Myocardial contraction in the reverse development of adaptation to short-term exposure to stress

Contractile function of an isolated right atrium was studied in short-term stressor effects-adapted male Wistar rats at different times after adaptation was completed. Adaptation to short-term stressor effects was shown to produce a restricted decrease of myocardial contractility shortly after adaptation was completed. At the 3d day another decrease of contractile function was noted. However, contractile function returned to the control level by the 5th day. At the same time adaptation completely prevented the impairment of myocardial contractility, induced by prolonged stress. The protective effect was seen immediately after adaptation, by days 3 and 5 after it, being reduced by day 10. It is assumed that at the 5th day after adaptation, the animals experience the post-adaptation state marked by disappearance of the negative adaptation effect and by remarkable protective effect of adaptation. As a result, all the characteristics of myocardial contractility evaluated after prolonged stress experienced by the animals at the 5th day following short-term stressor effects do not differ from control parameters.     

Adaptation to short-term stress exposure increases the activity ATP-sensitive potassium channels in the smooth muscle cells of coronary blood vessels

The study was aimed at the effect of prior adaptation to short-term stress exposure on changes in K(ATP)-channel activity induced by severe stress and the dependence of the changes on the state of endothelium which plays important role in autoregulation of the coronary flow and myocardial contractility. Experiments were conducted on isolation hearts of female rats. At the first step of experiment, the heart was perfused by Krebs-Henseleit solution; at the second step, the heart was perfused with the same solution in which glibenclamide (1 microM), glibenclamide with saponin or N(omega)-nitro-L-arginine (60 microM) methyl ether was added. During the experiment, the perfusion pressure was stepwise elevated from 40 to 120 mm Hg with 20 mm intervals (coronary autoregulation). Adaptation to short-term stress prevented development of stress-specific myocardial hyperperfusion (increased volumetric velocity of coronary flow against the background of decreased myocardial contractility) and the reduction of coronary dilation reserve. In coronary vessels of adapted rats, as distinct from control rats, basal glibenclamide-sensitive functional activity of K(ATP)-channels depended on presence and functional activity of endotheliocytes; it was reduced in presence of endothelium and increased after de-endothelization or NO synthase inhibition. In all experimental groups, the increase in glibenclamide-sensitive functional activity of K(ATP)-channels induced by NO synthase inhibition more than twice as great as after the endothelium denudation. In adapted animals, stress did not decrease the functional activity of K(ATP)-channels and their activity slightly depended on presence of endotheliocytes. In addition, the elevation of their functional activity characteristic of adaptation and evident after endothelium removal has vanished. Therefore adaptation to short-term stress exposure is associated with a potential increase in basal activity of K(ATP)-channels which enhances the potency of vascular dilation system and may apparently reduce the risk of high vascular tone when such important local regulatory system as the NO system is damaged.     

Comparative evaluation of the protective effect of adaptation to short-term stress exposures in damage to the heart and portal vein from long-term stress

The effect of the preliminary adaptation to short-term stress actions carried out under different conditions was studied in the myocardium and vascular smooth muscle damaged by long-term immobilization stress. The preliminary adaptation performed under "sparing" conditions was shown to protect more effectively the right atrial myocardium and portal vein against damages induced by long-term immobilization than that carried out under stringent conditions. The sparing adaptation allowed avoiding the appearance of the structural "price" of the adaptation, i.e. the depression of myocardial contractile function induced by adaptation itself.     

