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. 1995 Aug;96(2):1066–1084. doi: 10.1172/JCI118093

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

R Bolli 1, M Zughaib 1, X Y Li 1, X L Tang 1, J Z Sun 1, J F Triana 1, P B McCay 1
PMCID: PMC185296  PMID: 7635943

Abstract

Open-chest dogs (total number used, 117) underwent 10 5-min coronary occlusions (O) interspersed with 10 min of reperfusion (R). When systolic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight additional loss during the next four cycles and no further loss during the last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained when the total deficit of wall thickening during the final 4-h R interval was measured. The total deficit was similar after one and three 5-min O (groups V and VI, respectively), indicating that the first ischemic episode did precondition against the next two episodes; however, it was approximately 2.5-fold greater after 10 O (group IV) than after 3, indicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th O, the preconditioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with alpha-phenyl N-tert-butyl nitrone (PBN) demonstrated a burst of free radical generation immediately after the 1st, 5th, and 10th R (group VIII). The total cumulative release of PBN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the 1st (P < 0.05) but did not differ significantly between the 1st and 10th R. When administered throughout the 10 O-R cycles, the .OH scavenger mercaptopropionyl glycine significantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the beneficial effects of mercaptopropionyl glycine were completely, or largely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles was sufficient to cause severe postischemic dysfunction, and (b) the cumulative injury caused by repetitive ischemic episodes is mediated by recurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of myocardial stunning after repetitive ischemia, and implicates .OH as a primary culprit. Taken together, the data indicate that recurrent brief ischemic episodes result in recurrent bouts of oxyradical-mediated injury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning.

