Yasuhiro Kita (1,#), Shinichi Fukuyama (2) and Yoshimi Hirasawa (1)
(1) New Drug Research Laboratories, (2) Analytical Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, 2-chome Kashima, Yodogawa-ku, Osaka 532, Japan
(#) Present address: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 5-2-3, Tokodai, Tsukuba, Ibaraki 300-26, Japan
Abstract: 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-hexenamide (FK409) and 3-morpholinosydnonimine (SIN-1) spontaneously generated nitrite, an oxidative product of NO, in sodium phosphate buffer (PB) solution. On the other hand, sodium nitroprusside (SNP) did not generate nitrite. The rank order of the concentration of nitrite generated was SIN-1>FK409>>SNP. In biological studies using rats, these drugs showed anti-platelet effects and in vitro vasorelaxant and hypotensive 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>FK409>SIN-1 in rat plasma and in PB solution with L-cysteine (Cys), respectively. In conclusion, three NO releasers liberate NO with NO-releasing rates of different rank orders under different incubation conditions, and the anti-platelet effects and vasorelaxant and hypotensive effects of these NO releasers closely correlate with NO formation from the compounds in the plasma and PB solution with Cys, respectively, but not with that in PB solution without Cys.
Keywords: FK-409, 3-Morpholinosydnonimine (SIN-1), Sodium nitroprusside (SNP), Nitric oxide (NO)