EFFECTS OF SUBTYPE-SELECTIVE AND BALANCED ANGIOTENSIN-II RECEPTOR ANTAGONISTS IN A PORCINE CORONARY-ARTERY MODEL OF VASCULAR RESTENOSIS

Background Numerous studies have demonstrated the ability of angiotens in II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilatati on of noncoronary arteries in small-animal models, suggesting an impor tant role for Ang II in the response to injury. Although ACE inhibitor s have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy of AC E inhibitors against tissue ACE and the contributions of ACE-independe nt pathways of Ang II generation. Unlike ACE inhibitors, Ang II recept or antagonists have the potential to inhibit responses to Ang II indep endent of its biosynthetic origin. Methods and Results In separate stu dies, three Ang II receptor antagonists, including AT(1)-selective (L- 158,809), balanced AT(1)/AT(2) (L-163,082), and AT(2)-selective (L-164 ,282) agents, were evaluated for their ability to inhibit vascular int imal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that const ant infusion of L-158,809 (0.3 or 1.0 mg.kg(-1).d(-1)) reduced the neo intimal cross-sectional area by up to 37% measured 14 days after ballo on dilatation. In the porcine studies, animals were treated with vehic le or test compound beginning 2 days before and extending 28 days afte r experimental angioplasty. Left anterior descending, left cir cumflex , and/or right coronary arteries were injured by inflation of commerci ally available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg.kg(-1).d(-1)), L-163,082 (1 mg.kg( -1) .d(-1)), or L-164,282 (1.5 mg.kg(-1).d(-1)) in the study animals y ielded plasma drug levels sufficient either to chronically block or, f or L-164,282, to spare presser responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effe cts (P=.12, P=.75, and P=.48, respectively, compared with vehicle-trea ted controls) on neointimal thickness (normalized for degree of injury ) measured by morphometric analysis at day 28 after angioplasty. Concl usions These findings indicate that chronic blockade of Ang II recepto rs by either site-selective or balanced AT,I AT, antagonists is insuff icient to inhibit intimal hyperplasia after experimental coronary vasc ular injury in the pig. The results further suggest that, unlike in th e rat carotid artery, Ang II is not a major mediator of intimal thicke ning in the pig coronary artery.