title: Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis.
abstract: OBJECTIVE
  Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH.
  
  
  METHODS
  A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses.
  
  
  RESULTS
  Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21.
  
  
  CONCLUSIONS
  Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH.
authors.affiliation: Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bruce
authors.forename: V
authors.initials: V
authors.lastname: Shenoy
authors.forename: A
authors.initials: A
authors.lastname: Rathinasabapathy
authors.forename: A
authors.initials: A
authors.lastname: Espejo
authors.forename: A
authors.initials: A
authors.lastname: Horowitz
authors.forename: A
authors.initials: A
authors.lastname: Oswalt
authors.forename: J
authors.initials: J
authors.lastname: Francis
authors.forename: A
authors.initials: A
authors.lastname: Nair
authors.forename: T
authors.initials: T
authors.lastname: Unger
authors.forename: M K
authors.initials: MK
authors.lastname: Raizada
authors.forename: U M
authors.initials: UM
authors.lastname: Steckelings
authors.forename: C
authors.initials: C
authors.lastname: Sumners
authors.forename: M J
authors.initials: MJ
authors.lastname: Katovich
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C092006:7-Ala-angiotensin (1-7); D057912:Angiotensin II Type 2 Receptor Blockers; D002317:Cardiovascular Agents; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; C073402:PD 123319; D016686:Monocrotaline