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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Dec 20;91(26):12472–12476. doi: 10.1073/pnas.91.26.12472

Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase.

C Szabó 1, G J Southan 1, C Thiemermann 1
PMCID: PMC45460  PMID: 7528923

Abstract

Enhanced formation of nitric oxide (NO) by both the constitutive and the inducible isoforms of NO synthase (NOS) has been implicated in the pathophysiology of a variety of diseases, including circulatory shock. Non-isoform-selective inhibition of NO formation, however, may lead to side effects by inhibiting the constitutive isoform of NOS and, thus, the various physiological actions of NO. S-Methylisothiourea sulfate (SMT) is at least 10- to 30-fold more potent as an inhibitor of inducible NOS (iNOS) in immunostimulated cultured macrophages (EC50, 6 microM) and vascular smooth muscle cells (EC50, 2 microM) than NG-methyl-L-arginine (MeArg) or any other NOS inhibitor yet known. The effect of SMT on iNOS activity can be reversed by excess L-arginine in a concentration-dependent manner. SMT (up to 1 mM) does not inhibit the activity of xanthine oxidase, diaphorase, lactate dehydrogenase, monoamine oxidase, catalase, cytochrome P450, or superoxide dismutase. SMT is equipotent with MeArg in inhibiting the endothelial, constitutive isoform of NOS in vitro and causes increases in blood pressure similar to those produced by MeArg in normal rats. SMT, however, dose-dependently reverses (0.01-3 mg/kg) the hypotension and the vascular hyporeactivity to vasoconstrictor agents caused by endotoxin [bacterial lipopolysaccharide (LPS), 10 mg/kg, i.v.] in anesthetized rats. Moreover, therapeutic administration of SMT (5 mg/kg, i.p., given 2 hr after LPS, 10 mg/kg, i.p.) attenuates the rises in plasma alanine and aspartate aminotransferases, bilirubin, and creatinine and also prevents hypocalcaemia when measured 6 hr after administration of LPS. SMT (1 mg/kg, i.p.) improves 24-hr survival of mice treated with a high dose of LPS (60 mg/kg, i.p.). Thus, SMT is a potent and selective inhibitor of iNOS and exerts beneficial effects in rodent models of septic shock. SMT, therefore, may have considerable value in the therapy of circulatory shock of various etiologies and other pathophysiological conditions associated with induction of iNOS.

