Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 Oct;113(2):385–388. doi: 10.1111/j.1476-5381.1994.tb17000.x

Antiplatelet activities of FK409, a new spontaneous NO releaser.

Y Kita 1, Y Hirasawa 1, K Yoshida 1, K Maeda 1
PMCID: PMC1510097  PMID: 7834188

Abstract

1. We reported that (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409) released nitric oxide (NO) spontaneously with a chemiluminescence analyzer. The aim of this study was to compare antiplatelet activities of FK409, a new NO releaser, with those of isosorbide dinitrate (ISDN) in vivo and in vitro. In order to elucidate the differences in antiplatelet activities between FK409 and ISDN, we compared their modes of action. 2. In in vitro experiments, FK409 had a more potent inhibitory effect on rat platelet aggregation induced by adenosine 5'-diphosphate (2.0 microM) than ISDN (IC50 = 4.32 +/- 0.95 microM and > 100 microM respectively). 3. In the rat extracorporeal shunt model (in vivo experiments), FK409 suppressed thrombus formation dose-dependently from 0.32 mg kg-1, p.o. and showed the maximum inhibition (52% inhibition vs. vehicle treatment) at 10 mg kg-1, p.o., while ISDN showed no inhibition at 10 mg kg-1 and only 17% inhibition at 32 mg kg-1, p.o. 4. FK409 could generate nitrite, which is an oxidative product of NO, much faster than ISDN in phosphate buffer solution and rat plasma during 60-min incubation at 37 degrees C. 5. These data show that FK409 has more potent antiplatelet effects than ISDN, by acting through spontaneously released NO.

Full text

PDF
385

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BELL F. K., O'NEILL J. J., BURGISON R. M. Determination of the oil/water distribution coefficients of glyceryl trinitrate and two similar nitrate esters. J Pharm Sci. 1963 Jul;52:637–639. doi: 10.1002/jps.2600520706. [DOI] [PubMed] [Google Scholar]
  2. BORN G. V., CROSS M. J. THE AGGREGATION OF BLOOD PLATELETS. J Physiol. 1963 Aug;168:178–195. doi: 10.1113/jphysiol.1963.sp007185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chong S., Fung H. L. Thiol-mediated catalysis of nitroglycerin degradation by serum proteins. Increase in metabolism was not accompanied by S-nitrosothiol production. Drug Metab Dispos. 1990 Jan-Feb;18(1):61–67. [PubMed] [Google Scholar]
  4. De Caterina R., Giannessi D., Crea F., Chierchia S., Bernini W., Gazzetti P., L'Abbate A. Inhibition of platelet function by injectable isosorbide dinitrate. Am J Cardiol. 1984 Jun 1;53(11):1683–1687. doi: 10.1016/0002-9149(84)90602-7. [DOI] [PubMed] [Google Scholar]
  5. Feelisch M., Noack E. A. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol. 1987 Jul 2;139(1):19–30. doi: 10.1016/0014-2999(87)90493-6. [DOI] [PubMed] [Google Scholar]
  6. Feelisch M., Noack E. Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron. Eur J Pharmacol. 1987 Oct 27;142(3):465–469. doi: 10.1016/0014-2999(87)90090-2. [DOI] [PubMed] [Google Scholar]
  7. Fuster V., Badimon L., Cohen M., Ambrose J. A., Badimon J. J., Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation. 1988 Jun;77(6):1213–1220. doi: 10.1161/01.cir.77.6.1213. [DOI] [PubMed] [Google Scholar]
  8. Hampton J. R., Harrison M. J., Honour A. J., Mitchell J. R. Platelet behaviour and drugs used in cardiovascular disease. Cardiovasc Res. 1967 Apr;1(2):101–107. doi: 10.1093/cvr/1.2.101. [DOI] [PubMed] [Google Scholar]
  9. Hino M., Iwami M., Okamoto M., Yoshida K., Haruta H., Okuhara M., Hosoda J., Kohsaka M., Aoki H., Imanaka H. FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. I. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1989 Nov;42(11):1578–1583. doi: 10.7164/antibiotics.42.1578. [DOI] [PubMed] [Google Scholar]
  10. Hjemdahl-Monsen C. E., Lewis H. D., Cairns J., Chesebro J. H., Fuster V. Role of antithrombotic therapy in unstable angina, myocardial infarction and sudden death. J Am Coll Cardiol. 1986 Dec;8(6 Suppl B):67B–75B. doi: 10.1016/s0735-1097(86)80008-0. [DOI] [PubMed] [Google Scholar]
  11. Katsuki S., Arnold W., Mittal C., Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res. 1977 Feb;3(1):23–35. [PubMed] [Google Scholar]
  12. Kita Y., Hirasawa Y., Maeda K., Nishio M., Yoshida K. Spontaneous nitric oxide release accounts for the potent pharmacological actions of FK409. Eur J Pharmacol. 1994 May 12;257(1-2):123–130. doi: 10.1016/0014-2999(94)90703-x. [DOI] [PubMed] [Google Scholar]
  13. Mellion B. T., Ignarro L. J., Ohlstein E. H., Pontecorvo E. G., Hyman A. L., Kadowitz P. J. Evidence for the inhibitory role of guanosine 3', 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood. 1981 May;57(5):946–955. [PubMed] [Google Scholar]
  14. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  15. Radomski M. W., Palmer R. M., Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987 Sep;92(1):181–187. doi: 10.1111/j.1476-5381.1987.tb11310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schultz K., Schultz K., Schultz G. Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature. 1977 Feb 24;265(5596):750–751. doi: 10.1038/265750a0. [DOI] [PubMed] [Google Scholar]
  17. Shibata S., Satake N., Sato N., Matsuo M., Koibuchi Y., Hester R. K. 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. J Cardiovasc Pharmacol. 1991 Mar;17(3):508–518. doi: 10.1097/00005344-199103000-00022. [DOI] [PubMed] [Google Scholar]
  18. Umetsu T., Sanai K. Effect of 1-methyl-2-mercapto-5-(3-pyridyl)-imidazole (KC-6141), an anti-aggregating compound, on experimental thrombosis in rats. Thromb Haemost. 1978 Feb 28;39(1):74–83. [PubMed] [Google Scholar]
  19. Yamada H., Yoneyama F., Satoh K., Taira N. Comparison of the effects of the novel vasodilator FK409 with those of nitroglycerin in isolated coronary artery of the dog. Br J Pharmacol. 1991 Jul;103(3):1713–1718. doi: 10.1111/j.1476-5381.1991.tb09852.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES