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. 1993 Jun;109(2):430–436. doi: 10.1111/j.1476-5381.1993.tb13587.x

Release of nitric oxide from glyceryl trinitrate by captopril but not enalaprilat: in vitro and in vivo studies.

D Salvemini 1, A Pistelli 1, V Mollace 1
PMCID: PMC2175665  PMID: 8358544

Abstract

1. The hypotensive effects of glyceryl trinitrate (GTN, 0.5 mg kg-1) but not of 3-morpholino-sydnonimine (SIN-1, 0.125 mg kg-1) in anaesthetized rats were attenuated following a seven day (using a q.i.d. dosing schedule) oral treatment with isosorbide-5-mononitrate (IS-5-MN; 5 mg kg-1) indicative of the induction of tolerance to GTN but not to SIN-1. The hypotensive effects of GTN did not decline when the sulphydryl (SH) containing angiotensin converting enzyme inhibitor (ACE-1), captopril (CPT, 5 mg kg-1) or the structurally unrelated SH-containing, N-acetylcysteine (NAC, 10 mg kg-1) but not the non-SH-containing ACE-I, enalaprilat (ENA, 5 mg kg-1) were given together with IS-5-MN for the seven days treatment. 2. The attenuated hypotensive effects of GTN (0.5 mg kg-1) in rats treated with IS-5-MN were also restored when CPT (1 mg kg-1) or NAC (2.5 mg kg-1) but not ENA (1 mg kg-1) was administered intraperitoneally (i.p.) 30 min before GTN. Furthermore, in control rats, CPT or NAC but not ENA given i.p. 30 min before GTN, potentiated its haemodynamic effects. These effects were blocked by methylene blue (10 mg kg-1). At the same doses, CPT or NAC did not affect the hypotensive effects of SIN-1.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Ahlner J., Andersson R. G., Torfgård K., Axelsson K. L. Organic nitrate esters: clinical use and mechanisms of actions. Pharmacol Rev. 1991 Sep;43(3):351–423. [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. Bauer J. A., Fung H. L. Differential hemodynamic effects and tolerance properties of nitroglycerin and an S-nitrosothiol in experimental heart failure. J Pharmacol Exp Ther. 1991 Jan;256(1):249–254. [PubMed] [Google Scholar]
  4. Benjamin N., Dutton J. A., Ritter J. M. Human vascular smooth muscle cells inhibit platelet aggregation when incubated with glyceryl trinitrate: evidence for generation of nitric oxide. Br J Pharmacol. 1991 Apr;102(4):847–850. doi: 10.1111/j.1476-5381.1991.tb12264.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boesgaard S., Petersen J. S., Aldershvile J., Poulsen H. E., Flachs H. Nitrate tolerance: effect of thiol supplementation during prolonged nitroglycerin infusion in an in vivo rat model. J Pharmacol Exp Ther. 1991 Sep;258(3):851–856. [PubMed] [Google Scholar]
  6. Brien J. F., McLaughlin B. E., Breedon T. H., Bennett B. M., Nakatsu K., Marks G. S. Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta. J Pharmacol Exp Ther. 1986 May;237(2):608–614. [PubMed] [Google Scholar]
  7. Chung S. J., Fung H. L. Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells. J Pharmacol Exp Ther. 1990 May;253(2):614–619. [PubMed] [Google Scholar]
  8. Cooke J. P., Andon N., Loscalzo J. S-nitrosocaptopril. II. Effects on vascular reactivity. J Pharmacol Exp Ther. 1989 Jun;249(3):730–734. [PubMed] [Google Scholar]
  9. Elkayam U. Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med. 1991 Apr 15;114(8):667–677. doi: 10.7326/0003-4819-114-8-667. [DOI] [PubMed] [Google Scholar]
  10. Feelisch M., Kelm M. Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun. 1991 Oct 15;180(1):286–293. doi: 10.1016/s0006-291x(05)81290-2. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Feelisch M., Noack E., Schröder H. Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation. Eur Heart J. 1988 Jan;9 (Suppl A):57–62. doi: 10.1093/eurheartj/9.suppl_a.57. [DOI] [PubMed] [Google Scholar]
  13. Fung H. L., Chong S., Kowaluk E., Hough K., Kakemi M. Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine. J Pharmacol Exp Ther. 1988 May;245(2):524–530. [PubMed] [Google Scholar]
