Drugs in the PipelineAT2 Receptor Activities and Pathophysiological ImplicationsMatavelli, Luis C. MD; Siragy, Helmy M. MDAuthor Information Department of Medicine, University of Virginia Health System, Charlottesville, VA. Reprints: Helmy M. Siragy, MD, Department of Medicine, University of Virginia Health Sciences Center, PO Box 801409, Charlottesville, VA 22908-1409 (e-mail: firstname.lastname@example.org). Supported by National Institutes of Health grants DK078757 and HL091535 (to H. M. Siragy). The authors report no conflicts of interest. Received July 09, 2014 Accepted December 16, 2014 Journal of Cardiovascular Pharmacology: March 2015 - Volume 65 - Issue 3 - p 226-232 doi: 10.1097/FJC.0000000000000208 Buy Metrics Abstract Abstract: Although angiotensin II subtype-2 receptor (AT2R) was discovered over 2 decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the nonpeptidic antagonist PD123319. CGP42112A is nonspecific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific nonpeptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation by the release of bradykinin and nitric oxide, anti-inflammation, and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.