Molecular and Cellular Biochemistry

, Volume 147, Issue 1–2, pp 115–122 | Cite as

On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations

  • Ernst-Georg Krause
  • László Szekeres
Part II: Myocytic Adaptation and Myocardial Injury


Mild (not harmful) stress may initiate anadaptive mechanism, protecting the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress such as:
  1. a)

    the gradually developing long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure,

  2. b)

    the rapidly developing adaptation to moderate stress initiated by ‘preconditioning’ brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h against consequences of a subsequent, severe stress,

  3. c)

    the later appearing, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimuli, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings.

This form of cardiac adaptation to stress protects for 24–48 h against consequences of a more severe stress such as:
  1. 1.

    myocardial ischaemia;

  2. 2.

    early and late postocclusion and reperfusion arrhythmias;

  3. 3.

    early morphologic changes secondary to ischaemia and reperfusion;

  4. 4.

    ischaemia induced myocadial loss of K+ and accumulation of Na+ and Ca++;

  5. 5.

    it may increase the tolerance to the toxic effects of cardiac glycosides.


A reduced response to beta-adrenergic stimuli and a concomitant increase in activity and amount of PDE I and IV was shown by us earlier. The hypothesis that these factors may play a role in the mechanism of delayed protection was confirmed by our present findings according to which 7-oxo-PgI2-treatment greatly attenuated the dose dependent isoprenaline-induced increase in contractility, relaxation and myocardial cAMP level in rat hearts isolated 48h after 7-oxo-PgI2. In addition all these values are in close correlation with each other.

The endogenous ‘self-defence’ of the heart based on adaptation represents anew therapeutic concept, different from the classical drug-receptor interaction produced protection. Its possible exploitation to therapeutic use requires that the adaptation inducing stress should beapplicable topatients, furthermore prolongation of duration of protection should be possible. As a first step in testing applicability to therapy we had to show that drug induced adaptive protection is existing in the conscious animal. In our present study we found an attenuation of rapid pacing induced elevation of the ST-segment in the endocardial electrogram and in the left ventricular end diastolic pressure in conscious rabbits 24–48 h after treatment with Iloprost. Besides we found an attenuation of tachycardia and arrhythmias due to two stage coronary artery ligation in conscious dog 48 h after pretreatment with 7-oxo-PgI2. Finally we were able to demonstrate that protection against coronary artery occlusion-induced ST segment elevation and arrhythmias can be prolonged at will by periodically repeated maintenance doses.