  14. Goldschmidt J. E., Tallarida R. J. Pharmacological evidence that captopril possesses an endothelium-mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor. J Pharmacol Exp Ther. 1991 Jun;257(3):1136–1145. [PubMed] [Google Scholar]
  15. Gruetter C. A., Lemke S. M. Dissociation of cysteine and glutathione levels from nitroglycerin-induced relaxation. Eur J Pharmacol. 1985 Apr 23;111(1):85–95. doi: 10.1016/0014-2999(85)90116-5. [DOI] [PubMed] [Google Scholar]
  16. Halon D. A., Rosenfeld T., Hardoff R., Lewis B. S. Advantage of combined therapy with captopril and nitrates in severe congestive heart failure. Isr J Med Sci. 1988 Nov;24(11):664–670. [PubMed] [Google Scholar]
  17. Horowitz J. D., Antman E. M., Lorell B. H., Barry W. H., Smith T. W. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation. 1983 Dec;68(6):1247–1253. doi: 10.1161/01.cir.68.6.1247. [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. Jordan R. A., Seith L., Henry D. A., Wilen M. M., Franciosa J. A. Dose requirements and hemodynamic effects of transdermal nitroglycerin compared with placebo in patients with congestive heart failure. Circulation. 1985 May;71(5):980–986. doi: 10.1161/01.cir.71.5.980. [DOI] [PubMed] [Google Scholar]
  20. Kukovetz W. R., Holzmann S. Mode of action of nitrates with regard to vasodilatation and tolerance. Z Kardiol. 1986;75 (Suppl 3):8–11. [PubMed] [Google Scholar]
  21. Lawson D. L., Nichols W. W., Mehta P., Mehta J. L. Captopril-induced reversal of nitroglycerin tolerance: role of sulfhydryl group vs. ACE-inhibitory activity. J Cardiovasc Pharmacol. 1991 Mar;17(3):411–418. doi: 10.1097/00005344-199103000-00009. [DOI] [PubMed] [Google Scholar]
  22. Loscalzo J. N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest. 1985 Aug;76(2):703–708. doi: 10.1172/JCI112024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mollace V., Salvemini D., Anggard E., Vane J. Nitric oxide from vascular smooth muscle cells: regulation of platelet reactivity and smooth muscle cell guanylate cyclase. Br J Pharmacol. 1991 Nov;104(3):633–638. doi: 10.1111/j.1476-5381.1991.tb12481.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mollace V., Salvemini D., Sessa W. C., Vane J. R. Inhibition of human platelet aggregation by endothelium-derived relaxing factor, sodium nitroprusside or iloprost is potentiated by captopril and reduced thiols. J Pharmacol Exp Ther. 1991 Sep;258(3):820–823. [PubMed] [Google Scholar]
  25. Murad F. Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest. 1986 Jul;78(1):1–5. doi: 10.1172/JCI112536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mülsch A., Busse R., Bassenge E. Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. Eur J Pharmacol. 1988 Dec 13;158(3):191–198. doi: 10.1016/0014-2999(88)90066-0. [DOI] [PubMed] [Google Scholar]
  27. Needleman P., Jakschik B., Johnson E. M., Jr Sulfhydryl requirement for relaxation of vascular smooth muscle. J Pharmacol Exp Ther. 1973 Nov;187(2):324–331. [PubMed] [Google Scholar]
  28. 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]
  29. Packer M., Lee W. H., Kessler P. D., Gottlieb S. S., Medina N., Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med. 1987 Sep 24;317(13):799–804. doi: 10.1056/NEJM198709243171304. [DOI] [PubMed] [Google Scholar]
  30. Packer M., Meller J., Medina N., Yushak M., Gorlin R. Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy. Circulation. 1981 Sep;64(3):506–514. doi: 10.1161/01.cir.64.3.506. [DOI] [PubMed] [Google Scholar]
  31. Parker J. O., Farrell B., Lahey K. A., Rose B. F. Nitrate tolerance: the lack of effect of N-acetylcysteine. Circulation. 1987 Sep;76(3):572–576. doi: 10.1161/01.cir.76.3.572. [DOI] [PubMed] [Google Scholar]