Enhanced cAMP accumulation after termination of cholinergic action in the heart

Cholinergic agents decrease myocardial contractility in part by inhibiting adenylate cyclase (EC 4.6.1.1) activity. We have found that after a prolonged preincubation period (greater than 6 h), washout of cholinergic agents from embryonic chick hearts or cultured heart cells results in a persistent increase in their basal and catecholamine-stimulated cAMP content. Membranes prepared from pretreated cells have elevated basal, forskolin-, and catecholamine-stimulated adenylate cyclase activities. This myocardial adaptation to cholinergic agents is analogous to changes in nerve cells and other cell types after prolonged exposures to narcotics or other inhibitors of adenylate cyclase, respectively. A rapid (less than 5 min) adaptation response to cholinergic agents can also be demonstrated in heart cells by quickly blocking agonist action with atropine. Atropine alone has no effect, but after a brief preincubation period with agonists (methacholine or oxotremorine), the addition of atropine transiently enhances catecholamine-stimulated cAMP accumulation by 2.5-fold. These responses are absent in heart cells pretreated with pertussis toxin. The data indicate that the response is not mediated by the phosphoinositide pathway, which has been demonstrated to be insensitive to pertussis toxin in chick heart. Enhanced cAMP accumulation after termination of muscarinic agonist action may provide an explanation for the observation that acetylcholine sometimes produces biphasic contractile responses.     

Body adaptation to stress exposure enhances cardiac resistance to adrenotoxic damage

Models of adrenergic arrhythmias were produced on isolated rat heart under the adrenalin concentration in the perfusion solution of 5.10(-5) M. The rhythm disturbances were accompanied by a pronounced depression of contractile function. It was shown that preliminary adaptation of animals to short-term stress exposures reduced the duration of arrhythmias more than sixfold the contractile function, being maintained at a higher level than in control. The adaptation cardioprotective effect was compared with the effects of adaptation and propranolol appeared similar.     

The effect of adaptation to stress exposures and to periodic hypoxia on the cardiomyocyte trigger activity of the papillary muscles in the rat]

Action potential of cardiomyocytes was recorded in experiments on isolated papillary muscle of the rat left ventricle. The effect was estimated of preliminary adaptation to intermittent hypobaric hypoxia or to short-term stress exposure on the incidence and the pronouncement of delayed after depolarization and of trigger activity induced by a high frequency stimulation against the background of isoproterenol (10(-8) M). It was shown that adaptation to hypoxia or to stress reduced the incidence of delayed after depolarization and of trigger activity, adaptation to stress exerting a more pronounced effect. Immobilization stress (6 hours) potentiated the trigger activity, adaptation to stress exerting a more pronounced effect. Immobilization stress (6 hours) potentiated the trigger activity and this potentiation was effectively prevented by either type of adaptation.     

Effects of adaptation to exposure to short-term stress on indices of resistance of energy metabolism and contractile function of the myocardium to acute hypoxic hypoxia and reoxygenation

Effect of preliminary adaptation to immobilization stress with progressive duration from 15 min. to 1 h (every second day, 8 sessions) on the resistance of indices of myocardial energy metabolism and contractile function to acute hypoxic hypoxia and subsequent reoxygenation was studied. It was shown, that adaptation to short-term stress exposure by some way provided the retention of activities of important enzymes like creatine-phosphokinase and phosphorylase under the harmful action of acute hypoxia and subsequent reoxygenation. At the same time, the ATP restoration and the CP super-restoration were observed during reoxygenation. This effect, in its turn, was accompanied by a more pronounced super-restoration of the heart contractile function than in control.     

Alpha1 desensitization of the heart during adaptation to stress]

Results of the experiments evidence that a combination of three factors, limiting the Ca2+ concentration increase in myocardial cell, can play a role in the cardioprotective effect of adaptation of rats to short-term immobilization stress (every second day for a month) are presented. Those factors are as follows: desensitization of alpha 1-adrenoreceptors, M-cholinoreceptors up-regulation and reduced number of voltage-dependent Ca2+ channels in the myocardial membranes.     