Key words

cardioprotection delayed adaptation cAMP PDE-isoenzymes prolongation of protection 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Parratt JR: Protection of the heart by ischemic preconditioning: mechanisms and possibilities for pharmacological evaluation. Trends in Pharmacological Sciences (TIPS) 15: 19–25, 1994Google Scholar
  2. 2.
    Szekeres L, Krassói I, Udvary É: Delayed antischemic effect of PgI2 and of a new stable PgI2 analogue 7-oxo-prostacyclin-Na in experimental model angina in dogs. J Mol Cell Cardiol 15 (Suppl I): 394, 1983Google Scholar
  3. 3.
    Szekeres L, Pataricza J, Szilvássy Z, Udvary É, Végh Å: Cardioprotection: endogenous protective mechanisms promoted by prostacyclin. Basic Res Cardiol 86 (Suppl 3): 215–221, 1991Google Scholar
  4. 4.
    Szekeres L, Szilvássy Z, Udvary É, Végh Å: Rapid pacing evoking myocardial ischaemia induces both short-term and delayed cardioprotection. J Mol Cell Cardiol 23 (Suppl V): S72, p 47, 1991PubMedGoogle Scholar
  5. 5.
    Szekeres L, Papp JGy, Szilvassy Z, Udvary É, Végh Å: Moderate stress by cardiac pacing may induce both short term and long term cardio-protection. Cardiovasc Res 27: 593–596, 1993PubMedGoogle Scholar
  6. 6.
    Szekeres L, Krassói I, Pataricza J, Udvary É: Delayed antiischaemic effect of prostaglandin I2 and of a new stable prostaglandin I2 analogue, 7-oxo-prostacyclin-Na, in experimental model angina in dogs. In: N.S. Dhalla and D.J. Hearse (eds.). Advances in Myocardiology, Vol 6, Plenum Press, New York, 1985, pp 607–618Google Scholar
  7. 7.
    Szekeres L, Koltai M, Pataricza J, Takáts I, Udvary É: On the late antiischaemic action of the stable PgI2 analogue: 7-oxo-PgI2-Na and its possible mode of action. Biomed Biochim Acta 43: 135–142, 1984PubMedGoogle Scholar
  8. 8.
    Szekeres L, Bálint Zs, Karcsú S, Tósaki Å, Udvary É: On the 7-oxo-PgI2 induced late appearing long-lasting cytoprotective effect. Prostaglandins in Clinical Research: Cardiovascular System 143–147, 1989Google Scholar
  9. 9.
    Szekeres L, Bálint Zs, Karcsú S, Tósaki Å: Delayed protection by 7-oxo-PgI2 against cardiac transmembrane ion shifts and early morphological changes due to ischaemia and reperfusion. Cardiosci 1: 280–286, 1990Google Scholar
  10. 10.
    Ravingerová T, Tribulova N, Ziegelhöffer A, Džurba A, Szekeres L: 7-oxo-PgI2 prevents partially the postischemic reperfusion injury of the rat heart. J Mol Cel Cardiol 23 (Suppl V): 104, 1991Google Scholar
  11. 11.
    Udvary É, Szekeres L: Prostacyclin: antiischaemic or cardioprotective? Advances in pharmacological research and practice. Volume 3, Section 7. In: V. Kecskeméti, K. Gyires, and G. Kovács (eds.). Prostanoids. Akadémiai Kiadó, Budapest, 1986, pp 333–338Google Scholar
  12. 12.
    Szekeres L, Németh M, Papp JGy, Udvary É, Végh Å, Virág L: Neue Entwicklungen der antiarrhythmischen Therapie. In: B. Lüderitz and B. Antoni (eds). Perspektiven der Arrhythmiebehandlung Springer, Berlin, 1988, pp 24–34Google Scholar
  13. 13.
    Ravingerová T, Tribulová N, Ziegelhöffer A, Styk J, Szekeres L: Suppression of reperfusion induced arrhythmias in the isolated rat heart: pretreatment with 7-oxo-prostacyclinin vivo. Cardiovasc Res 27: 1052–1055, 1993Google Scholar
  14. 14.
    Végh Å: 7-oxo-PgI2 induced delayed protective action from late postocclusion arrhythmias in conscious dogs. East European Subsection Meeting, International Society for Heart Research, May 13–18. Smolenice CSR: 93, 1990Google Scholar
  15. 15.
    Szekeres L, Szilvássy Z, Udvary É, Végh Å: 7-oxo-PgI2 induced late appearing protection against ouabain induced cardiac arrhythmias in anesthetized guinea pigs. Pharmacol Res Commun 20: 77–78, 1988Google Scholar
  16. 16.
    Szilvássy Z, Szekeres L, Udvary É, Végh Å: On the 7-oxo-PgI2 induced lasting protection against ouabain arrhythmias in anesthetized guinea pigs. Biomed Biochim Acta 47 (Suppl): 35–38, 1988Google Scholar
  17. 17.
    Szilvássy Z, Szekeres L, Udvary É, Karcsú S, Végh Å: 7-oxo-PgI2 dramatically increases the safety margin of digitalis. Bratisl Lek Liety 92: 134–137, 1991Google Scholar
  18. 18.
    Szekeres L, Németh M, Papp JGy, Szilvássy Z, Udvary É, Végh Å: On the late appearing cardiac electrophysiological actions of the stable prostacyclin analogue: 7-oxo-PgI2-Na. Proceedings of the 10th International Congress of Pharmacology, Sydney, 356, 1987Google Scholar
  19. 19.
    Németh M, Papp JGy, Szekeres L: Class 3 antiarrhythmic features of 7-oxo-PgI2, a stable analogue of prostacyclin. Eur Heart J 9 (Suppl): 232, 1988Google Scholar
  20. 20.
    Szekeres L, Szilvássy Z, Udvary É, Végh Å: 7-oxo-PgI2 induced late appearing and long-lasting electrophysiological changes in the heartin situ of the rabbit, guinea pig, dog and cat. J Mol Cell Cardiol 21: 545–554, 1989PubMedGoogle Scholar
  21. 21.
    Szekeres L, Németh M, Papp JGy, Udvary É: Short incubation with 7-oxo-prostacyclin induces long lasting prolongation of repolarisation time and effective refractory period in rabbit papillary muscle preparation. Cardiovasc Res 24: 37–41, 1990PubMedGoogle Scholar
  22. 22.
    Džurba A, Ziegelhöffer A, Breier A, Vrbjar N, Szekeres L: Increased activity of sarcolemmal (Na+K+-ATPase is involved in the late cardio-protective action of 7-oxo-prostacyclin. Cardioscience 2: 105–108, 1991PubMedGoogle Scholar
  23. 23.
    Borchert G, Bartel S, Beyerdörfer I, Küttner I, Szekeres L, Krause EG: Long lasting anti-adrenergic effect of 7-oxo-prostacyclin in the heat: a cycloheximide sensitive increase of phosphodiesterase isoform I and IV activities. Mol Cell Biochem 132: 57–67, 1994PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Ernst-Georg Krause
    • 1
  • László Szekeres
    • 2
  1. 1.Department of Molecular CardiologyMax Delbrück Centre for Molecular MedicineBerlin-Buch.Germany
  2. 2.Institute of PharmacologyAlbert Szent-Györgyi Medical UniversitySzegedHungary

Personalised recommendations