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. 1996 Jun;118(4):923–928. doi: 10.1111/j.1476-5381.1996.tb15487.x

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363.

M Civelli 1, M Giossi 1, P Caruso 1, R Razzetti 1, M Bergamaschi 1, S Bongrani 1, A Gasco 1
PMCID: PMC1909539  PMID: 8799563

Abstract

1. The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4-ethoxy-3-phenylsulphonylfuroxan), were investigated. 2. Pre-incubation of CHF 2363 with human platelet-rich plasma produced a concentration-dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. 3. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). 4. Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 5. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-dependently released nitric oxide (NO) in platelet-rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. 6. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 microM), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. 7. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.

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Selected References

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  1. Amezcua J. L., Dusting G. J., Palmer R. M., Moncada S. Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol. 1988 Nov;95(3):830–834. doi: 10.1111/j.1476-5381.1988.tb11711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BORN G. V. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962 Jun 9;194:927–929. doi: 10.1038/194927b0. [DOI] [PubMed] [Google Scholar]
  3. Berdeaux A. Nitric oxide: an ubiquitous messenger. Fundam Clin Pharmacol. 1993;7(8):401–411. doi: 10.1111/j.1472-8206.1993.tb01037.x. [DOI] [PubMed] [Google Scholar]
  4. Bredt D. S., Hwang P. M., Glatt C. E., Lowenstein C., Reed R. R., Snyder S. H. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991 Jun 27;351(6329):714–718. doi: 10.1038/351714a0. [DOI] [PubMed] [Google Scholar]
  5. Bredt D. S., Snyder S. H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990 Jan;87(2):682–685. doi: 10.1073/pnas.87.2.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Civelli M., Caruso P., Giossi M., Bergamaschi M., Razzetti R., Bongrani S., Gasco A. CHF 2206, a new potent vasodilating and antiaggregating drug as potential nitric oxide donor. Eur J Pharmacol. 1994 Apr 1;255(1-3):17–24. doi: 10.1016/0014-2999(94)90077-9. [DOI] [PubMed] [Google Scholar]
  7. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Feelisch M., Schönafinger K., Noack E. Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans. Biochem Pharmacol. 1992 Sep 25;44(6):1149–1157. doi: 10.1016/0006-2952(92)90379-w. [DOI] [PubMed] [Google Scholar]
  10. Ferioli R., Folco G. C., Ferretti C., Gasco A. M., Medana C., Fruttero R., Civelli M., Gasco A. A new class of furoxan derivatives as NO donors: mechanism of action and biological activity. Br J Pharmacol. 1995 Feb;114(4):816–820. doi: 10.1111/j.1476-5381.1995.tb13277.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Furchgott R. F. The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol. 1984;24:175–197. doi: 10.1146/annurev.pa.24.040184.001135. [DOI] [PubMed] [Google Scholar]
  12. Förster S., Woditsch I., Schröder H., Schrör K. Reduced nitric oxide release causes nitrate tolerance in the intact coronary circulation. J Cardiovasc Pharmacol. 1991 Jun;17(6):867–872. doi: 10.1097/00005344-199106000-00002. [DOI] [PubMed] [Google Scholar]
  13. GIBSON Q. H., ROUGHTON F. J. The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol. 1957 May 23;136(3):507–524. doi: 10.1113/jphysiol.1957.sp005777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 1991 Feb;14(2):60–67. doi: 10.1016/0166-2236(91)90022-m. [DOI] [PubMed] [Google Scholar]
  15. Ghigo D., Heller R., Calvino R., Alessio P., Fruttero R., Gasco A., Bosia A., Pescarmona G. Characterization of a new compound, S35b, as a guanylate cyclase activator in human platelets. Biochem Pharmacol. 1992 Mar 17;43(6):1281–1288. doi: 10.1016/0006-2952(92)90504-c. [DOI] [PubMed] [Google Scholar]
  16. Ignarro L. J. Endothelium-derived nitric oxide: actions and properties. FASEB J. 1989 Jan;3(1):31–36. doi: 10.1096/fasebj.3.1.2642868. [DOI] [PubMed] [Google Scholar]
  17. Ignarro L. J., Kadowitz P. J. The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Annu Rev Pharmacol Toxicol. 1985;25:171–191. doi: 10.1146/annurev.pa.25.040185.001131. [DOI] [PubMed] [Google Scholar]
  18. Ignarro L. J., Lippton H., Edwards J. C., Baricos W. H., Hyman A. L., Kadowitz P. J., Gruetter C. A. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981 Sep;218(3):739–749. [PubMed] [Google Scholar]
  19. Keith R. A., Burkman A. M., Sokoloski T. D., Fertel R. H. Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle. J Pharmacol Exp Ther. 1982 Jun;221(3):525–531. [PubMed] [Google Scholar]
  20. Kojda G., Meyer W., Noack E. Influence of endothelium and nitrovasodilators on free thiols and disulfides in porcine coronary smooth muscle. Eur J Pharmacol. 1993 Dec 21;250(3):385–394. doi: 10.1016/0014-2999(93)90025-d. [DOI] [PubMed] [Google Scholar]
  21. Martin W., Villani G. M., Jothianandan D., Furchgott R. F. 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] [Google Scholar]
  22. 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]
  23. Needleman P., Johnson E. M., Jr Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther. 1973 Mar;184(3):709–715. [PubMed] [Google Scholar]
  24. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Radomski M. W., Palmer R. M., Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987 Nov;92(3):639–646. doi: 10.1111/j.1476-5381.1987.tb11367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Salvemini D., Radziszewski W., Korbut R., Vane J. The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors. Br J Pharmacol. 1990 Dec;101(4):991–995. doi: 10.1111/j.1476-5381.1990.tb14194.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schrör K., Förster S., Woditsch I. On-line measurement of nitric oxide release from organic nitrates in the intact coronary circulation. Naunyn Schmiedebergs Arch Pharmacol. 1991 Aug;344(2):240–246. doi: 10.1007/BF00167225. [DOI] [PubMed] [Google Scholar]
  29. Seth P., Fung H. L. Biochemical characterization of a membrane-bound enzyme responsible for generating nitric oxide from nitroglycerin in vascular smooth muscle cells. Biochem Pharmacol. 1993 Oct 19;46(8):1481–1486. doi: 10.1016/0006-2952(93)90115-d. [DOI] [PubMed] [Google Scholar]
  30. Waldman S. A., Rapoport R. M., Ginsburg R., Murad F. Desensitization to nitroglycerin in vascular smooth muscle from rat and human. Biochem Pharmacol. 1986 Oct 15;35(20):3525–3531. doi: 10.1016/0006-2952(86)90622-2. [DOI] [PubMed] [Google Scholar]
  31. Yeates R. A., Schmid M. Total prevention of the development of in vitro tolerance to organic nitrates. Experiments with antioxidants. Arzneimittelforschung. 1992 Mar;42(3):297–302. [PubMed] [Google Scholar]
  32. Zhang C. L., De la Lande I. S., Stafford I., Horowitz J. D. S-nitrosothiol modulation of tolerance to glyceryl trinitrate in bovine isolated coronary artery. Eur J Pharmacol. 1994 Feb 11;252(3):299–304. doi: 10.1016/0014-2999(94)90176-7. [DOI] [PubMed] [Google Scholar]

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