Azilsartan Is Associated With Increased Circulating Angiotensin-(1–7) Levels and Reduced Renovascular 20-HETE Levels

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Abstract

BACKGROUND

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).

METHODS

Sprague-Dawley rats were infused with ANG II (125ng/min) or vehicle (VEH). AZL (3mg/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.

RESULTS

Mean 24-hour blood pressure (BP) was not different between VEH and AZL treatment groups, whereas the BP elevation with ANG II infusion (121±5mm Hg) was completely normalized with AZL cotreatment (86±3mm 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.

CONCLUSIONS

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.

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