Azilsartan is associated with increased circulating angiotensin-(1-7) levels and reduced renovascular 20-HETE levels.
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 (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.


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 ± 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.


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.
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA; mairead_carroll@nymc.edu.
Mairéad A
MA
Carroll
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA;
YounJung
Y
Kang
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA.
Praveen N
PN
Chander
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA;
Charles T
CT
Stier
D000803:Angiotensin I / Q000097:blood*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
D001562:Benzimidazoles; D006893:Hydroxyeicosatetraenoic Acids; D010069:Oxadiazoles; D010446:Peptide Fragments; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000803:Angiotensin I; C521273:azilsartan; C118790:angiotensin I (1-7)
AT1 receptor blocker; angiotensins; blood pressure; eicosanoids; hypertension; kidney.