the first time that treatment with aliskiren associated with L arginine was effective in reducing BP and preventing endothelial dysfunction in LVM of rats with renovascular hypertension, in addition, we point out that the mechanisms involved in these effects seem to be related with a reduction of oxidative stress and inflammation and a consequent increase in NO production / bioavailability.