Antagonism of AT2 receptors augments Angiotensin II-induced abdominal aortic aneurysms and atherosclerosis

1. We have recently demonstrated that chronic infusion of Angiotensin II into apoE - / - mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co-infused Angiotensin II (1000 ng kg^-1 min^-1 for 28 days) with losartan (30 mg kg^-1 day^-1) or PD123319 (3 mg kg^-1 day^-1) to antagonize AT1 and AT2 receptors, respectively. 2. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE - / - mice. The formation of aortic aneurysms was totally inhibited by co-infusion of Angiotensin II with losartan (30 mg kg^-1 day^-1; P= 0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3. To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE - / - mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology.