Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade

Ang II acting at AT(1)Rs has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, effects which are believed to be opposed by AT(2)R stimulation. AT, and AT2R expression are up regulated in senescent hearts, and other components of the local renin-angiotensin system are also dramatically increased in the ageing heart. Therefore, the aim of this study was to determine the role of the AT,R in aged rats by determining their potential contribution to the chronic antihypertensive and cardiovascular effects of AT,R blockade. Radiotelemetry probes were implanted into senescent (20 months) male Wistar-Kyoto (WKY) rats, and baseline recordings of mean arterial pressure (MAP) were made for I week. Candesartan cilexetil (2 mg/kg per day) was given in drinking water, while an additional group simultaneously received the AT2R antagonist, PD123319 (10 mg/kg per day) via osmotic mini-pump. At the end of the 4 weeks treatment period, animals were perfusion-fixed to enable histological analysis of cardiovascular structure. MAP was decreased by candesartan cilexetil, however, this effect was not further influenced by PD 123319. Cardiac hypertrophy and fibrosis, and aortic hypertrophy were all significantly reduced by candesartan cilexetil. Most interestingly, these structural changes were reversed by concomitant PD123319 administration, despite the lack of AT,R-mediated effects on MAP. These results suggest that the AT,R does not exert a significant influence on chronic blood pressure regulation in senescent rats. However, PD 123319 did reverse AT,R-mediated regression of cardiovascular hypertrophy and fibrosis, highlighting the important role of the AT2R on cardiovascular structure in the ageing heart and vasculature. (C) 2004 Elsevier Ltd. All rights reserved.