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, -4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenam ide (FK409), in isolated canine coronary artery strips and to its hypo tensive effect in rats, and whether FK409 activates soluble guanylate cyclase isolated from vascular tissues in the absence of L-cysteine. N o 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 demonstrate d in in vitro and in vivo experiments, whereas the tolerance to glycer yl 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 solubl e guanylate cyclase without L-cysteine, but glyceryl trinitrate (1-100 mu M) required the addition of L-cysteine (5 mM) for the activation o f the enzyme. The results suggest that FK409 may be advantageous compa red to tolerance-producing nitrates currently in clinical use, and tha t this property of FK409 is probably due to its independence of a sulf hydryl group donor.