AT2 Receptor Activation Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-Dependent Hypertension
Rationale: Compound 21 (C-21) is a highly selective non-peptide 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 24h 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 (NHE-3) and Na+/K+ATPase (NKA). 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 NHE-3 and NKA, 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.
- antihypertensive therapy/diuretics
- hypertension, high blood pressure
- blood pressure
- hypertension, kidney
- natriuretic hormone
- sodium channels
- angiotensin receptor
- Received January 19, 2016.
- Revision received June 16, 2016.
- Accepted June 20, 2016.