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 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.

Update on angiotensin AT2 receptors

“…Interestingly, C-21 significantly increased 24h urine Na + excretion in both control and HSD-fed animals chronically (on days 11–14 of the study) (**43). This observation is similar to earlier findings of an enhanced natriuresis in response to C-21 at 2 weeks in this model (42) and is reminiscent of the chronic negative Na + balance induced by C-21 in the Ang II infusion model of experimental hypertension (**28), with obese Zucker rats and Ang II-infused rats having increased Ang II levels in common. Thus, pathophysiologic states characterized as having an activated RAS may respond best to the chronic natriuretic and BP lowering power of AT 2 R activation.…”

“…Building on the findings that acute AT 2 R activation induces natriuresis, Kemp et al (**28) demonstrated in the Ang II infusion model of experimental hypertension that chronic AT 2 R activation with C-21 prevented the initial (24h) Ang II-induced reduction in Na + excretion, induced sustained negative Na + balance and lowered BP to near-control levels during a 7-day infusion period. As with acute C-21 administration, concurrent AT 1 R blockade was not required to unmask the natriuretic and hypotensive actions of chronic C-21.…”

“…Again, similar to the acute studies, chronic administration of C-21 was equally effective administered intrarenally or systemically, translocated AT 2 Rs to the apical plasma membranes and internalized/inactivated NHE-3 and NKA in RPT cells. C-21-induced natriuresis derived from RPT inhibition of Na + reabsorption because it was additive to that of chlorothiazide and amiloride (**28). In addition to preventing Na+ retention and hypertension, the results demonstrated that C-21 was equally effective in lowering BP once the Ang II-dependent hypertension had been established.…”

“…Thus, pathophysiologic states characterized as having an activated RAS may respond best to the chronic natriuretic and BP lowering power of AT 2 R activation. Since AT 2 Rs are translocated to the apical plasma membranes of RPT cells (22,**28) and do not internalize in renal epithelial cells (45), these receptors likely remain active in promoting natriuresis without desensitization and, thereby, reducing BP over a prolonged period of time (46). …”

AT1 receptor signaling pathways in the cardiovascular system

“…AT2 receptor stimulation causes vasorelaxation through protein kinase A (PKA)-dependent endothelial nitric oxide (NO) synthase (eNOS) activation or paracrine signaling induced by bradykinin/NO/cyclic GMP production (1, 8). Mice overexpressing the AT2 receptor exhibit vasodilation (11), and pharmacological stimulation of AT2 receptor promotes natriuresis, lowering of blood pressure, and inhibits AngII-mediated hypertension (12, 13). In systemic AT2 receptor transgenic mice with AngII infusion, perivascular fibrosis but not cardiac hypertrophy is attenuated compared with wild-type mice (14).…”