The angiotensin II type 2 (AT 2 ) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT 2 receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT 2 receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal

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... space by using an osmotic pump at 1 L/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (PϽ0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109Ϯ4 to 130Ϯ4 mm Hg (nϭ8, PϽ0.01), whereas S-ODN-treated (nϭ8) and vehicle-treated (nϭ8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (PϽ0.01). Renal interstitial fluid cGMP decreased from 11.9Ϯ0.8 to 3.6Ϯ0.5 pmol/mL (PϽ0.001), and bradykinin decreased from 0.05Ϯ0.05 to 0.18Ϯ0.03 ng/mL (PϽ0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT 2 receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had Ϸ40% less expression of AT 2 receptor than did kidneys treated with S-ODN or vehicle (PϽ0.05). These results suggest that AS-ODN directed selectively against the renal AT 2 receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT 2 receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade. (Hypertension. 2001;37:1285-1291.)