• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Dec 1986; 83(23): 9164–9168.
PMCID: PMC387095

Mechanism of action of some inhibitors of endothelium-derived relaxing factor.


The mechanism of the inhibitory action of phenidone, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C), dithiothreitol, hydroquinone, and pyrogallol on the vascular relaxation induced by endothelium-derived relaxing factor (EDRF) was investigated. EDRF was released from porcine aortic endothelial cells in culture and bioassayed on a cascade of superfused rabbit aortic strips. These compounds inhibited EDRF-induced relaxation of vascular strips, without affecting the relaxation induced by glyceryl trinitrate, and their inhibitory potency was markedly attenuated (by more than 1 order of magnitude) by the addition of superoxide dismutase (5-15 units/ml) or oxidized cytochrome c (20-40 microM) but not by catalase (30 units/ml) or heat-inactivated superoxide dismutase. These data indicate that the above five inhibitors inactivate EDRF through the formation of superoxide ions, which have recently been shown to destroy EDRF. The inhibition of EDRF by these compounds is therefore attributable to their redox properties rather than to any specific biological action.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (834K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Furchgott RF. The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol. 1984;24:175–197. [PubMed]
  • Griffith TM, Edwards DH, Lewis MJ, Newby AC, Henderson AH. The nature of endothelium-derived vascular relaxant factor. Nature. 1984 Apr 12;308(5960):645–647. [PubMed]
  • Singer HA, Peach MJ. Endothelium-dependent relaxation of rabbit aorta. II. Inhibition of relaxation stimulated by methacholine and A23187 with antagonists of arachidonic acid metabolism. J Pharmacol Exp Ther. 1983 Sep;226(3):796–801. [PubMed]
  • Pinto A, Abraham NG, Mullane KM. Cytochrome P-450-dependent monooxygenase activity and endothelial-dependent relaxations induced by arachidonic acid. J Pharmacol Exp Ther. 1986 Feb;236(2):445–451. [PubMed]
  • Gryglewski RJ, Moncada S, Palmer RM. Bioassay of prostacyclin and endothelium-derived relaxing factor (EDRF) from porcine aortic endothelial cells. Br J Pharmacol. 1986 Apr;87(4):685–694. [PMC free article] [PubMed]
  • Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986 Apr 3;320(6061):454–456. [PubMed]
  • Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther. 1985 Mar;232(3):708–716. [PubMed]
  • Blackwell GJ, Flower RJ. 1-phenyl-3-pyrazolidone: an inhibitor of cyclo-oxygenase and lipoxygenase pathways in lung and platelets. Prostaglandins. 1978 Sep;16(3):417–425. [PubMed]
  • Higgs GA, Flower RJ, Vane JR. A new approach to anti-inflammatory drugs. Biochem Pharmacol. 1979 Jun 15;28(12):1959–1961. [PubMed]
  • Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973 Mar;52(3):741–744. [PMC free article] [PubMed]
  • Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974 Sep 16;47(3):469–474. [PubMed]
  • Rubanyi GM, Lorenz RR, Vanhoutte PM. Bioassay of endothelium-derived relaxing factor(s): inactivation by catecholamines. Am J Physiol. 1985 Jul;249(1 Pt 2):H95–101. [PubMed]
  • Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972 May 25;247(10):3170–3175. [PubMed]
  • Misra HP. Generation of superoxide free radical during the autoxidation of thiols. J Biol Chem. 1974 Apr 10;249(7):2151–2155. [PubMed]
  • Marnett LJ, Siedlik PH, Fung LW. Oxidation of phenidone and BW755C by prostaglandin endoperoxide synthetase. J Biol Chem. 1982 Jun 25;257(12):6957–6964. [PubMed]
  • Peters JH, Gordon GR, Kashiwase D, Lown JW, Yen SF, Plambeck JA. Redox activities of antitumor anthracyclines determined by microsomal oxygen consumption and assays for superoxide anion and hydroxyl radical generation. Biochem Pharmacol. 1986 Apr 15;35(8):1309–1323. [PubMed]
  • Wei EP, Kontos HA, Christman CW, DeWitt DS, Povlishock JT. Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilation after acute hypertension. Circ Res. 1985 Nov;57(5):781–787. [PubMed]
  • Halliwell B, Gutteridge JM. The importance of free radicals and catalytic metal ions in human diseases. Mol Aspects Med. 1985;8(2):89–193. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...