A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression.
BACKGROUND
NO-releasing statins are new chemical entities, combining HMG-CoA reductase inhibition and slow NO release, that possess stronger anti-inflammatory and antiproliferative activities than the native statins.


OBJECTIVE
We evaluated the antithrombotic effects of nitropravastatin (NCX-6550) by assessing its activity on platelet activation and tissue factor (TF) expression by mononuclear cells in vitro and in vivo.


RESULTS
In vitro, NCX-6550 inhibited (1) U46619- and collagen-induced platelet aggregation in buffer and plasma; (2) collagen-induced P-selectin expression in whole blood and (3) platelet adhesion to collagen-coated coverslips under high shear stress. These effects were displayed at concentrations of NCX-6550 ranging from 25 to 100 mum, and were totally reverted by the guanylylcyclase inhibitor ODQ (10 microm). Equimolar concentrations of pravastatin had no influence on these parameters of platelet function. LPS- and PMA-induced TF expression by blood mononuclear cells was also inhibited by NCX-6550 (IC50 13 microm), but not by pravastatin, as assessed by functional and immunological assays and by real-time PCR. In a mouse model of platelet pulmonary thromboembolism, induced by the i.v. injection of collagen plus epinephrine, pretreatment with NCX-6550 (24-48 mg kg(-1)) significantly reduced platelet consumption, lung vessel occlusion and mortality. Moreover, nitropravastatin markedly inhibited the generation of procoagulant activity by spleen mononuclear cells and peritoneal macrophages in mice treated with LPS. In these in vivo models too, pravastatin failed to affect platelet activation and monocyte/macrophage procoagulant activity.


CONCLUSIONS
Our results show that nitropravastatin exerts strong antithrombotic effects in vitro and in vivo, and may represent an interesting antiatherothrombotic agent for testing in acute coronary syndromes.
Rossiello
M R
MR
Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy.
Momi
S
S
Caracchini
R
R
Giannini
S
S
Guglielmini
G
G
Monopoli
A
A
Ongini
E
E
Semeraro
N
N
Colucci
M
M
Gresele
P
P
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019007:P-Selectin / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D017035:Pravastatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D011655:Pulmonary Embolism / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009574:Nitro Compounds; D019007:P-Selectin; D012333:RNA, Messenger; D009569:Nitric Oxide; D013925:Thromboplastin; D017035:Pravastatin