(Circulation. 1996;93:848-852.)
© 1996 American Heart Association, Inc.
Articles |
Pharmacological Strategies to Prevent Restenosis
Lessons Learned From Blockade of the Renin-Angiotensin System
From the Falk Cardiovascular Research Center, Stanford (Calif) University School of Medicine.
Correspondence to Victor J. Dzau, MD, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94301. E-mail ml.vjd@forsythe.stanford.edu.
Key Words: Editorials • angioplasty • angiotensin • stenosis • atherosclerosis • receptors
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Introduction |
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A major challenge in the field of cardiovascular therapeutics is the discovery of a drug that is capable of preventing restenosis. To date, unfortunately, all pharmacological strategies for limiting restenosis have fallen short of the goal. Crucial to the successful discovery of an efficacious agent is the understanding of the mechanisms responsible for restenosis in humans. However, despite enormous research efforts, the exact pathological processes responsible for the disease in humans are not well understood, and animal models have not been able to simulate the complexity of the clinical situation. Indeed, none of the drugs that have been shown to limit restenosis in animal models have yielded positive results in human clinical trials. On the basis of animal experimentation and pathological examination of human restenotic lesions, a major hypothesis for the development of restenosis involves VSMC migration and proliferation. Thus, a popular strategy for therapeutic discovery is to use one of the animal models of neointimal hyperplasia and to examine the effects of specific drugs designed to block the processes of VSMC migration and/or proliferation. Multiple biologically active mediators have been shown to participate in these processes. Among these, Ang II is of particular interest, because pharmacological inhibitors of Ang II production or action are now clinically available. In cell culture, Ang II has been shown to stimulate growth of VSMCs isolated from several species such as rats, rabbits, and humans.1 2 3 4 More importantly, in vivo infusion of Ang II significantly increases DNA synthesis in normal, uninjured arteries and enhances neointimal
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