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 sites to the apical plasma membranes of RPT cells without altering the total cellular pool of AT2Rs 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 AT2R 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.