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

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. 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. 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. 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.British Journal of Pharmacology (2001) 134 , 865–870; doi: 10.1038/sj.bjp.0704331