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(Circulation. 1996;93:1009-1019.)
© 1996 American Heart Association, Inc.

Articles

Effects of Subtype-Selective and Balanced Angiotensin II Receptor Antagonists in a Porcine Coronary Artery Model of Vascular Restenosis

William R. Huckle, PhD; Marlene D. Drag, DVM; Wayne R. Acker, MS; Michele Powers, BS; Rosemary C. McFall, BS; Daniel J. Holder, PhD; Tsuneo Fujita, BS; Inez I. Stabilito, BS; Dooseop Kim, PhD; Debra L. Ondeyka, BS; Nathan B. Mantlo, PhD; Raymond S.L. Chang, PhD; Christopher F. Reilly, PhD; Robert S. Schwartz, MD; William J. Greenlee, PhD; Robert G. Johnson Jr, MD, PhD

From the Departments of Pharmacology (W.R.H., R.C.M., T.F., I.I.S., R.S.L.C., C.F.R., R.G.J.), Laboratory Animal Resources (M.D.D., W.R.A., M.P.), Biometrics (D.J.H.), and Exploratory Chemistry (D.K., D.L.O., N.B.M., W.J.G.), Merck Research Laboratories, West Point, Pa; and the Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic and Foundation, Rochester, Minn (R.S.S.).

Correspondence to Dr William R. Huckle, Merck Research Laboratories, WP42-300, West Point, PA 19486. E-mail huckle@merck.com.

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 dilatation 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 of 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.

Methods and 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·kg^-1·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·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 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.

Key Words: angiotensin • restenosis • angioplasty • receptors • coronary disease

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