ON THE MECHANISM AND POSSIBLE THERAPEUTIC APPLICATION OF DELAYED ADAPTATION OF THE HEART TO STRESS SITUATIONS

Mild (not harmful) stress may initiate an adaptive mechanism, protecti ng the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress, such a s: a) the gradually developing, long lasting adaptation to chronic mec hanical overload, leading to cardiac hypertrophy, later to cardiomyopa thy and heart failure, b) the rapidly developing adaptation to moderat e stress initiated by 'preconditioning' brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h a gainst consequences of a subsequent, severe stress, c) the later appea ring, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimul i, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings. This form of cardiac adap tation to stress protects for 24-48 h against consequences of a more s evere stress such as: 1. myocardial ischaemia; 2. early and late posto cclusion and reperfusion arrhythmias; 3. early morphologic changes sec ondary to ischaemia and reperfusion; 4. ischaemia induced myocardial l oss of K+ and accumulation of Na+ and Ca++; 5. it may increase the tol erance 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 th ese factors may play a role in the mechanism of delayed protection was confirmed by our present findings according to which 7-oxo-PgI(2)-tre atment greatly attenuated the dose dependent isoprenaline-induced incr ease in contractility, relaxation and myocardial cAMP level in rat hea rts isolated 48 h after 7-oxo-PgI(2). In addition all these values are in close correlation with each other. The endogenous 'self-defence' o f the heart, based on adaptation represents a new therapeutic concept, different from the classical drug-receptor interaction produced prote ction. Its possible exploitation to therapeutic use requires that the adaptation inducing stress should be applicable to patients, furthermo re prolongation of duration of protection should be possible. As a fir st step in testing applicability to therapy we had to show that drug i nduced adaptive protection is existing in the conscious animal. In our present study we found an attenuation of rapid pacing induced elevati on of the ST-segment in the endocardial electrogram and in the left ve ntricular end diastolic pressure in conscious rabbits 24-48 h after tr eatment with Iloprost. Besides we found an attenuation of tachycardia and arrhythmias due to two stage coronary artery ligation in conscious dogs 48 h after pretreatment with 7-oxo-PgI(2). Finally we were able to demonstrate that protection against coronary artery occlusion-induc ed ST segment elevation and arrhythmias can be prolonged at will by pe riodically repeated maintenance doses.