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Selected References

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  1. Basuk W. L., Reimer K. A., Jennings R. B. Effect of repetitive brief episodes of ischemia on cell volume, electrolytes and ultrastructure. J Am Coll Cardiol. 1986 Jul;8(1 Suppl A):33A–41A. doi: 10.1016/s0735-1097(86)80026-2. [DOI] [PubMed] [Google Scholar]
  2. Becker L. C., Levine J. H., DiPaula A. F., Guarnieri T., Aversano T. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J Am Coll Cardiol. 1986 Mar;7(3):580–589. doi: 10.1016/s0735-1097(86)80468-5. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Bolli R., Jeroudi M. O., Patel B. S., DuBose C. M., Lai E. K., Roberts R., McCay P. B. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4695–4699. doi: 10.1073/pnas.86.12.4695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bolli R., McCay P. B. Use of spin traps in intact animals undergoing myocardial ischemia/reperfusion: a new approach to assessing the role of oxygen radicals in myocardial "stunning". Free Radic Res Commun. 1990;9(3-6):169–180. doi: 10.3109/10715769009145674. [DOI] [PubMed] [Google Scholar]
  6. Bolli R. Mechanism of myocardial "stunning". Circulation. 1990 Sep;82(3):723–738. doi: 10.1161/01.cir.82.3.723. [DOI] [PubMed] [Google Scholar]
  7. Bolli R. Myocardial 'stunning' in man. Circulation. 1992 Dec;86(6):1671–1691. doi: 10.1161/01.cir.86.6.1671. [DOI] [PubMed] [Google Scholar]
  8. Bolli R., Patel B. S., Jeroudi M. O., Lai E. K., McCay P. B. Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone. J Clin Invest. 1988 Aug;82(2):476–485. doi: 10.1172/JCI113621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bolli R., Patel B. S., Jeroudi M. O., Li X. Y., Triana J. F., Lai E. K., McCay P. B. Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning". Am J Physiol. 1990 Dec;259(6 Pt 2):H1901–H1911. doi: 10.1152/ajpheart.1990.259.6.H1901. [DOI] [PubMed] [Google Scholar]
  10. Bolli R., Patel B. S., Zhu W. X., O'Neill P. G., Hartley C. J., Charlat M. L., Roberts R. The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am J Physiol. 1987 Dec;253(6 Pt 2):H1372–H1380. doi: 10.1152/ajpheart.1987.253.6.H1372. [DOI] [PubMed] [Google Scholar]
  11. Bolli R., Triana J. F., Jeroudi M. O. Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning". Circ Res. 1990 Aug;67(2):332–343. doi: 10.1161/01.res.67.2.332. [DOI] [PubMed] [Google Scholar]
  12. Bolli R., Zhu W. X., Thornby J. I., O'Neill P. G., Roberts R. Time course and determinants of recovery of function after reversible ischemia in conscious dogs. Am J Physiol. 1988 Jan;254(1 Pt 2):H102–H114. doi: 10.1152/ajpheart.1988.254.1.H102. [DOI] [PubMed] [Google Scholar]
  13. Braunwald E., Kloner R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982 Dec;66(6):1146–1149. doi: 10.1161/01.cir.66.6.1146. [DOI] [PubMed] [Google Scholar]
  14. Bunch F. T., Thornton J., Cohen M. V., Downey J. M. Adenosine is an endogenous protectant against stunning during repetitive ischemic episodes in the heart. Am Heart J. 1992 Dec;124(6):1440–1446. doi: 10.1016/0002-8703(92)90055-z. [DOI] [PubMed] [Google Scholar]
  15. Cohen M. V., Downey J. M. Myocardial stunning in dogs: preconditioning effect and influence of coronary collateral flow. Am Heart J. 1990 Aug;120(2):282–291. doi: 10.1016/0002-8703(90)90071-5. [DOI] [PubMed] [Google Scholar]
  16. Cohn P. F. Silent myocardial ischemia: classification, prevalence, and prognosis. Am J Med. 1985 Sep 13;79(3A):2–6. doi: 10.1016/0002-9343(85)90486-3. [DOI] [PubMed] [Google Scholar]
  17. Deanfield J. E., Maseri A., Selwyn A. P., Ribeiro P., Chierchia S., Krikler S., Morgan M. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet. 1983 Oct 1;2(8353):753–758. doi: 10.1016/s0140-6736(83)92295-x. [DOI] [PubMed] [Google Scholar]
  18. Figueras J., Cinca J., Senador G., Rius J. Progressive mechanical impairment associated with progressive but reversible electrocardiographic ischaemic changes during repeated brief coronary artery occlusion in pigs. Cardiovasc Res. 1986 Nov;20(11):797–806. doi: 10.1093/cvr/20.11.797. [DOI] [PubMed] [Google Scholar]
  19. Fuster V., Badimon L., Cohen M., Ambrose J. A., Badimon J. J., Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation. 1988 Jun;77(6):1213–1220. doi: 10.1161/01.cir.77.6.1213. [DOI] [PubMed] [Google Scholar]
