Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: antiplatelet effect.
Nitric oxide (NO) inhibits platelet aggregation. Accordingly, we hypothesized that complexes of diethylamine and spermine with NO (DEA/NO and SPER/NO, respectively), two vasodilators previously shown to release NO spontaneously in aqueous solution, may also be useful antiplatelet agents. Platelet aggregation was measured in whole blood or platelet-rich plasma by impedance aggregometry after addition of collagen. In whole blood, the dose response curve for DEA/NO added 1 min before collagen was similar to that for aspirin (60% inhibition at 10(-4) M), while SPER/NO and sodium nitroprusside were less potent by an order of magnitude. In platelet-rich plasma, 10(-6) M DEA/NO caused 60% inhibition, while SPER/NO and sodium nitroprusside were as active only at 10(-5) M; aspirin's potency was unchanged from that in whole blood. In vivo, DEA/NO and sodium nitroprusside produced significant platelet inhibition 1 min after intravenous injection in the rabbit at 50 nmol/kg. Similar in vivo platelet inhibition was observed with SPER/NO and aspirin, but only at higher dose. The effects of DEA/NO and sodium nitroprusside were transient, lasting less than 30 min after treatment, while the activity of SPER/NO and aspirin was sustained throughout the 30 min experiment. The magnitude and duration of the antiplatelet effects of DEA/NO and SPER/NO correlate with the rates at which they release nitric oxide spontaneously in aqueous solution. Thus, NO/nucleophile complexes merit further exploration both as research tools and as potential antiplatelet agents.
Diodati
J G
JG
Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
Quyyumi
A A
AA
Hussain
N
N
Keefer
L K
LK
D000818:Animals; D004048:Diethylamines / Q000737:chemistry*; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009569:Nitric Oxide / Q000097:blood / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count; D011817:Rabbits; D013096:Spermine / Q000737:chemistry*
D004048:Diethylamines; D010975:Platelet Aggregation Inhibitors; D013096:Spermine; D009569:Nitric Oxide; C034281:diethylamine