CLOSE CORRELATION BETWEEN NITRIC-OXIDE (NO) FORMATION FROM NO RELEASERS AND THE BIOLOGICAL-ACTIVITIES OF THESE AGENTS IN RATS

The aim of this study was to clarify the difference in the profiles of nitric oxide (NO) formation of three NO releasers and to examine the correlation between NO formation from these drugs and their biological activities in rats. E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamid e (FK409) and 3-morpholinosydnonimine (SIN-1) spontaneously generated nitrite, an oxidative product of NO, in sodium phosphate buffer (PB) s olution. On the other hand, sodium nitroprusside (SNP) did not generat e nitrite. The rank order of the concentrations of nitrite generated w as SIN-1 > FK409 >> SNP. In biological studies using rats, these drugs showed anti-platelet effects and in vitro vasorelaxant and hypotensiv e effects with potencies in the rank order of FK409 > SIN-1 > SNP and SNP > FK409 > SIN-1, respectively. These drugs generated nitrite with concentrations in the rank order of FK409 > SIN-1 > SNP and SNP > FK40 9 > SIN-1 in rat plasma and in PB solution with L-cysteine (Cys), resp ectively. In conclusion, three NO releasers liberate NO with NO-releas ing rates of different rank orders under different incubation conditio ns, and the anti-platelet effects and vasorelaxant and hypotensive eff ects of these NO releasers closely correlate with NO formation from th e compounds in the plasma and PB solution with Cys, respectively, but not with that in PB solution without Cys.