Skip to main content
SpringerLink
Log in

Improved functional recovery after ischemic preconditioning in the globally ischemic rabbit heart is not mediated by adenosine A1 receptor activation

  • Original Contributions
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Summary

Experiments were carried out to test the hypothesis that preconditioning reduces the impairment of recovery of cardiac mechanical function and that this effect is mediated by activation of adenosine A1 receptors. Isolated hearts were Langendorff-perfused at 37°C with oxygenated blood and paced at 3 Hz. They were divided into 5 groups, all subjected to 45 min global ischemia followed by one hour of reperfusion: 1) Control hearts (n=7) which received no treatment or short ischemia before the long ischemia, 2) preconditioned hearts (n=7), submitted to 5-min zero-flow global ischemia, followed by 5 min reperfusion before the long ischemia, 3) hearts pretreated with sulfophenyltheophylline (SPT 100 μM) before preconditioning and long ischemia (n=6), 4) hearts in which preconditioning was substituted by administration of 10 μM phenyl-isopropyl-adenosine (PIA) over 5 min, and 5) hearts in which preconditioning was substituted by the administration of 1.5 mg adenosine over 5 min. Hemodynamic results show significant improvement of the postischemic recovery of left ventricular developed pressure (DP) by preconditioning. SPT pretreatment did not reverse the improvement of recovery, obtained by preconditioning, whereas PIA treatment could not mimic preconditioning. Adenosine treatment caused some improvement of recovery of DP, but which remained lower compared to that caused by preconditioning. The contracture developed during ischemia persisted in control hearts, whereas contracture disappeared in non-treated preconditioned hearts. SPT did not prevent the decrease in contracture by preconditioning although values remained slightly higher than in the nontreated preconditioned hearts. PIA did not substitute for preconditioning in preventing contracture. In the adenosine treated group, some decrease of contracture occurred during reperfusion, but values remained significantly higher than in preconditioning.

We conclude that receptor A1 activation is not the main mechanism underlying improved functional recovery conferred by preconditioning since an A1 receptor blocker (SPT) cannot reverse the effect of preconditioning and an A1 receptor agonist (PIA) cannot mimic it. Administration of exogenous adenosine reduces functional impairment to a certain extent, but less than preconditioning.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Asimakis GK, Inners-McBride K, Medellin G, Conti VR (1992) Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart. Am J Physiol 263:H887-H894

    Google Scholar 

  2. Cave AC, Downey JM, Hearse DJ (1991) Adenosine fails to substitute for preconditioning in the globally ischemic rat heart. J Mol Cell Cardiol 23 (Suppl III):S76 (abstract)

    Google Scholar 

  3. Cohen MV, Liu GS, Downey JM (1991) Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits. Circulation 84:341–349

    Google Scholar 

  4. Daut J, Maier-Rudolph W, Von Beckerath N, Mehrke G, Gunther K, Goedel-Meinen L (1990) Hypoxic dilatation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 247:1341–1344

    Google Scholar 

  5. Dorheim TA, Hoffman A, Van Wylen DGL, Mentzer RM (1991) Enhanced interstitial fluid adenosine attenuates myocardial stunning. Surgery 110:136–145

    Google Scholar 

  6. Downey JM, Jordan M (1989) Preconditioning limits infarct size in rabbits. Circulation 80 (Suppl II):II-238 (abstract)

    Google Scholar 

  7. Fenton RA, Bruttig SP, Rubio R, Berne RM (1982) Effect of adenosine on calcium uptake by intact and cultured vascular smooth muscle. Am J Physiol 242 (Heart Circ Physiol 220):H797-H804

    Google Scholar 

  8. Flameng W, Andres J, Ferdinande P, Mattheussen M, Van Belle H (1991) Mitochondrial function in myocardial stunning. J Mol Cell Cardiol 21:1–11

    Google Scholar 

  9. Gross GJ, Auchampach JA (1992) Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 70:223–233

    Google Scholar 

  10. Hopwood AM, Harding SE, Harris P (1987) An antiadrenergic effect of adenosine on guinea-pig but not rabbit ventricles. Eur J Pharmacol 137:67–75

    Google Scholar 

  11. Iwamoto T, Miura T, Adachi T, Noto T, Ogawa T, Tsuchida A, Jimura O (1991) Myocardial infarct size-limiting effect of ischemic preconditioning was not attenuated by oxygen free-radical scavengers in the rabbit. Circulation 83:1015–1022

    Google Scholar 

  12. Kaplan P, Hendrikx M, Mattheusen M, Mubagwa K, Flameng W (1992) Effect of ischemia and reperfusion on sarcoplasmic reticulum calcium uptake. Circ Res 71:1123–1130

    Google Scholar 

  13. Kida M, Fujiwara H, Ishida M, Kawai C, Ohura M, Miura I, Yabuuchi Y (1991) Ischemic preconditioning preserves creatine phosphate and intracellular pH. Circulation 84:2495–2503

    Google Scholar 

  14. Kihara Y, Grossman W, Morgan JE (1989) Direct measurement of changes in intracellular Ca++ transient during hypoxia, ischemia and reperfusion in intact mammalian heart. Circ Res 65:1029–1044

    Google Scholar 

  15. Kimura Y, Iyengar J, Subramanian R, Cordis GA, Das DK (1992) Preconditioning of the heart by repeated stunning: attenuation of post-ischemic dysfunction. Bas Res Cardiol 87:128–138

    Google Scholar 

  16. Kitakaze M, Hori M, Takashima S, Sato H, Kamada T (1991) Augmentation of adenosine production during ischemia as a possible mechanism of myocardial protection in ischemic preconditioning. Circulation 84 (Suppl II):306 (abstract)

    Google Scholar 

  17. Kupriyanov VV, Lakomkim VL, Steinschneider AYA, Severina MYU, Kapelko VI, Ruuge FK, Saks VA (1988) Relationships between pre-ischemic ATP and glycogen content and post-ischemic recovery of rat heart. J Mol Cell Cardiol 20:1151–1162

    Google Scholar 

  18. Lasley RD, Rhee JW, Van Wylen DGL, Mentzer RM Jr (1990) Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J Mol Cell Cardiol 22:39–47

    Google Scholar 

  19. Li GC, Vasquez JA, Gallagher KP, Lucchesi BR (1990) Myocardial protection with preconditioning. Circulation 82:609–619

    Google Scholar 

  20. Li Y, Kloner R (1992) Ischemic “preconditioning” is not mediated by adenosine receptors in the rat heart. Circulation 86 (Suppl I):24 (abstract)

    Google Scholar 

  21. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM (1991) Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in the rabbit heart. Circulation 84:350–356

    Google Scholar 

  22. Marban E, Kitakaze M, Koretsune Y, Yue DT, Chacko VP, Pike MM (1990) Quantification of [Ca2+] in perfused hearts. Critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ Res 66: 1255–1267

    Google Scholar 

  23. Masuda M, Demeulemeester A, Chen C-C, Hendrikx M, Van Belle H, Flameng W (1991) Cardioprotective effects of nucleoside transport inhibition in rabbit hearts. Ann Thorac Surg 52:1300–1305

    Google Scholar 

  24. Miura T, Yellon DM, Hearse DJ, Downey JM (1987) Determinants of infarct size during permanent occlusion of a coronary artery in closed chest dogs. J Am Coll Cardiol 9:647–654

    Google Scholar 

  25. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    Google Scholar 

  26. Murry CE, Richard VJ, Reimer KA, Jennings RB (1990) Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic period. Circ Res 66:913–931

    Google Scholar 

  27. Omar BA, Bose SK, McCord J (1991) Seasonal variation in myocardial postischemic injury. Cor Artery Dis 2:481–485

    Google Scholar 

  28. Omar BA, Hanson A, Bose S, McCord J (1991) Reperfusion with pyruvate eliminates ischemic preconditioning: an apparent role for enhanced glycolysis. Faseb J 5 (5):A1257 (abstract)

    Google Scholar 

  29. Ovize M, Przyklenk K, Hale SL, Kloner RA (1992) Preconditioning does not attenuate myocardial stunning. Circulation 85:2247–2254

    Google Scholar 

  30. Reimer KA, Jennings RB (1992) Preconditioning. Definitions, proposed mechanisms, and implications for myocardial protection in ischemia and reperfusion. In: Yellon DM, Jennings RB (eds) Myocardial protection: the pathophysiology of reperfusion and reperfusion injury. Raven Press, New York, pp 165–183

    Google Scholar 

  31. Rubanyi G, Romero JC, Vanhoutte PM (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250 (Heart Circ Physiol 19):H1145-H1149

    Google Scholar 

  32. Schott RJ, Rohmann S, Braun ER, Schaper W (1990) Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 66:1133–1142

    Google Scholar 

  33. Schwarz ER, Mohri M, Sack S, Arras M (1991) The role of adenosine and its A1 receptor in ischemic preconditioning. Circulation 84 (Suppl II):306 (abstract)

    Google Scholar 

  34. Shiki K, Hearse DJ (1987) Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am J Physiol 253 (Heart Circ Physiol 22):H1470-H1476

    Google Scholar 

  35. Steenbergen C, Murphy E, Levy L, London RE (1987) Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res 60:700–707

    Google Scholar 

  36. Steenbergen C, Perlman ME, London RE, Murphy E (1993) Mechanisms of preconditioning. Ionic alterations. Circ Res 72:112–125

    Google Scholar 

  37. Tani M, Neely JR (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+−Na+ and Na+−Ca2+ exchange. Circ Res 65:1045–1056

    Google Scholar 

  38. Thornton JD, Liu GS, Olsson RA, Downey JM (1992) Intravenous pretreatment with A1-selective adenosine analogues protects the hearts against infarction. Circulation 85:659–665

    Google Scholar 

  39. Thornton JD, Thornton CS, Sterling DL, Downey JM (1993) Blockade of ATP-sensitive potassium channels increases infarct size but does not prevent preconditioning in rabbit hearts. Circ Res 72:44–49

    Google Scholar 

  40. Tsuchida A, Miura T, Miki T, Kazuaki S, Iimura O (1992) Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning. Cardiovasc Res 26:456–461

    Google Scholar 

  41. Vander Heide R, Steenbergen C, Fralix T, London R, Murphy E (1991) The rise in Cai during ischemia is lessened by preconditioning. A possible role for Na/H and Na/Ca exchange. J Cell Mol Cardiol 23 (Suppl III):S.21 (abstract)

    Google Scholar 

  42. Von Beckerath N, Cyrys S, Dischner A, Daut J (1991) Hypoxic vasodilatation in isolated, perfused guinea-pig heart: an analysis of the underlying mechanisms. J Physiol 442:297–319

    Google Scholar 

  43. Wolfe CL, Sievers RE, Visseren FLJ, Donnelly TJ (1993) Loss of myocardial protection after preconditioning correlates with the time course of glycogen recovery within the preconditioned segment. Circulation 87:881–892

    Google Scholar 

  44. Zhu G-Y, Chen S-G, Zou C-M (1990) Protective effect of an adenosine deaminase inhibitor on ischemia-reperfusion injury in isolated perfused rat heart. Am J Physiol 259 (Heart Circ Physiol 28):H835-H838

    Google Scholar 

Download references

Author information

Author notes

  1. W. Flameng

    Present address: Laboratory for Experimental Cardiac Surgery, Provisorium I, Katholieke Universiteit Leuven, 17 Minderbroedersstraat, 3000, Leuven, Belgium

Authors and Affiliations

  1. Laboratory for Experimental Cardiac Surgery, Provisorium I, Katholieke Universiteit Leuven, 17 Minderbroedersstraat, 3000, Leuven, Belgium

    M. Hendrikx, Y. Toshima & K. Mubagwa

Authors
  1. M. Hendrikx
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Toshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Mubagwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Flameng
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hendrikx, M., Toshima, Y., Mubagwa, K. et al. Improved functional recovery after ischemic preconditioning in the globally ischemic rabbit heart is not mediated by adenosine A1 receptor activation. Basic Res Cardiol 88, 576–593 (1993). https://doi.org/10.1007/BF00788876

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00788876

Key words

Search

Navigation