  32. Parker J. O., Fung H. L. Transdermal nitroglycerin in angina pectoris. Am J Cardiol. 1984 Sep 1;54(6):471–476. doi: 10.1016/0002-9149(84)90233-9. [DOI] [PubMed] [Google Scholar]
  33. Puri R. N., Meister A. Transport of glutathione, as gamma-glutamylcysteinylglycyl ester, into liver and kidney. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5258–5260. doi: 10.1073/pnas.80.17.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Radomski M., Moncada S. An improved method for washing of human platelets with prostacyclin. Thromb Res. 1983 May 15;30(4):383–389. doi: 10.1016/0049-3848(83)90230-x. [DOI] [PubMed] [Google Scholar]
  35. Sakanashi M., Matsuzaki T., Aniya Y. Nitroglycerin relaxes coronary artery of the pig with no change in glutathione content or glutathione S-transferase activity. Br J Pharmacol. 1991 Aug;103(4):1905–1908. doi: 10.1111/j.1476-5381.1991.tb12350.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Salvemini D., Mollace V., Pistelli A., Anggard E., Vane J. Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):982–986. doi: 10.1073/pnas.89.3.982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Salvemini D., Pistelli A., Vane J. Conversion of glyceryl trinitrate to nitric oxide in tolerant and non-tolerant smooth muscle and endothelial cells. Br J Pharmacol. 1993 Jan;108(1):162–169. doi: 10.1111/j.1476-5381.1993.tb13457.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Salvemini D., de Nucci G., Gryglewski R. J., Vane J. R. Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6328–6332. doi: 10.1073/pnas.86.16.6328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Servent D., Delaforge M., Ducrocq C., Mansuy D., Lenfant M. Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate: involvement of cytochrome P-450. Biochem Biophys Res Commun. 1989 Sep 29;163(3):1210–1216. doi: 10.1016/0006-291x(89)91106-6. [DOI] [PubMed] [Google Scholar]
  40. Sneddon J. M., Vane J. R. Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2800–2804. doi: 10.1073/pnas.85.8.2800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Thadani U., Manyari D., Parker J. O., Fung H. L. Tolerance to the circulatory effects of oral isosorbide dinitrate. Rate of development and cross-tolerance to glyceryl trinitrate. Circulation. 1980 Mar;61(3):526–535. doi: 10.1161/01.cir.61.3.526. [DOI] [PubMed] [Google Scholar]
  42. Torresi J., Horowitz J. D., Dusting G. J. Prevention and reversal of tolerance to nitroglycerine with N-acetylcysteine. J Cardiovasc Pharmacol. 1985 Jul-Aug;7(4):777–783. doi: 10.1097/00005344-198507000-00024. [DOI] [PubMed] [Google Scholar]
  43. Winniford M. D., Kennedy P. L., Wells P. J., Hillis L. D. Potentiation of nitroglycerin-induced coronary dilatation by N-acetylcysteine. Circulation. 1986 Jan;73(1):138–142. doi: 10.1161/01.cir.73.1.138. [DOI] [PubMed] [Google Scholar]
  44. Yeates R. A., Schmid M., Leitold M. Antagonism of glycerol trinitrate activity by an inhibitor of glutathione S-transferase. Biochem Pharmacol. 1989 Jun 1;38(11):1749–1753. doi: 10.1016/0006-2952(89)90408-5. [DOI] [PubMed] [Google Scholar]
  45. Zelis R., Mason D. T. Isosorbide dinitrate. Effect on the vasodilator response to nitroglycerin. JAMA. 1975 Oct 13;234(2):166–170. doi: 10.1001/jama.234.2.166. [DOI] [PubMed] [Google Scholar]
  46. de Nucci G., Gryglewski R. J., Warner T. D., Vane J. R. Receptor-mediated release of endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells is coupled. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2334–2338. doi: 10.1073/pnas.85.7.2334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. van Gilst W. H., de Graeff P. A., Scholtens E., de Langen C. D., Wesseling H. Potentiation of isosorbide dinitrate-induced coronary dilatation by captopril. J Cardiovasc Pharmacol. 1987 Feb;9(2):254–255. doi: 10.1097/00005344-198702000-00021. [DOI] [PubMed] [Google Scholar]

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