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

Abstract

Mild (not harmful) stress may initiate an adaptive 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:

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

• 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

• 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 myocardial ischaemia

• 2 early and late postocclusion and reperfusion arrhythmias

• 3 early morphologic changes secondary to ischaemia and reperfusion

• 4 ischaemia induced myocardial loss of K⁺and accumulationof Na⁺ and Ca⁺⁺

• 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 AMP level in rat hearts isolated 48 h 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 representsa new therapeutic concept, different from the classical drug-receptor interaction produced protection. Its possible exploitation to therapeutic use requires that the adaptation inducing stress should be applicable to patients, 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 dogs 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. (Mol Cell Biochem 147: 115-122, 1995)