title: Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis.
abstract: BACKGROUND
  Numerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.
  
  
  RESULTS
  In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg X kg-1 X d-1), L-163,082 (1 mg X kg-1 X d-1), or L-164,282 (1.5 mg X kg-1 X d-1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty.
  
  
  CONCLUSIONS
  These findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2 antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Huckle
authors.forename: M D
authors.initials: MD
authors.lastname: Drag
authors.forename: W R
authors.initials: WR
authors.lastname: Acker
authors.forename: M
authors.initials: M
authors.lastname: Powers
authors.forename: R C
authors.initials: RC
authors.lastname: McFall
authors.forename: D J
authors.initials: DJ
authors.lastname: Holder
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: I I
authors.initials: II
authors.lastname: Stabilito
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.forename: D L
authors.initials: DL
authors.lastname: Ondeyka
authors.forename: N B
authors.initials: NB
authors.lastname: Mantlo
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: C F
authors.initials: CF
authors.lastname: Reilly
authors.forename: R S
authors.initials: RS
authors.lastname: Schwartz
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: R G
authors.initials: RG
authors.lastname: Johnson
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D003327:Coronary Disease / Q000473:pathology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D012008:Recurrence; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; C098412:L 163082; C098413:L 164282; D013449:Sulfonamides; D013777:Tetrazoles; D000804:Angiotensin II; C070967:L 158809