HMG-CoA reductase inhibitor protects against in vivo arterial thrombosis by augmenting platelet-derived nitric oxide release in rats.
Acute coronary syndromes are caused by platelet-mediated thrombosis following rupture of a plaque. HMG-CoA reductase inhibitors (statins) reduce the incidence of events early after acute coronary syndromes, which are independent of its cholesterol-lowering effect. Accordingly, we investigated whether statins inhibit platelet-mediated arterial thrombus formation in vivo and, if so, the underlying mechanisms. Rats were divided into 4 groups. Group 1 was treated with the vehicle, whereas groups 2, 3, and 4 were treated with cerivastatin for 7 days (1, 2, and 5 mg/kg i.p., respectively). Cerivatatin did not change serum cholesterol levels. Carotid arterial thrombosis was created by perivascular FeCl3 delivery. Cerivastatin significantly prolonged the time to thrombotic occlusion of carotid artery. Cerivastatin significantly dose-dependently inhibited both ex vivo platelet P-selectin expression, a marker of platelet activation, and platelet aggregation. Cerivastatin significantly augmented platelet-derived nitric oxide (NO) release, and up-regulated platelet and endothelial nitric oxide synthase (NOS) mRNA expressions. N-nitro-L-arginine methylester abolished the effects of cerivastatin. This study demonstrates that in vivo administration of statin protects against platelet-mediated arterial thrombosis, possibly by augmenting platelet- and endothelium-derived NO releases via up-regulation of platelet and endothelial NOS.
Yokoyama
Shinji
S
Department of Internal Medicine III, Kurume University School of Medicine, Kurume, Japan.
Ikeda
Hisao
H
Haramaki
Nobuya
N
Yasukawa
Hideo
H
Katoh
Atsushi
A
Imaizumi
Tsutomu
T
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000378:metabolism / Q000517:prevention & control*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide