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Background-The precise function of angiotensin II type 2 receptor (AT 2 -R) in the mammalian heart in vivo is unknown.Here, we investigated the role of AT 2 -R in cardiac pressure overload. Methods and Results-Rats were infused with vehicle, angiotensin II (Ang II), PD123319 (an AT 2 -R antagonist), or the combination of Ang II and PD123319 via subcutaneously implanted osmotic minipumps for 12 or 72 hours. Ang II-induced increases in mean arterial pressure, left ventricular weight/body weight ratio, and elevation of skeletal ␣-actin and ␤-myosin heavy chain mRNA levels were not altered by PD123319. In contrast, AT 2 -R blockade resulted in a marked increase in the gene expression of c-fos, endothelin-1, and insulin-like growth factor-1 in Ang II-induced hypertension. In parallel, Ang II-stimulated mRNA and protein expression of atrial natriuretic peptide were significantly augmented by AT 2 -R blockade. Moreover, PD123319 markedly increased the synthesis of B-type natriuretic peptide. Furthermore, the expression of vascular endothelial growth factor and fibroblast growth factor-1 was downregulated by Ang II only in the presence of AT 2 -R blockade. Conclusions-Our