Angiotensin II type 2 receptor expression after vascular injury - Differing effects of angiotensin-converting enzyme inhibition and angiotensin receptor blockade

It has been suggested that the effects of angiotensin II type 1 receptor (AT(1)R) blockers are in part because of angiotensin II type 2 receptor (AT(2)R) signaling. Interactions between the AT(2)R and kinins modulate cardiovascular function. Because AT(2)R expression increases after vascular injury, we hypothesized that the effects on vascular remodeling of the AT1R blocker valsartan and the ACE inhibitor benazepril require AT2R signaling through the bradykinin 1 and 2 receptors (B1R and B2R). To test this hypothesis, Brown Norway rats were assigned to 8 treatments (n = 16): valsartan, valsartan + PD123319 (AT(2)R inhibitor), valsartan + des-arg(9)-[Leu(8)]- bradykinin (B1R inhibitor), valsartan + HOE140 (B2R inhibitor), benazepril, benazepril + HOE140, amlodipine, and vehicle. After 1 week of treatment, carotid balloon injury was performed. Two weeks later, carotids were harvested for morphometry and analysis of receptor expression by immunohistochemistry and Western blotting. Valsartan and benazepril significantly reduced the intima: media ratio compared with vehicle. Blockade of AT(2)R, B1R, or B2R in the presence of valsartan prevented the reduction seen with valsartan alone. B2R blockade inhibited the effect of benazepril. Injury increased AT(1)R, AT(2)R, B1R, and B2R expression. Treatment with valsartan but not benazepril significantly increased intima AT(2)R expression 2- fold compared with vehicle, which was not reversed by inhibition of AT(2)R, B1R, and B2R. Functionally, valsartan increased intimal cGMP levels compared with vehicle, and this increase was inhibited by blocking the AT(2)R, B1R, and B2R. Results suggest that AT(2)R expression and increased cGMP represent a molecular mechanism that differentiates AT(1)R blockers, such as valsartan, from angiotensin- converting enzyme inhibitors like benazepril.