On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations
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the gradually developing long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure,
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,
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.
early and late postocclusion and reperfusion arrhythmias;
early morphologic changes secondary to ischaemia and reperfusion;
ischaemia induced myocadial loss of K+ and accumulation of Na+ and Ca++;
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 wordscardioprotection delayed adaptation cAMP PDE-isoenzymes prolongation of protection
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- 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.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.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
- 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
- 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.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.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.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.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.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.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.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.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.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.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.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