AT2 Receptor Activation Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-Dependent Hypertension.

Rationale:Compound 21 (C-21) is a highly selective nonpeptide angiotensin AT2 receptor (AT2R) agonist. Objective:To test the hypothesis that chronic AT2R activation with C-21 induces natriuresis via an action at the renal proximal tubule (RPT) and lowers blood pressure (BP) in experimental angiotensin II (Ang II)–dependent hypertension. Methods and Results:In rats, Ang II infusion increased both sodium (Na+) retention and BP on day 1, and BP remained elevated throughout the 7-day infusion period. Either intrarenal or systemic administration of C-21 prevented Ang II–mediated Na+ retention on day 1, induced continuously negative cumulative Na+ balance compared with Ang II alone, and reduced BP chronically. The effects of C-21 are likely to be mediated by action on the RPT as acute systemic C-21–induced natriuresis was additive to that induced by chlorothiazide and amiloride. At 24 hours of Ang II infusion, AT2R activation with C-21, both intrarenally and systemically, translocated AT2Rs from intracellular s...