  20. Geft I. L., Fishbein M. C., Ninomiya K., Hashida J., Chaux E., Yano J., Y-Rit J., Genov T., Shell W., Ganz W. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation. 1982 Dec;66(6):1150–1153. doi: 10.1161/01.cir.66.6.1150. [DOI] [PubMed] [Google Scholar]
  21. Gross G. J., Farber N. E., Hardman H. F., Warltier D. C. Beneficial actions of superoxide dismutase and catalase in stunned myocardium of dogs. Am J Physiol. 1986 Mar;250(3 Pt 2):H372–H377. doi: 10.1152/ajpheart.1986.250.3.H372. [DOI] [PubMed] [Google Scholar]
  22. Gross G. J., O'Rourke S. T., Pelc L. R., Warltier D. C. Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals. Am J Physiol. 1992 Dec;263(6 Pt 2):H1703–H1709. doi: 10.1152/ajpheart.1992.263.6.H1703. [DOI] [PubMed] [Google Scholar]
  23. Gross G. J., O'Rourke S. T., Pelc L. R., Warltier D. C. Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals. Am J Physiol. 1992 Dec;263(6 Pt 2):H1703–H1709. doi: 10.1152/ajpheart.1992.263.6.H1703. [DOI] [PubMed] [Google Scholar]
  24. Halliwell B., Gutteridge J. M. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J. 1984 Apr 1;219(1):1–14. doi: 10.1042/bj2190001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Henrichs K. J., Matsuoka H., Schaper J. Influence of repetitive coronary occlusions on myocardial adenine nucleosides, high energy phosphates and ultrastructure. Basic Res Cardiol. 1987 Nov-Dec;82(6):557–565. doi: 10.1007/BF01907226. [DOI] [PubMed] [Google Scholar]
  26. Heyndrickx G. R., Millard R. W., McRitchie R. J., Maroko P. R., Vatner S. F. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest. 1975 Oct;56(4):978–985. doi: 10.1172/JCI108178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hoffmeister H. M., Mauser M., Schaper W. Repeated short periods of regional myocardial ischemia: effect on local function and high energy phosphate levels. Basic Res Cardiol. 1986 Jul-Aug;81(4):361–372. doi: 10.1007/BF01907457. [DOI] [PubMed] [Google Scholar]
  28. Homans D. C., Laxson D. D., Sublett E., Lindstrom P., Bache R. J. Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia. Am J Physiol. 1989 May;256(5 Pt 2):H1462–H1471. doi: 10.1152/ajpheart.1989.256.5.H1462. [DOI] [PubMed] [Google Scholar]
  29. Lange R., Ware J., Kloner R. A. Absence of a cumulative deterioration of regional function during three repeated 5 or 15 minute coronary occlusions. Circulation. 1984 Feb;69(2):400–408. doi: 10.1161/01.cir.69.2.400. [DOI] [PubMed] [Google Scholar]
  30. Li X. Y., McCay P. B., Zughaib M., Jeroudi M. O., Triana J. F., Bolli R. Demonstration of free radical generation in the "stunned" myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs. J Clin Invest. 1993 Aug;92(2):1025–1041. doi: 10.1172/JCI116608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. McCay P. B., Lai E. K., Poyer J. L., DuBose C. M., Janzen E. G. Oxygen- and carbon-centered free radical formation during carbon tetrachloride metabolism. Observation of lipid radicals in vivo and in vitro. J Biol Chem. 1984 Feb 25;259(4):2135–2143. [PubMed] [Google Scholar]
  32. McCay P. B. Vitamin E: interactions with free radicals and ascorbate. Annu Rev Nutr. 1985;5:323–340. doi: 10.1146/annurev.nu.05.070185.001543. [DOI] [PubMed] [Google Scholar]
  33. Murry C. E., Jennings R. B., Reimer K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 Nov;74(5):1124–1136. doi: 10.1161/01.cir.74.5.1124. [DOI] [PubMed] [Google Scholar]
  34. Nicklas J. M., Becker L. C., Bulkley B. H. Effects of repeated brief coronary occlusion on regional left ventricular function and dimension in dogs. Am J Cardiol. 1985 Sep 1;56(7):473–478. doi: 10.1016/0002-9149(85)90889-6. [DOI] [PubMed] [Google Scholar]
  35. Nienaber C. A., Brunken R. C., Sherman C. T., Yeatman L. A., Gambhir S. S., Krivokapich J., Demer L. L., Ratib O., Child J. S., Phelps M. E. Metabolic and functional recovery of ischemic human myocardium after coronary angioplasty. J Am Coll Cardiol. 1991 Oct;18(4):966–978. doi: 10.1016/0735-1097(91)90755-x. [DOI] [PubMed] [Google Scholar]
  36. Reimer K. A., Murry C. E., Yamasawa I., Hill M. L., Jennings R. B. Four brief periods of myocardial ischemia cause no cumulative ATP loss or necrosis. Am J Physiol. 1986 Dec;251(6 Pt 2):H1306–H1315. doi: 10.1152/ajpheart.1986.251.6.H1306. [DOI] [PubMed] [Google Scholar]
