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(Hypertension. 2001;37:1285.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats

Allan F. Moore; Nicolas T. Heiderstadt; Esther Huang; Nancy L. Howell; Zhi-Qin Wang; Helmy M. Siragy; Robert M. Carey

From the Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville.

Abstract—The angiotensin II type 2 (AT₂) 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 AT₂ receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT₂ 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 interstitial space by using an osmotic pump at 1 µL/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 (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN–treated rats experienced an increase in systolic BP from 109±4 to 130±4 mm Hg (n=8, P<0.01), whereas S-ODN–treated (n=8) and vehicle-treated (n=8) 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 (P<0.01). Renal interstitial fluid cGMP decreased from 11.9±0.8 to 3.6±0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05±0.05 to 0.18±0.03 ng/mL (P<0.001) 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 AT₂ receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had 40% less expression of AT₂ receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT₂ receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT₂ receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.

Key Words: blood pressure • receptors, angiotensin II • hypertension, experimental • kidney • rats

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