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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2801-2807.)
© 1997 American Heart Association, Inc.

Articles

Long-term Probucol Treatment Reverses the Severity of Myocardial Injury in Watanabe Heritable Hyperlipidemic Rabbits

Shiro Hoshida; Nobushige Yamashita; Junsuke Igarashi; Kazuhiro Aoki; Tsunehiko Kuzuya; ; Masatsugu Hori

From the First Department of Medicine (S.H., N.Y., J.I., K.A., T.K., M.H.) and Department of Pathophysiology (K.A., T.K.), Osaka University Medical School, Osaka, Japan.

Correspondence to Shiro Hoshida, MD, PhD, Cardiovascular Division, Osaka Rosai Hospital, 479-3 Nagasone-cho, Sakai, Osaka 591, Japan.

Abstract We previously reported that administration of NO donors ameliorates the severity of myocardial injury in cholesterol-fed rabbits. We now evaluated the effects of probucol, a lipid-lowering antioxidant that can preserve endothelium-dependent relaxation (EDR), in the aortas of cholesterol-fed rabbits. We examined the effects of short-term (7 days) or long-term (24 weeks) administration of 1% probucol on the size of infarcts resulting from 30 minutes of coronary occlusion followed by reperfusion (for 48 hours) in Watanabe heritable hyperlipidemic (WHHL) rabbits. Infarcts in untreated WHHL rabbits were significantly larger than those in the rabbits receiving the long-term but not the short-term treatment with probucol (72.2±5.4%, 37.6±6.4%, and 66.7±3.5%, respectively). Long-term probucol treatment also significantly reduced myeloperoxidase activity in both ischemic and nonischemic myocardium and suppressed P-selectin expression in the coronary vasculature. No significant differences were observed in hemodynamic parameters during myocardial ischemia/reperfusion. Long-term probucol treatment significantly reduced the surface area of atherosclerotic plaque lesions in the aorta (24.4±3.8% vs 46.3±6.3, P<.05). Moreover, long-term probucol treatment restored acetylcholine-induced EDR in aortic rings but did not affect sodium nitroprusside–induced relaxation. Finally, long-term probucol treatment resulted in significantly elevated cGMP levels in the aorta. These results indicate that long-term probucol treatment significantly ameliorates myocardial injury in heritable atherosclerotic rabbits, perhaps by reducing the accumulation of leukocytes in the myocardium and atherosclerotic vascular lesions. Thus, long-term administration appears to suppress the progression of atherosclerotic vascular disease in this animal model.

Key Words: infarct limitation • atherosclerosis • endothelium-dependent relaxation • P-selectin • probucol

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