Skip to main content
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Apr;31(4):373–379. doi: 10.1111/j.1365-2125.1991.tb05549.x

Influence of ACE inhibitors on free radicals and reperfusion injury: pharmacological curiosity or therapeutic hope?

J McMurray 1, M Chopra 1
PMCID: PMC1368321  PMID: 2049244

Abstract

1. The currently available evidence shows that thiol containing ACE inhibitors are free radical (FR) scavengers in vitro; in particular the OH. radical is effectively scavenged by these compounds. There is also good evidence that, in vivo, ACE inhibitors can preserve myocardial contractile function following a period of reversible ischaemia (by directly protecting myocytes and/or preserving coronary flow through protection of endothelial cells). These in vivo benefits are probably also due to FR scavening, mainly due to the presence of a thiol group but, also as a consequence of augmented prostanoid production. 2. Use of more relevant animal models and testing of a range of doses of ACE inhibitors might be undertaken before clinical investigation is considered. Because of its nature, however, the existence and importance of reperfusion injury in man will only be proven or disproven by pharmacological intervention. One option is to compare a thiol containing agent with absent or minimal haemodynamic effects with placebo as an adjunct to thrombolysis. This is the simplest approach. An alternative approach is to conduct a comparative study of a -SH containing ACE inhibitor and a non -SH containing ACE inhibitor given prior to thrombolysis. There are many problems with either approach. The lack of reliable measures of FR activity in man and difficulty in measuring accurately left ventricular function post-myocardial infarction means that mortality is likely to be the only reliable end-point in such a study.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
373