Increased vagal tone in adaptation to the effects of continuous stress and termination of cardiac arrhythmias

It was established in experiments on rats exposed to 5 day stress that 1 day stress resulted in a twofold decreased heart fibrillation threshold (HFT) and 5 day stress resulted in bradycardia and in the restoration of HFT to the control level. The restoration of the heart electric stability was due to an increased vagal tone because atropine eliminated the bradycardia and reduced HFT again. Adaptation to continuous 5 day stress increased 3-7-fold the heart resistance to ischemic and reperfusion arrhythmias. This protective effect was completely abolished with atropine. Thus adaptation to continuous mild stress has a potent antiarrhythmic effect which occurs due to the increased vagal tone.     

Adaptation of the body to stress effects increases resistance of nuclear DNA of cardiac cells due to accumulation of heat shock proteins in the nucleus]

It was shown that adaptation to stress exposure increased the resistance of nuclear DNA in myocardial cells to the damaging action of exogenous one-chain DNA (50 micrograms/ml). This protective effect was accompanied by a pronounced accumulation of heat shock proteins (hsp) 70 in nucleoplasm of myocardial cells from adapted animals. Possible mechanism of the DNA protective effect of adaptation and the role of hsp 70 are under discussion.     

Effect of adaptation to short-term stress exposure on the fibrillation threshold and ectopic activity of the heart in experimental myocardial infarct

Preliminary adaptation to short-term stress was shown to prevent the decrease in the heart fibrillation threshold and an increase in ectopic activity which is usually observed in experimental myocardial infarction. This protective effect involves an enhanced activity of the antioxidant system. Therefore, a synthetic antioxidant ionol was applied to prevent disturbances of the heart electrical stability in infarction. It was established that ionol completely prevents the decrease in the electrical threshold and the increase in ectopic activity of the heart in experimental infarction. Thus, it can be concluded that ionol possesses an antiarrhythmic effect.     

Prevention of stress-induced disorders of myocardial contractile function by using sparing adaptation to short-term stress effects

Adaptation to repeated short-term stress is known to prevent to a considerable extent the depression of the myocardial contractile function which usually develops under long-term stress. But the adaptation itself has a "cost", i. e. it results in limited but significant disturbances of myocardial contractile function. The present review documents the method of adaptation involving few actions with prolonged intervals between them. It has been established that such an adaptation per se does not induce any disturbances of contractile function. At the same time it prevents completely the depression of contractile function caused by stress.     

Effect of past stress on the resistance of the myocardium to hypoxia

The effect of emotional painful stress on myocardial contractility and resistance to hypoxia was studied on the rat isolated atrium. It was established that in stress-exposed rats, myocardial resistance to hypoxia was reduced and contractility was depressed. It was manifested in accelerated development and greater degree of hypoxic contracture, as well as in a slower recovery of myocardial contractility under reoxygenation. The decreased myocardial resistance to hypoxia under stress is suggested to be related to the stress-induced alterations in glycolysis and calcium transport in cardiomyocytes.     

Resistance of Penicillium piceum F-648 to hydrogen peroxide under short term and prolonged oxidative stress

Resistance of Penicillium piceum F-648 to hydrogen peroxide under short-term and prolonged oxidative stress was studied. An increase in the activity of intracellular catalase in fungal cells after short-term exposure to hydrogen peroxide was shown. Activation of fungal cells induced by H2O2 depends on H2O2 concentration, time of exposure, and the growth phase of the fungus. Variants of P. piceum F-648 that produced two forms of extracellular catalase with different catalytic properties were obtained due to prolonged adaptation to H2O2. Catalase with low affinity for substrate was produced predominantly by the parent culture and variant 3; however, a high substrate affinity of catalase was observed in variant 5. Variant 5 of P. peniceum F-648 displayed a high catalytic activity and operational stability of catalase in the presence of phosphate ions and the concentration of substrate less than 30 mM at pH more than 7.     

