This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor
(AT1R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral
arteries (MCA) of Sprague-Dawley rats. Eleven-weeks old, healthy male Sprague-Dawley
rats on a standard diet were given the AT1R blocker losartan (1 mg/mL) in drinking
water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade
of AT1R attenuated FID and acetylcholine-induced dilations was compared to control
group. Nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME)
and cyclooxygenase inhibitor indomethacin (INDO) significantly reduced FID in control
group. The attenuated FID in losartan group was further reduced by INDO only at ∆100
mmHg, whereas L-NAME had no effect. In losartan group, TEMPOL (a superoxide scavenger)
restored dilatation, while TEMPOL+L-NAME together significantly reduced FID compared
to restored dilatation with TEMPOL alone. Direct fluorescence measurements of NO and
reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly
reduced vascular NO levels with AT1R blockade compared to control group, while flow
increased the NO and ROS production in losartan group and had no effect in control
group. In losartan group, TEMPOL decreased ROS production in both no-flow and flow
conditions. AT1R blockade elicited increased serum concentrations of AngII, 8-iso-PGF2α,
and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results
suggest that in small isolated cerebral arteries: 1) AT1 receptor maintains dilations
in physiological conditions; 2) AT1R blockade leads to increased vascular and systemic
oxidative stress, which underlies impaired FID.
