Chronic hypotensive effects of losartan are not dependent on the actions of angiotensin II at AT₂ receptors

We have previously demonstrated the chronic hypotensive effects of the AT₁ antagonist, losartan, in normotensive, salt-replete rats. One explanation for this response is a reduction in vascular resistance due to blockade of AT₁ receptors. Another explanation is that increases in angiotensin II levels during losartan administration can bind to AT₂ receptors. Studies suggest that binding of angiotensin II at AT₂ receptors lowers arterial pressure by vasodilation. We hypothesized that the chronic effects of losartan are mediated by activation of angiotensin II effects at AT₂ receptors. We tested this hypothesis by infusing the AT₂ receptor antagonist, PD123319 (74 mg/kg/day), in conjunction with losartan (10 mg/kg/day) for 10 days in rats and compared the hypotensive response in rats treated with losartan alone. After 6 days of treatment, arterial pressure decreased similarly in losartan (-21 ± 2 mm Hg) and losartan+PD123319 (-23 ± 2 mm Hg) treated rats. However, by day 10 of the infusion, arterial pressure had decreased to a greater extent (p < 0.05) in rats treated with losartan and PD123319 (-31 ± 2 mm Hg) compared with rats treated with losartan alone (-22 ± 2 mm Hg). We conclude that the hypotensive effects of losartan are not dependent on the actions of angiotensin II at AT₂ receptors in normotensive, salt-replete rats.