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Tolerance to the vascular effect of a novel nitric oxide-donating vasodilator, FK409

1994; Elsevier BV; Volume: 260; Issue: 2-3 Linguagem: Inglês

10.1016/0014-2999(94)90333-6

1879-0712

Toyokazu Isono, Natsuki Sato, Takao Yamamoto, Tadashi Sawada, Shunji Yamazaki, Shintaro Miura, Atsuko Furuichi, Reiko Ozaki, Yasushi Koibuchi, Minoru Ohtsuka,

Free Radicals and Antioxidants

We investigated whether tolerance develops to the vasorelaxant effects of a new vasodilator, (+-)-(E)-4-ethyl-2-[(E)-hydroxy-imino]-5-nitro-3-hexenamide (FK409), in isolated canine coronary artery strips and to its hypotensive effect in rats, and whether FK409 activates soluble guanylate cyclase isolated from vascular tissues in the absence of L-cysteine. No tolerance to FK409 (0.46 nM to 0.46 microM or 1-1000 micrograms/kg, i.v.) or cross-tolerance between FK409 and glyceryl trinitrate was demonstrated in in vitro and in vivo experiments, whereas the tolerance to glyceryl trinitrate (0.44 nM to 4.4 microM or 1-1000 micrograms/kg, i.v.) was marked in both conditions. In addition, FK409 (0.1-10 microM) activated soluble guanylate cyclase without L-cysteine, but glyceryl trinitrate (1-100 microM) required the addition of L-cysteine (5 mM) for the activation of the enzyme. The results suggest that FK409 may be advantageous compared to tolerance-producing nitrates currently in clinical use, and that this property of FK409 is probably due to its independence of a sulfhydryl group donor.