Carroll Mairéad A, Kang YounJung, Chander Praveen N, Stier Charles T
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA;
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA.
Am J Hypertens. 2015 May;28(5):664-71. doi: 10.1093/ajh/hpu201. Epub 2014 Nov 10.
Activation of angiotensin (ANG) II type 1 receptors (AT1R) promotes vasoconstriction, inflammation, and renal dysfunction. In this study, we addressed the ability of azilsartan (AZL), a new AT1R antagonist, to modulate levels of plasma ANG-(1-7) and renal epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE).
Sprague-Dawley rats were infused with ANG II (125 ng/min) or vehicle (VEH). AZL (3 mg/kg/day) or VEH was administered starting 1 day prior to ANG II or VEH infusion. On day 10, plasma was obtained for measurement of ANG-(1-7) and kidneys for isolation of microvessels for EET and 20-HETE determination and histological evaluation.
Mean 24-hour blood pressure (BP) was not different between VEH and AZL treatment groups, whereas the BP elevation with ANG II infusion (121 ± 5 mm Hg) was completely normalized with AZL cotreatment (86 ± 3 mm Hg). The ANG II-induced renal damage was attenuated and cardiac hypertrophy prevented with AZL cotreatment. Plasma ANG-(1-7) levels (pg/ml) were increased with AZL treatment (219 ± 22) and AZL + ANG II infusion (264 ± 93) compared to VEH controls (74.62 ± 8). AZL treatment increased the ratio of EETs to their dihydroxyeicosatrienoic acid (DHET) metabolites and reduced 20-HETE levels.
Treatment with AZL completely antagonized the elevation of BP induced by ANG II, prevented cardiac hypertrophy, attenuated renal damage, and increased ANG-(1-7) and EET/DHET ratio while diminishing 20-HETE levels. Increased ANG-(1-7) and EETs levels may emerge as novel therapeutic mechanisms contributing to the antihypertensive and antihypertrophic actions of AZL treatment and their relative role compared to AT1R blockade may depend on the etiology of the hypertension.
血管紧张素（ANG）II 1型受体（AT1R）的激活会促进血管收缩、炎症反应和肾功能障碍。在本研究中，我们探讨了新型AT1R拮抗剂阿齐沙坦（AZL）调节血浆ANG-(1-7)水平以及肾环氧二十碳三烯酸（EETs）和20-羟基二十碳四烯酸（20-HETE）水平的能力。
将血管紧张素II（125 ng/分钟）或赋形剂（VEH）注入斯普拉格-道利大鼠体内。在注入血管紧张素II或赋形剂前一天开始给予AZL（3毫克/千克/天）或赋形剂。在第10天，采集血浆用于测量ANG-(1-7)，并取肾脏分离微血管用于测定EET和20-HETE以及进行组织学评估。
赋形剂治疗组和AZL治疗组的24小时平均血压（BP）无差异，而注入血管紧张素II时血压升高（121±5毫米汞柱），与AZL联合治疗时完全恢复正常（86±3毫米汞柱）。AZL联合治疗减轻了血管紧张素II诱导的肾损伤并预防了心脏肥大。与赋形剂对照组（74.62±8）相比，AZL治疗组（219±22）和AZL +血管紧张素II注入组（264±93）的血浆ANG-(1-7)水平（皮克/毫升）升高。AZL治疗增加了EETs与其二羟基二十碳三烯酸（DHET）代谢产物的比例，并降低了20-HETE水平。
AZL治疗完全拮抗了血管紧张素II诱导的血压升高，预防了心脏肥大，减轻了肾损伤，并增加了ANG-(1-7)和EET/DHET比例，同时降低了20-HETE水平。ANG-(1-7)和EETs水平升高可能是AZL治疗的降压和抗肥大作用的新治疗机制，与AT1R阻断相比，它们的相对作用可能取决于高血压的病因。
