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(Circulation. 2001;104:2478.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Intraplatelet Tetrahydrobiopterin Plays an Important Role in Regulating Canine Coronary Arterial Thrombosis by Modulating Intraplatelet Nitric Oxide and Superoxide Generation

Seiji Kanaya, MD; Hisao Ikeda, MD, PhD; Nobuya Haramaki, MD, PhD; Toyoaki Murohara, MD, PhD; Tsutomu Imaizumi, MD,PhD

From the Department of Internal Medicine III and the Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.

Correspondence to Hisao Ikeda, MD, PhD, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail ikeikeda{at}med.kurume-u.ac.jp

Background— Platelet-derived nitric oxide inhibits platelet aggregation via constitutive NO synthase (NOS). Tetrahydrobiopterin (BH₄), a cofactor of NOS, augments NO formation, whereas its deficiency decreases NO bioactivity and increases superoxide generation by NOS. The roles of intraplatelet BH₄ in platelet aggregation and thrombus formation, however, are unknown. Accordingly, we investigated whether intraplatelet BH₄ is involved in regulating cyclic flow variations (CFVs) and platelet aggregation in a canine model with stenosed and endothelium-injured coronary arteries that mimics acute coronary syndromes in humans.

Methods and Results— After developing CFVs, dogs received saline or BH₄ (10 or 30 mg/kg) intravenously. Intraplatelet BH₄ and cGMP levels were decreased and intraplatelet nitrotyrosine production was increased during CFVs. ADP- and U46619-induced ex vivo platelet aggregation and platelet P-selectin expression were augmented during CFVs. BH₄ administration restored intraplatelet BH₄ and cGMP levels and decreased intraplatelet nitrotyrosine production, resulting in reduced CFVs and inhibited ex vivo platelet aggregation and platelet P-selectin expression. CFVs again developed after N^G-monomethyl-L-arginine, an inhibitor of NOS, in BH₄-treated dogs. Ex vivo platelet NOS activity at baseline, during CFVs, and after BH₄ administration did not differ.

Conclusions— Intraplatelet BH₄ may play an important role in regulating thrombus formation by modulating platelet-derived nitric oxide and superoxide generation by platelet NOS.

Key Words: platelets • nitric oxide • thrombosis

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