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


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.
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
Brandon A
BA
Kemp
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
Nancy L
NL
Howell
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
Susanna R
SR
Keller
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
John J
JJ
Gildea
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
Shetal H
SH
Padia
From the Division of Endocrinology and Metabolism, Department of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Department of Pathology (J.J.G.), University of Virginia Health System, Charlottesville. rmc4c@virginia.edu.
Robert M
RM
Carey
D000804:Angiotensin II / Q000633:toxicity*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D012964:Sodium / Q000652:urine*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
D057912:Angiotensin II Type 2 Receptor Blockers; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D000804:Angiotensin II; D012964:Sodium
blood pressure; hypertension; kidney; natriuresis; sodium channels