Selected References

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

  1. Aruoma O. I., Halliwell B., Hoey B. M., Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593–597. doi: 10.1016/0891-5849(89)90066-x. [DOI] [PubMed] [Google Scholar]
  2. Bagchi D., Iyengar J., Stockwell P., Das D. K. Enhanced prostaglandin production in the ischemic-reperfused myocardium by captopril linked with its free radical scavenging action. Prostaglandins Leukot Essent Fatty Acids. 1989 Nov;38(2):145–150. doi: 10.1016/0952-3278(89)90099-9. [DOI] [PubMed] [Google Scholar]
  3. Bagchi D., Prasad R., Das D. K. Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Commun. 1989 Jan 16;158(1):52–57. doi: 10.1016/s0006-291x(89)80175-5. [DOI] [PubMed] [Google Scholar]
  4. Bolli R., Jeroudi M. O., Patel B. S., Aruoma O. I., Halliwell B., Lai E. K., McCay P. B. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury. Circ Res. 1989 Sep;65(3):607–622. doi: 10.1161/01.res.65.3.607. [DOI] [PubMed] [Google Scholar]
  5. Bolli R., Zhu W. X., Hartley C. J., Michael L. H., Repine J. E., Hess M. L., Kukreja R. C., Roberts R. Attenuation of dysfunction in the postischemic 'stunned' myocardium by dimethylthiourea. Circulation. 1987 Aug;76(2):458–468. doi: 10.1161/01.cir.76.2.458. [DOI] [PubMed] [Google Scholar]
  6. Buderus S., Siegmund B., Spahr R., Krützfeldt A., Piper H. M. Resistance of endothelial cells to anoxia-reoxygenation in isolated guinea pig hearts. Am J Physiol. 1989 Aug;257(2 Pt 2):H488–H493. doi: 10.1152/ajpheart.1989.257.2.H488. [DOI] [PubMed] [Google Scholar]
  7. Ceconi C., Curello S., Cargnoni A., Boffa G. M., Ferrari R. Antioxidant protection against damage during cardiac ischemia and reperfusion: effect of dimercapto-propanol. Cardioscience. 1990 Sep;1(3):191–198. [PubMed] [Google Scholar]
  8. Chopra M., McMurray J., Stewart J., Dargie H. J., Smith W. E. Free radical scavenging: a potentially beneficial action of thiol-containing angiotensin converting enzyme inhibitors. Biochem Soc Trans. 1990 Dec;18(6):1184–1185. doi: 10.1042/bst0181184. [DOI] [PubMed] [Google Scholar]
  9. Chopra M., Scott N., McMurray J., McLay J., Bridges A., Smith W. E., Belch J. J. Captopril: a free radical scavenger. Br J Clin Pharmacol. 1989 Mar;27(3):396–399. doi: 10.1111/j.1365-2125.1989.tb05384.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cross A. R. Inhibitors of the leukocyte superoxide generating oxidase: mechanisms of action and methods for their elucidation. Free Radic Biol Med. 1990;8(1):71–93. doi: 10.1016/0891-5849(90)90147-b. [DOI] [PubMed] [Google Scholar]
  11. Cuperus R. A., Muijsers A. O., Wever R. Antiarthritic drugs containing thiol groups scavenge hypochlorite and inhibit its formation by myeloperoxidase from human leukocytes. A therapeutic mechanism of these drugs in rheumatoid arthritis? Arthritis Rheum. 1985 Nov;28(11):1228–1233. doi: 10.1002/art.1780281106. [DOI] [PubMed] [Google Scholar]
  12. Dargie H. J., Ray S. G. The effects of angiotensin-converting enzyme inhibition on coronary blood flow and infarct size limitation. J Hum Hypertens. 1989 Jun;3 (Suppl 1):101–106. [PubMed] [Google Scholar]
  13. Dormandy T. L. Free-radical pathology and medicine. A review. J R Coll Physicians Lond. 1989 Oct;23(4):221–227. [PMC free article] [PubMed] [Google Scholar]
  14. Egan T. M., Minta J. O., Scrimgeour K. G., Cooper J. D. Captopril--a potential free radical scavenger: inhibition of PMN NADPH oxidase. Clin Invest Med. 1988 Oct;11(5):351–356. [PubMed] [Google Scholar]
  15. Forman M. B., Puett D. W., Cates C. U., McCroskey D. E., Beckman J. K., Greene H. L., Virmani R. Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function. Circulation. 1988 Jul;78(1):202–213. doi: 10.1161/01.cir.78.1.202. [DOI] [PubMed] [Google Scholar]
  16. Haenen G. R., Plug H. J., Vermeulen N. P., Timmerman H., Bast A. Contribution of 4-hydroxy-2,3-trans-nonenal to the reduction of beta-adrenoceptor function in the heart by oxidative stress. Life Sci. 1989;45(1):71–76. doi: 10.1016/0024-3205(89)90437-2. [DOI] [PubMed] [Google Scholar]
  17. Kloner R. A., Przyklenk K., Patel B. Altered myocardial states. The stunned and hibernating myocardium. Am J Med. 1989 Jan 16;86(1A):14–22. doi: 10.1016/0002-9343(89)90005-3. [DOI] [PubMed] [Google Scholar]
  18. Kloner R. A., Przyklenk K., Whittaker P. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation. 1989 Nov;80(5):1115–1127. doi: 10.1161/01.cir.80.5.1115. [DOI] [PubMed] [Google Scholar]
  19. Mak I. T., Freedman A. M., Dickens B. F., Weglicki W. B. Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol. 1990 Nov 1;40(9):2169–2175. doi: 10.1016/0006-2952(90)90250-o. [DOI] [PubMed] [Google Scholar]
  20. Mehta J. L., Nicolini F. A., Lawson D. L. Sulfhydryl group in angiotensin converting enzyme inhibitors and superoxide radical formation. J Cardiovasc Pharmacol. 1990 Nov;16(5):847–849. doi: 10.1097/00005344-199011000-00023. [DOI] [PubMed] [Google Scholar]
  21. Mitsos S. E., Fantone J. C., Gallagher K. P., Walden K. M., Simpson P. J., Abrams G. D., Schork M. A., Lucchesi B. R. Canine myocardial reperfusion injury: protection by a free radical scavenger, N-2-mercaptopropionyl glycine. J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):978–988. [PubMed] [Google Scholar]
  22. Opie L. H. Reperfusion injury and its pharmacologic modification. Circulation. 1989 Oct;80(4):1049–1062. doi: 10.1161/01.cir.80.4.1049. [DOI] [PubMed] [Google Scholar]
  23. Patel B., Kloner R. A., Przyklenk K., Braunwald E. Postischemic myocardial "stunning": a clinically relevant phenomenon. Ann Intern Med. 1988 Apr;108(4):626–628. doi: 10.7326/0003-4819-108-4-626. [DOI] [PubMed] [Google Scholar]
  24. Patrone F., Dallegri F., Maggi A. M., Rapetto C., Lanzi G. Stimulation of neutrophil chemotaxis, adhesiveness, phagocytosis, and hexose monophosphate shunt activity by N-(2-mercaptopropionyl)glycine. Res Exp Med (Berl) 1981;178(3):257–262. doi: 10.1007/BF01851015. [DOI] [PubMed] [Google Scholar]
  25. Pfeffer M. A., Lamas G. A., Vaughan D. E., Parisi A. F., Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988 Jul 14;319(2):80–86. doi: 10.1056/NEJM198807143190204. [DOI] [PubMed] [Google Scholar]
  26. Pi X. J., Chen X. Captopril and ramiprilat protect against free radical injury in isolated working rat hearts. J Mol Cell Cardiol. 1989 Dec;21(12):1261–1271. doi: 10.1016/0022-2828(89)90672-x. [DOI] [PubMed] [Google Scholar]
  27. Przyklenk K., Kloner R. A. Acute effects of hydralazine and enalapril on contractile function of postischemic "stunned" myocardium. Am J Cardiol. 1987 Oct 1;60(10):934–936. doi: 10.1016/0002-9149(87)91059-9. [DOI] [PubMed] [Google Scholar]
  28. Qiu Y., Bernier M., Hearse D. J. The influence of N-acetylcysteine on cardiac function and rhythm disorders during ischemia and reperfusion. Cardioscience. 1990 Mar;1(1):65–74. [PubMed] [Google Scholar]
  29. Sharpe N., Murphy J., Smith H., Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988 Feb 6;1(8580):255–259. doi: 10.1016/s0140-6736(88)90347-9. [DOI] [PubMed] [Google Scholar]
  30. Southorn P. A., Powis G. Free radicals in medicine. I. Chemical nature and biologic reactions. Mayo Clin Proc. 1988 Apr;63(4):381–389. doi: 10.1016/s0025-6196(12)64861-7. [DOI] [PubMed] [Google Scholar]

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

RESOURCES