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Selected References

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  1. Billiar T. R., Curran R. D., Harbrecht B. G., Stuehr D. J., Demetris A. J., Simmons R. L. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol. 1990 Dec;48(6):565–569. doi: 10.1002/jlb.48.6.565. [DOI] [PubMed] [Google Scholar]
  2. Bucala R., Tracey K. J., Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432–438. doi: 10.1172/JCI115014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burke M. D., Thompson S., Elcombe C. R., Halpert J., Haaparanta T., Mayer R. T. Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol. 1985 Sep 15;34(18):3337–3345. doi: 10.1016/0006-2952(85)90355-7. [DOI] [PubMed] [Google Scholar]
  4. Calver A., Collier J., Vallance P. Nitric oxide and cardiovascular control. Exp Physiol. 1993 May;78(3):303–326. doi: 10.1113/expphysiol.1993.sp003687. [DOI] [PubMed] [Google Scholar]
  5. Corbett J. A., Tilton R. G., Chang K., Hasan K. S., Ido Y., Wang J. L., Sweetland M. A., Lancaster J. R., Jr, Williamson J. R., McDaniel M. L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992 Apr;41(4):552–556. doi: 10.2337/diab.41.4.552. [DOI] [PubMed] [Google Scholar]
  6. Dawson T. M., Dawson V. L., Snyder S. H. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol. 1992 Sep;32(3):297–311. doi: 10.1002/ana.410320302. [DOI] [PubMed] [Google Scholar]
  7. Dinerman J. L., Lowenstein C. J., Snyder S. H. Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ Res. 1993 Aug;73(2):217–222. doi: 10.1161/01.res.73.2.217. [DOI] [PubMed] [Google Scholar]
  8. Fujiwara S., Kassell N. F., Sasaki T., Nakagomi T., Lehman R. M. Selective hemoglobin inhibition of endothelium-dependent vasodilation of rabbit basilar artery. J Neurosurg. 1986 Mar;64(3):445–452. doi: 10.3171/jns.1986.64.3.0445. [DOI] [PubMed] [Google Scholar]
  9. Gross S. S., Jaffe E. A., Levi R., Kilbourn R. G. Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages. Biochem Biophys Res Commun. 1991 Aug 15;178(3):823–829. doi: 10.1016/0006-291x(91)90965-a. [DOI] [PubMed] [Google Scholar]
  10. Gross S. S., Stuehr D. J., Aisaka K., Jaffe E. A., Levi R., Griffith O. W. Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine. Biochem Biophys Res Commun. 1990 Jul 16;170(1):96–103. doi: 10.1016/0006-291x(90)91245-n. [DOI] [PubMed] [Google Scholar]
  11. Hasan K., Heesen B. J., Corbett J. A., McDaniel M. L., Chang K., Allison W., Wolffenbuttel B. H., Williamson J. R., Tilton R. G. Inhibition of nitric oxide formation by guanidines. Eur J Pharmacol. 1993 Nov 2;249(1):101–106. doi: 10.1016/0014-2999(93)90667-7. [DOI] [PubMed] [Google Scholar]
  12. Hutcheson I. R., Whittle B. J., Boughton-Smith N. K. Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol. 1990 Dec;101(4):815–820. doi: 10.1111/j.1476-5381.1990.tb14163.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Joly G. A., Ayres M., Chelly F., Kilbourn R. G. Effects of NG-methyl-L-arginine, NG-nitro-L-arginine, and aminoguanidine on constitutive and inducible nitric oxide synthase in rat aorta. Biochem Biophys Res Commun. 1994 Feb 28;199(1):147–154. doi: 10.1006/bbrc.1994.1207. [DOI] [PubMed] [Google Scholar]
  14. Koprowski H., Zheng Y. M., Heber-Katz E., Fraser N., Rorke L., Fu Z. F., Hanlon C., Dietzschold B. In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):3024–3027. doi: 10.1073/pnas.90.7.3024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kubes P., Granger D. N. Nitric oxide modulates microvascular permeability. Am J Physiol. 1992 Feb;262(2 Pt 2):H611–H615. doi: 10.1152/ajpheart.1992.262.2.H611. [DOI] [PubMed] [Google Scholar]
  16. Lambert L. E., French J. F., Whitten J. P., Baron B. M., McDonald I. A. Characterization of cell selectivity of two novel inhibitors of nitric oxide synthesis. Eur J Pharmacol. 1992 May 27;216(1):131–134. doi: 10.1016/0014-2999(92)90221-o. [DOI] [PubMed] [Google Scholar]
  17. Lambert L. E., Whitten J. P., Baron B. M., Cheng H. C., Doherty N. S., McDonald I. A. Nitric oxide synthesis in the CNS endothelium and macrophages differs in its sensitivity to inhibition by arginine analogues. Life Sci. 1991;48(1):69–75. doi: 10.1016/0024-3205(91)90426-c. [DOI] [PubMed] [Google Scholar]
  18. Langrehr J. M., Hoffman R. A., Lancaster J. R., Jr, Simmons R. L. Nitric oxide--a new endogenous immunomodulator. Transplantation. 1993 Jun;55(6):1205–1212. doi: 10.1097/00007890-199306000-00001. [DOI] [PubMed] [Google Scholar]
