Endothelium-derived relaxing factor (EDRF), which plays important regulatory roles in the cardiovascular system (10,26,30), has recently been identified as nitric oxide (26,27). Generation of nitric oxide requires the presence of functionally normal endothelium, and any alteration of its function could contribute to the genesis of a wide variety of diseases. Recent studies have demonstrated decreased endothelium-dependent relaxation in response to pharmacological stimulation of human atherosclerotic coronary arteries ( 1,2, 7,8), of vessels from atherosclerotic rabbits (13,41,44) or other hypertensive animals (21,22,39,43). Therefore, compounds which have an ability to donate nitric oxide seem to represent likely candidates for use in the treatment of such cardiovascular diseases as coronary vasospasm, myocardial ischemia, or hypertension.FK409 is a novel semisynthetic fermentation product of Streptomyces griseosporeus with vasodilator and antiplatelet activities (14). FK409 has a nitric oxide-donating ability, and exerts a potent dilating effect on dog and rabbit isolated arteries, especially coronary arteries, through elevation of 3' ,5'-cyclic guanosine monophosphate (cyclic GMP) levels in vascular smooth muscle.FK409 has no nitro ester in its chemical structure, and, compared with glyceryl trinitrate (GTN), elicits less selftolerance to its vasodilator effect and relatively little crosstolerance to organic nitrates. Thus, FK409 appears to be a unique vasodilator with the ability to accumulate cyclic GMP. This article reviews the chemistry, pharmacology, pharmacokinetics, and toxicology of FK409 in animals and clinical findings in humans.
CHEMISTRY
The chemical structure of FK409, (*)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide, is shown in Fig. 1. The compound was discovered in the search for agents with vasodilator and antiplatelet activities in fermentation products of Streptomyces
