AT 2 Receptor Activation Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II–Dependent Hypertension

Abstract

Rationale: Compound 21 (C-21) is a highly selective nonpeptide angiotensin AT 2 receptor (AT 2 R) agonist. Objective: To test the hypothesis that chronic AT 2 R 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, AT 2 R activation with C-21, both intrarenally and systemically, translocated AT 2 Rs from intracellular sites to the apical plasma membranes of RPT cells without altering the total cellular pool of AT 2 Rs and internalized/inactivated major RPT Na + transporters Na + -H + -exchanger-3 and Na + /K + ATPase. C-21 lowered BP to a similar degree whether administered before or subsequent to the establishment of Ang II–dependent hypertension. Conclusions: Chronic AT 2 R activation initiates and sustains receptor translocation to RPT apical plasma membranes, internalizes/inactivates Na + -H + -exchanger-3 and Na + /K + ATPase, prevents Na + retention resulting in negative cumulative Na + balance, and lowers BP in experimental Ang II–induced hypertension. Acting uniquely at the RPT, C-21 is a promising candidate for the treatment of hypertension and Na + -retaining states in humans.