Angiotensin II and Angiotensin‐(1–7) Restore Salt‐Induced Vascular Dysfunction via Distinct Mechanisms

This study determined the effect of 3 day chronic i.v. infusion of low doses of angiotensin II (ANG II; 5 ng/kg/min) and angiotensin‐(1–7) [ANG (1–7); 4 ng/kg/min] on endothelium‐dependent vascular relaxation in isolated mesenteric resistance arteries of Sprague‐Dawley rats fed high salt (HS; 4% NaCl) diet, which compromises vasodilation in this normotensive model. Both ANG II and ANG (1–7) restored vasodilator responses to acetylcholine that were absent in HS‐fed rats. Restoration of dilation by ANG II infusion could be blocked by coinfusion of losartan (20 μg/kg/min) but not by the AT 2 and mas receptor blockers PD123319 (5 μg/kg/min) and A779 (400 ng/kg/min), respectively. Stimulation of the AT 1 receptor led to transactivation of the EGF receptor and ERK 1/2 activation, because EGF infusion (2 μg/h) mimicked and EGFR kinase inhibition (AG1478‐20 μg/h) and ERK 1/2 inhibition (PD98059‐10 μg/h) blocked the effect of ANG II on vascular relaxation. By contrast, the protective effect of ANG (1–7) to restore vascular relaxation in HS‐fed rats was blocked by A779 and PD123319, but unaffected by losartan. ANG 1–7 infusion was accompanied by an upregulation of mas (but not AT 1 or AT 2 ) receptor protein expression, but not eNOS phosphorylation. These results indicate that both ANG II and ANG (1–7) ameliorate vascular dysfunction with HS diet, but via different mechanisms (NIH #HL65289; #HL72920; and #HL‐92026).