Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin.
We studied the antithrombotic activity of 2-acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), a novel nitric oxide (NO)-releasing aspirin derivative, in vivo in different animal models of platelet-dependent and independent pulmonary thromboembolism and compared it with that of aspirin. NCX 4016 protected mice from death induced by the intravenous (i.v.) injection of collagen plus epinephrine, of 9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F(2alpha) (U46619) and of thrombin while aspirin was only active against collagen plus epinephrine. The drop in platelet count and number of lung emboli were reduced by NCX 4016 more effectively than aspirin. NCX 4016 protected mice also from mechanical pulmonary embolism (i.v. injection of hardened rat red blood cells) while aspirin was ineffective. In rabbits, NCX 4016 significantly reduced the accumulation of [111In]oxine-labeled platelets in the pulmonary vasculature induced by collagen and by thrombin while aspirin produced reductions which were significant only versus collagen. In conclusion, NCX 4016 exerts a more pronounced antithrombotic activity than aspirin in vivo in two different animal species, largely due to a deeper inhibitory effect on platelets. NCX 4016 may represent a better antithrombotic agent than aspirin.
Momi
S
S
Institute of Internal and Vascular Medicine, University of Perugia, Via E. dal Pozzo, I-06126, Perugia, Italy.
Emerson
M
M
Paul
W
W
Leone
M
M
Mezzasoma
A M
AM
Del Soldato
P
P
Page
C P
CP
Gresele
P
P
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D019335:Nitroarginine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D011817:Rabbits; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000139:chemically induced / Q000517:prevention & control
D010975:Platelet Aggregation Inhibitors; D019335:Nitroarginine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; C102148:nitroaspirin; D001241:Aspirin