Inhibition of natural killer activity in emotional stress and elimination of this phenomenon by interferon inducer

The authors provide the data on the effect of emotional painful stress (EPS) of varying duration on the activity of natural killers (NK) of August rats' spleen 1 to 9 days after exposure to stress is discontinued. The activity of NK was tested against target cells K 562 labeled with 51Cr in a 14-hour test. The effect of stress was found to depend on the duration of the stressor reaction. 1 1/2- and 3-hour stress activated NK, while prolonged 6-hour stress suppressed the activity of natural killers within the first 2 days, followed by the recovery by day 7-9 of the activity of lymphocytes having natural cytotoxicity. Tiloron, a synthetic inducer of endogenous interferon, corrected the post-stressor depression of NK activity.     

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

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. the gradually developing long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure,
2. 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. 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 myocadial loss of K⁺ and accumulation of 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 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.     

Increase of calcium-dependent activity of phospholipase C in the myocardium in adaptation of animals to short-term stress effects]

The effect of adaptation of rats to repeated short-term stress exposures was studied on the density and the affinity of alpha 1-adrenoceptors in the heart and on the phospholipase C activity and sensitivity to changes in Ca2+ concentration. It was found that adaptation to stress was accompanied by a desensitization of alpha 1-adrenoceptors and also by an increase in Ca(2+)-dependence of phospholipase C activity in the heart. The role of increased activity of phospholipase C and activated inositol triphosphate-diacylglycerol regulatory cascade is discussed as regard to the previously revealed accumulation of heat shock proteins in the myocardium and to the adaptive protection of the heart.     

Prevention of disorders of the electric stability of the heart in experimental infarct using adaptation to hypoxia

It has been shown on rats preadapted to hypoxia in an altitude chamber that myocardial infarction induced by ligation of the coronary artery was accompanied by less disturbances in the electrical stability of the heart, namely by a twofold decrease in ventricular fibrillation threshold and a considerable decrease in the heart ectopic activity. Preliminary adaptation provided the maintenance of myocardial contractility in infarction.     

Cardiodynamic response to psychological and cold pressor stress: further evidence for stimulus response specificity and directional fractionation

In the present study 36 police officers were exposed to a psychological stressor (IQ quiz) and to cold pressor stress while several cardiovascular variables were monitored. Impedance cardiography was used to provide measures of heart rate, stroke volume, cardiac output, myocardial contractility, and total peripheral resistance. In addition, measures of systolic and diastolic blood pressure and peripheral skin temperature were obtained. A multivariate analysis of variance (MANOVA) indicated that significant increases in diastolic and systolic blood pressure during the cold pressor test were mediated by large increases in total peripheral resistance, whereas blood pressure elevation during the IQ quiz were accompanied by significant increases in heart rate and, to a lesser extent, cardiac output. Peripheral skin temperature decreased in response to each stressor. Additional analysis indicated a degree of stimulus specificity for several variables. For example, diastolic blood pressure showed greater increases to cold pressor than quiz, whereas systolic blood pressure increased more with the psychological than the physical stressor. Directional fractionation occurred for both myocardial contractility and cardiac output.     

Cardiodynamic response to psychological and cold pressor stress: Further evidence for stimulus response specificity and directional fractionation

In the present study 36 police officers were exposed to a psychological stressor (IQ quiz) and to cold pressor stress while several cardiovascular variables were monitored. Impedance cardiography was used to provide measures of heart rate, stroke volume, cardiac output, myocardial contractility, and total peripheral resistance. In addition, measures of systolic and diastolic blood pressure and peripheral skin temperature were obtained. A multivariate analysis of variance (MANOVA) indicated that significant increases in diastolic and systolic blood pressure during the cold pressor test were mediated by large increases in total peripheral resistance, whereas blood pressure elevation during the IQ quiz were accompanied by significant increases in heart rate and, to a lesser extent, cardiac output. Peripheral skin temperature decreased in response to each stressor. Additional analysis indicated a degree of stimulus specificity for several variables. For example, diastolic blood pressure showed greater increases to cold pressor than quiz, whereas systolic blood pressure increased more with the psychological than the physical stressor. Directional fractionation occurred for both myocardial contractility and cardiac output.