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(Circulation. 1998;97:2406-2413.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Differential Leukotriene Constrictor Responses in Human Atherosclerotic Coronary Arteries

Sean Allen, PhD; Michael Dashwood, PhD; Karen Morrison, PhD; ; Magdi Yacoub, FRCS

From the Department of Cardiothoracic Surgery (S.A., K.M., M.Y.), Imperial College of Science, Technology & Medicine, Harefield Hospital, Harefield, Middlesex, UK; and Department of Physiology (M.D.), Royal Free Hospital School of Medicine, London, UK.

Correspondence to Professor Sir Magdi H. Yacoub, FRCS, Department of Cardiothoracic Surgery, Imperial College of Science, Technology & Medicine, Heart Science Centre, Harefield Hospital, Hill End Rd, Harefield, Middlesex, UB9 6JH, UK.

Background—Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries.

Methods and Results—The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC₄ and LTD₄. In contrast, LTC₄ and LTD₄ induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [³H]-LTC₄ but not LTD₄ binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [³H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [³H]-LTC₄ binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A₄ hydrolase were also present in the coronary arteries and had a similar distribution to macrophages.

Conclusions—Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC₄ and LTD₄.

Key Words: atherosclerosis • leukotrienes • coronary disease

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