Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists

Background: Vasoconstrictive, proliferative and oxidative effects of angiotensin II (Ang II) are mediated by Ang II type 1 (AT,) receptors. The effects of Ang II via the Ang II type 2 (AT(2)) receptor subtype (ATR) are less well defined. Growing evidence shows the existence of crosstalk between the Ang II receptor subtypes, which is revealed by AT(1)R blockade. Hence, under certain conditions, AT(2)R may act as an antagonistic system with respect to the AT(2)R. Methods: The present study was designed to investigate the effects of long-term treatment with the AT(1)R antagonist losartan on the AT(2)R-mediated response to Ang II in thoracic aortas isolated from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Untreated animals from both groups were used as controls. The mRNA expression of AT(1)R and AT(2)R was measured by reverse transcription-polymerase chain reaction. Results: During contraction in response to norepinephrine, Ang II induced concentration-dependent relaxation only in aortas isolated from STIR chronically treated with losartan (8 weeks; 30 mg/kg/day in drinking water). These relaxations were inhibited by the selective AT(2)R blocker PD123319, N-G-nitro-L-arginine methyl ester (L-NAME), and B(2)receptor antagonist HOE-140. Accordingly, nitric oxide (NO) production was increased by Ang II only in the aortas of treated SHR. After AT(1)R blockade, AT(2)R mRNA was significantly increased. These findings demonstrate that, in hypertensive rats, chronic AT(1)R blockade is associated with an inverted vasornotor response to Ang II via AT(2)R-mediated NO production. Conclusions: The losartan-unmasked AT(2)R-vasore-laxation could significantly contribute to the beneficial hernodynamic effects of AT,R blockade. In view of this, our study highlights the importance of the integrated Ang II receptor network, which may help to define further the mechanisms of the well-established vascular protective effects of AT(1)R blockers. (c) 2005 American Journal of Hypertension, Ltd.