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

Abstract

We investigated whether tolerance develops to the vasorelaxant effects of a new vasodilator, (±)-( E)-4-ethyl-2-[( E)-hydroxyimino]-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 μM or 1–1000 μg/kg, i.v.) or cross-tolerance between FK409 and glyceryl trinitrate was demonstrated in vitro and in vivo experiments, whereas the tolerance to glyceryl trinitrate (0.44 nM to 4.4 μM or 1–1000 μg/kg, i.v.) was marked in both conditions. In addition, FK409 (0.1–10 μM) activated soluble guanylate cyclase without L-cysteine, but glyceryl trinitrate (1–100 μM) 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 sulfhyhydryl donor.