On the mechanism and possible therapeutic application of delayed cardiac adaptation to stress.
Several forms of cardiac adaptation to stress are known, differing in the evoking stress, in the time needed for adaptation and in the duration of the protective effect. A delayed adaptation produced a late appearing, prolonged protection against consequences of ischemia, such as early morphological changes, early and late postocclusion and reperfusion arrhythmias due to coronary artery occlusion or ouabain intoxication. Delayed adaptation was evoked by ischemic stress (repeated brief periods of rapid cardiac pacing or brief coronary occlusions) or by drugs (prostaglandin I2 and its stable derivatives). The protection produced by delayed adaptation proved to be time- and dose-dependent. Optimal effects appeared 24 to 48 h after treatment with an optimal dose of 50 microg/kg 7-oxo-prostacyclin or 10 microg/kg Iloprost. It is suggested that the mechanism of delayed cardioprotection is based on the fact that the stress-evoking adaptation stimulates the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system; the resulting elevation of cardiac cAMP level triggers the induction of some key enzymes such as Na/K-ATPase and phosphodiesterase (PDE) isoforms I and IV. Increased amount and activity of Na/K-ATPase accounts for preservation of normal membrane function and moderation of ischemic loss of potassium, and accumulation of sodium and calcium in the myocardium, as well as for reduced ouabain toxicity. The detrimental consequences of heavy stress-induced accumulation of cAMP in the heart are mitigated by hydrolysis of the latter, carried out by an enhanced amount and activity of PDE isoforms. Response to beta-adrenergic stimuli is also attenuated. In addition, electrophysiological changes such as prolongation of the effective refractory period and of the action potential duration may attenuate arrhythmias due to ischemia and reperfusion.
Szekeres
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Institute of Pharmacology, Albert Szent-Györgyi Medical University, Szeged, Hungary.
D000222:Adaptation, Physiological; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D013312:Stress, Physiological / Q000503:physiopathology*; D013997:Time Factors
D000242:Cyclic AMP; D000251:Adenosine Triphosphatases