TOLERANCE TO THE VASCULAR EFFECT OF A NOVEL NITRIC OXIDE-DONATING VASODILATOR, FK409

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 mu M or 1-1000 mu g/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 mu M or 1-1000 mu g/kg, i.v.) was marked in both conditions. In addition, FK409 (0.1-10 mu M) activated soluble guanylate cyclase without L-cysteine, but glyceryl trinitrate (1-100 mu M) 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.