  19. Lowenstein C. J., Dinerman J. L., Snyder S. H. Nitric oxide: a physiologic messenger. Ann Intern Med. 1994 Feb 1;120(3):227–237. doi: 10.7326/0003-4819-120-3-199402010-00009. [DOI] [PubMed] [Google Scholar]
  20. McCartney-Francis N., Allen J. B., Mizel D. E., Albina J. E., Xie Q. W., Nathan C. F., Wahl S. M. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med. 1993 Aug 1;178(2):749–754. doi: 10.1084/jem.178.2.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Meyer J., Traber L. D., Nelson S., Lentz C. W., Nakazawa H., Herndon D. N., Noda H., Traber D. L. Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol (1985) 1992 Jul;73(1):324–328. doi: 10.1152/jappl.1992.73.1.324. [DOI] [PubMed] [Google Scholar]
  22. Miller M. J., Sadowska-Krowicka H., Chotinaruemol S., Kakkis J. L., Clark D. A. Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther. 1993 Jan;264(1):11–16. [PubMed] [Google Scholar]
  23. Mills C. D., Shearer J., Evans R., Caldwell M. D. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J Immunol. 1992 Oct 15;149(8):2709–2714. [PubMed] [Google Scholar]
  24. Misko T. P., Moore W. M., Kasten T. P., Nickols G. A., Corbett J. A., Tilton R. G., McDaniel M. L., Williamson J. R., Currie M. G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119–125. doi: 10.1016/0014-2999(93)90357-n. [DOI] [PubMed] [Google Scholar]
  25. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  26. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  27. Ou P., Wolff S. P. Aminoguanidine: a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem Pharmacol. 1993 Oct 5;46(7):1139–1144. doi: 10.1016/0006-2952(93)90461-5. [DOI] [PubMed] [Google Scholar]
  28. Parker J. L., Adams H. R. Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. Circ Res. 1993 Mar;72(3):539–551. doi: 10.1161/01.res.72.3.539. [DOI] [PubMed] [Google Scholar]
  29. Shultz P. J., Raij L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest. 1992 Nov;90(5):1718–1725. doi: 10.1172/JCI116045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stefanovic-Racic M., Stadler J., Evans C. H. Nitric oxide and arthritis. Arthritis Rheum. 1993 Aug;36(8):1036–1044. doi: 10.1002/art.1780360803. [DOI] [PubMed] [Google Scholar]
  31. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Szabó C., Faragó M., Horváth I., Lohinai Z., Kovách A. G. Hemorrhagic hypotension impairs endothelium-dependent relaxations in the renal artery of the cat. Circ Shock. 1992 Mar;36(3):238–241. [PubMed] [Google Scholar]
  33. Szabó C., Mitchell J. A., Thiemermann C., Vane J. R. Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol. 1993 Mar;108(3):786–792. doi: 10.1111/j.1476-5381.1993.tb12879.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Szabó C., Southan G. J., Wood E., Thiemermann C., Vane J. R. Inhibition by spermine of the induction of nitric oxide synthase in J774.2 macrophages: requirement of a serum factor. Br J Pharmacol. 1994 Jun;112(2):355–356. doi: 10.1111/j.1476-5381.1994.tb13078.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Szabó C., Thiemermann C., Vane J. R. Dihydropyridine antagonists and agonists of calcium channels inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages. Biochem Biophys Res Commun. 1993 Oct 29;196(2):825–830. doi: 10.1006/bbrc.1993.2323. [DOI] [PubMed] [Google Scholar]
  36. Thiemermann C., Szabó C., Mitchell J. A., Vane J. R. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):267–271. doi: 10.1073/pnas.90.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Thiemermann C., Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol. 1990 Jul 17;182(3):591–595. doi: 10.1016/0014-2999(90)90062-b. [DOI] [PubMed] [Google Scholar]
  38. Tilton R. G., Chang K., Hasan K. S., Smith S. R., Petrash J. M., Misko T. P., Moore W. M., Currie M. G., Corbett J. A., McDaniel M. L. Prevention of diabetic vascular dysfunction by guanidines. Inhibition of nitric oxide synthase versus advanced glycation end-product formation. Diabetes. 1993 Feb;42(2):221–232. doi: 10.2337/diab.42.2.221. [DOI] [PubMed] [Google Scholar]
  39. Vane J. R. The Croonian Lecture, 1993. The endothelium: maestro of the blood circulation. Philos Trans R Soc Lond B Biol Sci. 1994 Jan 29;343(1304):225–246. doi: 10.1098/rstb.1994.0023. [DOI] [PubMed] [Google Scholar]
  40. Whittle B. J., Lopez-Belmonte J., Moncada S. Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol. 1990 Mar;99(3):607–611. doi: 10.1111/j.1476-5381.1990.tb12977.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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