Chronic Hypotensive Effects of Losartan Are Not Dependent on the Actions of Angiotensin II at AT 2 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 AT 2 receptors in normotensive, salt-replete rats.