A novel anti-ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects.
BACKGROUND
Platelet and endothelial production of nitric oxide (NO) is known to be impaired in coronary artery disease patients. Compounds that release NO (e.g. nitrates) have antiplatelet effects, but at supratherapeutic doses with hypotensive side effects.


OBJECTIVE
To investigate the antithrombotic effect on human blood of a novel NO donor (LA419) with known anti-ischemic properties but without hypotensive side effects and to compare with abciximab.


METHODS
Healthy subjects (n = 8; 32 +/- 3 years) received daily aspirin starting three days prior to the study day. Treatments (LA419 10 and 20 microm, and abciximab 4 microm) were added ex vivo to non-anticoagulated blood, and the antithrombotic properties were assessed by measuring changes in thrombus size from pretreatment baseline in the Badimon perfusion chamber at low and high shear rates. Platelet surface adhesion using a Cone and Platelet Analyzer (CPA) and platelet fibrinogen-receptor activation with flow cytometry were also evaluated.


RESULTS
At low shear rates, LA419 displayed a reduction in thrombus area of 43% +/- 8% (10 microm) and 56% +/- 6% (20 microm), whereas at high shear rates the reductions were 44% +/- 3% (10 microm) and 62% +/- 6% (20 microm). Platelet surface adhesion with the CPA was also reduced. Abciximab exhibited a strong inhibitory effect on thrombus formation, platelet surface adhesion and fibrinogen receptor activation.


CONCLUSIONS
The novel NO donor, LA419, shows a strong antithrombotic effect in human blood, which is comparable to abciximab, especially under high shear rate conditions. Our observations suggest that the availability of an NO donor could prove beneficial in the prevention of thrombotic complications of cardiovascular disease. Further clinical studies are warranted.
Zafar
M U
MU
Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, NY, USA.
Vilahur
G
G
Choi
B G
BG
Ibanez
B
B
Viles-Gonzalez
J F
JF
Salas
E
E
Badimon
J J
JJ
D000077284:Abciximab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D039341:Receptors, Fibrinogen / Q000187:drug effects; D013927:Thrombosis / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; C503157:LA 419; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D039341:Receptors, Fibrinogen; D007548:Isosorbide Dinitrate; D000077284:Abciximab