Characteristics of the Vasorelaxing Action of (3E)-4-Ethyl-2-Hydroximino-5-Nitro-3-Hexamide FK409, a New Vasodilator Isolated From Microbial Sources, in Isolated Rabbit Arteries

Abstract

We examined the vasoinhibitory effect of (3E)-4-ethyl-2-hydroximino-5-nitro-3-hexamide FK409, a new vasodilator, on contractile responses in isolated rabbit arteries. FK409 (10(-8)-10(-5) M) inhibited contractile responses to norepinephrine (NE), histamine (His), and 5-hydroxytryptamine (5-HT) in rabbit aorta. The pattern of inhibition by FK409 was not competitive. The inhibitory effect of FK409 on the 5-HT response was much greater than that of nitroglycerin (NG). A high concentration of FK409 (10(-5) M) was necessary to inhibit the response to KCl (10-70 mM). The effect of combined treatment with FK409 (10(-5) M) and a subthreshold concentration of nifedipine (10(-9) M) on the KCl response was much greater than a single treatment with either agent. In addition, 3 x 10(-6) M D600, but not FK409 (10(-6) or 10(-5) M), inhibited the increase in the rate of 45Ca influx stimulated by a 40-mM KCl substituted solution. In a Ca2(+)-free medium containing EGTA and nifedipine, FK409 (10(-9)-10(-5) M) inhibited phasic responses to NE, His, and 5-HT, and subsequent sustained responses owing to addition of Ca2+. The response to caffeine in rabbit iliac arteries incubated in Ca2(+)-free medium was also inhibited by FK409 (10(-6) and 10(-5) M). In rabbit aorta precontracted with NE (10(-5) M) and partially inhibited by prior exposure to NG (10(-5) M), the relaxing effect of FK409 was slightly attenuated. Pretreatment of tissues with FK409 (10(-6) M) inhibited the relaxing action of NG much more than prior NG inhibited the relaxing action of FK409. Methylene blue (10(-5) M), but not hemoglobin (10(-6) M), inhibited the relaxing action of FK409, whereas M&B 22,948 (3 x 10(-4) M) potentiated it. FK409 caused a relaxation of precontracted aorta without endothelium that was inhibited by methylene blue. In rabbit aorta precontracted with NE, FK409 (10(-6) M) increased cyclic GMP but not cyclic AMP content. FK409 (10(-5) M) had no effect on the NE-mediated increase in tissue inositol monophosphate (IP). These results suggest that FK409 inhibits the responses attributed to both intracellular Ca2+ release and Ca2+ influx through receptor-operated channels. The inhibitory effect of FK409 on both the KCl contractile response and KCl-stimulated 45Ca influx appears to be different from that of nifedipine or D600. Furthermore, the inhibitory action of FK409 may be partially mediated by cyclic GMP.