  37. Schott R. J., Rohmann S., Braun E. R., Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res. 1990 Apr;66(4):1133–1142. doi: 10.1161/01.res.66.4.1133. [DOI] [PubMed] [Google Scholar]
  38. Sedlak J., Lindsay R. H. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968 Oct 24;25(1):192–205. doi: 10.1016/0003-2697(68)90092-4. [DOI] [PubMed] [Google Scholar]
  39. Sekili S., McCay P. B., Li X. Y., Zughaib M., Sun J. Z., Tang L., Thornby J. I., Bolli R. Direct evidence that the hydroxyl radical plays a pathogenetic role in myocardial "stunning" in the conscious dog and demonstration that stunning can be markedly attenuated without subsequent adverse effects. Circ Res. 1993 Oct;73(4):705–723. doi: 10.1161/01.res.73.4.705. [DOI] [PubMed] [Google Scholar]
  40. Stahl L. D., Aversano T. R., Becker L. C. Selective enhancement of function of stunned myocardium by increased flow. Circulation. 1986 Oct;74(4):843–851. doi: 10.1161/01.cir.74.4.843. [DOI] [PubMed] [Google Scholar]
  41. Stahl L. D., Weiss H. R., Becker L. C. Myocardial oxygen consumption, oxygen supply/demand heterogeneity, and microvascular patency in regionally stunned myocardium. Circulation. 1988 Apr;77(4):865–872. doi: 10.1161/01.cir.77.4.865. [DOI] [PubMed] [Google Scholar]
  42. Sun J. Z., Kaur H., Halliwell B., Li X. Y., Bolli R. Use of aromatic hydroxylation of phenylalanine to measure production of hydroxyl radicals after myocardial ischemia in vivo. Direct evidence for a pathogenetic role of the hydroxyl radical in myocardial stunning. Circ Res. 1993 Sep;73(3):534–549. doi: 10.1161/01.res.73.3.534. [DOI] [PubMed] [Google Scholar]
  43. Tillisch J., Brunken R., Marshall R., Schwaiger M., Mandelkern M., Phelps M., Schelbert H. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. 1986 Apr 3;314(14):884–888. doi: 10.1056/NEJM198604033141405. [DOI] [PubMed] [Google Scholar]
  44. Triana J. F., Li X. Y., Jamaluddin U., Thornby J. I., Bolli R. Postischemic myocardial "stunning". Identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog. Circ Res. 1991 Sep;69(3):731–747. doi: 10.1161/01.res.69.3.731. [DOI] [PubMed] [Google Scholar]
  45. Uma Devi P. Chemical radiation protection by alpha-mercaptopropionylglycine. J Nucl Med Allied Sci. 1983 Oct-Dec;27(4):327–336. [PubMed] [Google Scholar]
  46. Vanoverschelde J. L., Wijns W., Depré C., Essamri B., Heyndrickx G. R., Borgers M., Bol A., Melin J. A. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation. 1993 May;87(5):1513–1523. doi: 10.1161/01.cir.87.5.1513. [DOI] [PubMed] [Google Scholar]
  47. Vinten-Johansen J., Gayheart P. A., Johnston W. E., Julian J. S., Cordell A. R. Regional function, blood flow, and oxygen utilization relations in repetitively occluded-reperfused canine myocardium. Am J Physiol. 1991 Aug;261(2 Pt 2):H538–H547. doi: 10.1152/ajpheart.1991.261.2.H538. [DOI] [PubMed] [Google Scholar]
  48. Wallenstein S., Zucker C. L., Fleiss J. L. Some statistical methods useful in circulation research. Circ Res. 1980 Jul;47(1):1–9. doi: 10.1161/01.res.47.1.1. [DOI] [PubMed] [Google Scholar]
  49. Warner K. G., Khuri S. F., Marston W., Sharma S., Butler M. D., Assousa S. N., Saad A. J., Siouffi S. Y., Lavin P. T. Significance of the transmural diminution in regional hydrogen ion production after repeated coronary artery occlusions. Circ Res. 1989 Mar;64(3):616–628. doi: 10.1161/01.res.64.3.616. [DOI] [PubMed] [Google Scholar]
  50. Weiner J. M., Astein C. S., Arthur J. H., Pirzada F. A., Hood W. B., Jr Persistence of myocardial injury following brief periods of coronary occlusion. Cardiovasc Res. 1976 Nov;10(6):678–686. doi: 10.1093/cvr/10.6.678. [DOI] [PubMed] [Google Scholar]
  51. Wynsen J. C., Kenny D., Brooks H. L., Warltier D. C. Regional myocardial function after repetitive brief episodes of ischemia: effect of altering the duration of the reperfusion period. Am Heart J. 1991 May;121(5):1331–1338. doi: 10.1016/0002-8703(91)90135-5. [DOI] [PubMed] [Google Scholar]
  52. Yao Z., Gross G. J. Glibenclamide antagonizes adenosine A1 receptor-mediated cardioprotection in stunned canine myocardium. Circulation. 1993 Jul;88(1):235–244. doi: 10.1161/01.cir.88.1.235. [DOI] [PubMed] [Google Scholar]

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