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 hypot hesized that complexes of diethylamine and spermine with NO (DEA/NO an d 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 w hole blood, the dose response curve for DEA/NO added 1 min before coll agen was similar to that for aspirin (60% inhibition at 10(-4) M), whi le SPER/NO and sodium nitroprusside were less potent by an order of ma gnitude. In platelet-rich plasma, 10(-6) M DEA/NO caused 60% inhibitio n, 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 inhibi tion 1 min after intravenous injection in the rabbit at 50 nmol/kg. Si milar in vivo platelet inhibition was observed with SPER/NO and aspiri n, but only at higher dose. The effects of DEA/NO and sodium nitroprus side were transient, lasting less than 30 min after treatment, while t he 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 nit ric oxide spontaneously in aqueous solution. Thus, NO/nucleophile comp lexes merit further exploration both as research tools and as potentia l antiplatelet agents.